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Table of Contents
REVIEW ARTICLE: GUIDELINES
Year : 2021  |  Volume : 4  |  Issue : 2  |  Page : 279-314

Treatment of advanced non-small-cell lung cancer: First line, maintenance, and second line– Indian consensus statement update(Under the aegis of Lung Cancer Consortium Asia, Indian Cooperative Oncology Network, Indian Society of Medical and Pediatric Oncology, Molecular Oncology Society, and Association of Physicians of India)


1 Department of Medical Oncology, Tata Memorial Hospital, Homi Bhabha National Institute, New Delhi, India
2 Department of Medical Oncology, HOPE Oncology Care Clinic, New Delhi, India
3 Department of Medical Oncology, Clinical and Translational Oncology Research, Kokilaben Dhirubhai Ambani Hospital and Medical Research Institute, Ernakulam, India
4 Department of Medical Oncology, Silverline Hospital, Ernakulam, India
5 Department of Medical Oncology, Rajiv Gandhi Cancer Institute and Research Centre, Delhi, India
6 Department of Medical Oncology, Bangalore Institute of Oncology, Kerala, India
7 Department of Medical Oncology, Bombay Hospital and Medical Research Centre, Kerala, India
8 Department of Medical Oncology, Bhaktivedanta Hospital and Research Institute Adult Solid Medical Oncology, Kerala, India
9 Department of Medical Oncology, MVR Cancer Institute, Calicut, India
10 Department of Medical Oncology, Yashoda Cancer Institute, Secunderabad, Telangana, India
11 Department of Medical Oncology, St. Johns Medical College and Hospital, HCG Hospitals, Bengaluru, Karnataka, India
12 Department of Medical Oncology, Prince Aly Khan Hospital, Oncology Clinic, Mumbai, Maharashtra, India
13 Department of Medical Oncology, Max Institute of Cancer Care, Saket, India
14 Department of Medical Oncology, Shatabdi Super Speciality Hospital, Nashik, Maharashtra, India

Date of Submission24-Mar-2020
Date of Decision16-May-2021
Date of Acceptance10-Jun-2021
Date of Web Publication30-Jun-2021

Correspondence Address:
Kumar Prabhash
Department of Medical Oncology, Tata Memorial Hospital, Dr. Ernest Borges Road, Homi Bhabha National Institute, Parel, Mumbai, Maharashtra
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/crst.crst_61_21

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  Abstract 


The management of patients with advanced non-small-cell lung cancer (NSCLC) is becoming increasingly complex, with the identification of driver mutations/rearrangements and the development and availability of appropriate targeted therapies. In 2018, a group of medical oncologists with expertise in treating lung cancers used data from the published literature and experience to arrive at practical consensus recommendations for the treatment of advanced NSCLC for use by the community oncologists. These recommendations were subsequently published in 2019, with a plan to be updated annually. This article is an update to the 2019 consensus statement. For updating the consensus statement, a total of 25 clinically relevant questions on the management of patients with NSCLC on which consensus would be sought were drafted. The PubMed database was searched using the following terms combined with the Boolean operator “AND:” (lung cancer, phase 3, non-small cell lung cancer AND non-small-cell lung cancer [MeSH Terms]) AND (clinical trial, phase 3 [MeSH Terms]) AND (clinical trial, phase iii [MeSH Terms]). In addition, “carcinoma, non-smallcell lung/drug therapy” (MeSH Terms), “lung neoplasms/drug therapy” (MeSH), clinical trial, phase III (MeSH Terms) were used to refine the search. The survey results and literature were reviewed by the core members to draft the consensus statements. The expert consensus was that molecular testing is a crucial step to be considered for patients with NSCLC at baseline, and in those who progress on first-line chemotherapy and have not undergone any prior testing. For mutations/rearrangement-negative patients who progress on first-line immunotherapy, doublet or single-agent chemotherapy with docetaxel and/or gemcitabine and/or ramucirumab should be considered. Patients who progress on the newer anaplastic lymphoma kinase inhibitors should be considered for second-line therapy with lorlatinib or systemic chemotherapy. Maintenance therapy with pemetrexed is preferred for NSCLC with non-squamous histology and should be avoided in NSCLC with squamous histology.

Keywords: Consensus, driver mutations, management, nonsmall cell lung cancer, targeted therapy, NSCLC


How to cite this article:
Prabhash K, Vora A, Limaye S, Sahoo TP, Batra U, Patil S, Patil VM, Noronha V, Bhosale B, Raut NV, Warrier N, Vaswani B, Babu G, Gore A, Rohatgi N, Bondarde S. Treatment of advanced non-small-cell lung cancer: First line, maintenance, and second line– Indian consensus statement update(Under the aegis of Lung Cancer Consortium Asia, Indian Cooperative Oncology Network, Indian Society of Medical and Pediatric Oncology, Molecular Oncology Society, and Association of Physicians of India). Cancer Res Stat Treat 2021;4:279-314

How to cite this URL:
Prabhash K, Vora A, Limaye S, Sahoo TP, Batra U, Patil S, Patil VM, Noronha V, Bhosale B, Raut NV, Warrier N, Vaswani B, Babu G, Gore A, Rohatgi N, Bondarde S. Treatment of advanced non-small-cell lung cancer: First line, maintenance, and second line– Indian consensus statement update(Under the aegis of Lung Cancer Consortium Asia, Indian Cooperative Oncology Network, Indian Society of Medical and Pediatric Oncology, Molecular Oncology Society, and Association of Physicians of India). Cancer Res Stat Treat [serial online] 2021 [cited 2021 Sep 24];4:279-314. Available from: https://www.crstonline.com/text.asp?2021/4/2/279/320155




  Introduction Top


Non-small-cell lung cancers (NSCLCs) constitute about 85% of all lung cancers.[1] Over the last decade, lung cancer management has changed from the use of standard treatment for all to the use of a target-based approach following the detection of driver mutations/rearrangements.[2] With the emergence of target therapies, the treatment of advanced NSCLC has become more more customized. In 2016 and 2018, experts from the Indian Cooperative Oncology Network, Lung Cancer Consortium Asia, Indian Society of Medical and Pediatric Oncology, Molecular Oncology Society, and Association of Physicians of India met to discuss and arrive at consensus statements to provide practical recommendations for the community oncologists for the treatment of this complex disease. These recommendations were subsequently published in the Indian Journal of Cancer in 2017[3] and the South Asian Journal of Cancer in 2019.[4] The discussion was based on the review of published literature, subject expertise of the participating faculty, and practical experience in the management of patients with lung cancer. As this field is constantly evolving, these guidelines must be updated at frequent intervals. This article is an update to the 2019 consensus statement and reflects the changes in the evidence since the previous consensus.


  Methods Top


A total of 20 (core and contributing members) lung cancer experts from all over India participated in the development of the consensus statement. A total of 25 clinically relevant questions on the management of patients with NSCLC on which consensus would be sought were drafted by the first author. A search for the latest evidence and a review of the available literature on these clinically relevant questions were performed. Simultaneously, an electronic survey link to these questions was sent to all the participants to record their views. The PubMed database was searched using the following terms combined with the Boolean operator “AND:” (lung cancer, phase 3, non-small cell-lung cancer AND non-small-cell lung cancer [MeSH Terms]) AND (clinical trial, phase 3 [MeSH Terms]) AND (clinical trial, phase iii [MeSH Terms]). In addition, “carcinoma, non-small-cell lung/drug therapy” [MeSH Terms], “Lung Neoplasms/drug therapy” [MeSH], clinical trial, phase III [MeSH Terms] were used to refine the search. The articles after “2001” were searched and included in the manuscript. The flow diagram for summary of search process and selection of included studies is depicted in [Figure 1]. Following this, an in-person meeting was held with 20 core members on December 21, 2019, where the survey results and review of literature were presented to the panel, based on which the consensus statements were drafted and agreed upon by the core members. The final draft of the consensus was e-mailed to the core members for the final review.
Figure 1: Flow diagram for summary of search process and selection of included studies. *2 drugs namely necitumumab and nintedanib. #Vandetanib

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  Initial Diagnosis Top


What are the initial diagnostic recommendations for patients with advanced metastatic non-small-cell lung cancers? Should programmed death-ligand 1 testing be considered as a part of the initial diagnostic workup for patients diagnosed with lung cancer?

Literature review

An accurate diagnosis of advanced lung cancer is crucial to provide the patients with the best possible treatment. Patients with alterations in the epidermal growth factor receptor (EGFR) gene and the B-raf proto-oncogene (BRAF) and those harboring anaplastic lymphoma kinase (ALK) and ROS proto-oncogene 1 receptor (ROS1) tyrosine kinase rearrangements have been shown to benefit from targeted therapies in the first-line setting as well as in the subsequent lines [Table 1].[4] In patients with no known driver mutations, immunotherapy with checkpoint inhibitors has revolutionized the treatment.[4] The scope of molecular testing has expanded to include other targetable genetic alterations, such as the mesenchymal-epithelial transition factor (MET) exon 14 skipping mutation, MET amplification, and mutations in the RET, human epidermal growth factor receptor 2 (HER2), and neurotropic receptor tyrosine kinase (NTRK) genes.[5] In India, the incidence of EGFR mutations ranges from 24.8% to 48% and is more frequent in patients with adenocarcinomas.[6],[7],[8] In women and non-smokers, the prevalence of EGFR mutations is reported to be as high as 50%.[8] Of the various mutations occurring in the EGFR kinase domain, the most common are exon 19 deletions (51.4%) and the L858R mutation in exon 21 (42.9%); these are sensitive to tyrosine kinase inhibitors (TKIs).[9] Other uncommon mutations that may be clinically relevant are exon 20 insertions, which are typically intrinsically resistant to EGFR-TKIs, and exon 18 alterations.[10] Mutations in the BRAF gene and ALK rearrangements have been reported to occur in 2%–2.4%[7],[8],[9],[10],[11] and 4%–10%[12],[13] of the patients with advanced NSCLC, respectively. The clinical benefit provided by targeted therapies makes it essential to identify all the patients with molecularly driven lung cancers. Further, ROS1 gene rearrangements have been reported in 0.3%–4%,[14],[15] and a high level of expression of the programmed death-ligand 1 (PD-L1) gene has been reported in 27% of the patients with resectable NSCLCs in India.[16]
Table 1: Essential biomarkers, predictive alterations, and testing methods in patients with advanced metastatic non-small-cell lung cancer

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Understanding of the tumor–immune interactions and development of immune checkpoint inhibitors (ICIs) have changed the therapeutic landscape of NSCLC. The excitement about using immunotherapy is primarily driven by the fact that antibodies against the programmed death receptor 1 (PD-1) and PD-L1 have prolonged antitumor responses in patients with metastatic NSCLCs who progress on the first-line chemotherapy regimen.[17],[18],[19],[20] In patients with advanced NSCLC, overexpression of PD-L1 is predictive of clinical benefit with PD-1/PD-L1 inhibitors.[21] In metastatic disease and in the first-line palliative setting, PD-L1 status has been shown to be predictive of the efficacy of monotherapy with pembrolizumab, an anti-PD-1 antibody, in the treatment of naïve patients with ≥50% tumor cell staining for PD-L1 as determined by the 22C3 pharmDx test.[22]

Methods for testing gene mutations

EGFR mutation testing can be performed by direct sequencing, real-time polymerase chain reaction (PCR), droplet digital PCR, or other commercial assays.[23],[24] When selecting a particular method, its turnaround time and sensitivity should be taken into consideration. ALK gene rearrangements can be detected using fluorescence in situ hybridization (FISH), reverse-transcriptase polymerase chain reaction (RT-PCR), immunohistochemistry (IHC), and next-generation sequencing (NGS). Several studies have reported that IHC can be used as an alternative to FISH for the detection of ALK rearrangements, as protein expression can serve as a surrogate marker for gene rearrangement.[25],[26],[27] ROS1 gene rearrangements are rare and mutually exclusive with EGFR mutations and ALK rearrangements.[28] ROS1 IHC may be used to screen for the presence of ROS1 mutations in patients with NSCLC.[29] However, positive results on IHC should be confirmed using a molecular (RT-PCR) or cytogenetic (FISH) method [Table 1].[30] PD-L1 expression determined by IHC is currently the only validated biomarker for anti-PD-1/PD-L1 therapy in patients with advanced NSCLC [Table 1].[21] It has been reported that PD-LI expression (evaluated by IHC) can augment the PD-L1 blockade efficacy. Further, according to the studies, PD-1 inhibitors have demonstrated higher response rates and better outcomes in comparison to other checkpoint inhibitors.[18],[31] The BRAF gene may also be included as part of a larger testing panel, which can be used either initially or when common driver mutations (EGFR, ALK, and ROS1) are not identified.[30]

Role of liquid biopsy in advanced metastatic non-small-cell lung cancer

Several molecular testing assays are being developed to improve the accuracy and speed of diagnosis. Biopsies are usually invasive and high-risk in nature, and the amount of tumor tissue obtained by biopsy can be inadequate for carrying out comprehensive molecular studies; in addition, in some cases, a biopsy cannot be performed because of the inaccessibility of the tumor. Therefore, liquid biopsy can be used as an alternative as it allows for the collection of biological samples using a minimally invasive approach.[32],[33] Liquid biopsy refers to a molecular assay involving circulating tumor cells, circulating tumor DNA (ctDNA), circulating exosomes, and circulating tumor RNA obtained from the blood, cerebrospinal fluid (CSF), and other bodily fluids. These circulating biomarkers have the potential to provide novel information about the tumor dynamics during treatment and disease progression.[33],[34] ctDNA has been widely used in clinical practice to test for genetic and epigenetic abnormalities specific to the tumor. In a study that assessed the EGFR mutation status in 803 plasma samples (using the Therascreen EGFR RGQ PCR kit-based real-time quantitative PCR assay), the concordance between the baseline tumor and plasma samples was 94.3%, and the sensitivity and specificity for mutation detection in the plasma samples were 65.7% and 99.8%, respectively. The high concordance, specificity, and sensitivity indicate that liquid biopsy using ctDNA can be used to accurately detect EGFR mutations.[35] Real-world data also suggest that ctDNA is suitable for an upfront EGFR mutation analysis when a tumor tissue sample is unavailable.[36],[37] Liquid biopsy may also be useful in the detection of ALK rearrangements. In one study on 77 patients with NSCLC, the fusion of the echinoderm microtubule-associated protein-like 4 (EML4) with ALK was identified by RT-PCR in the platelets and plasma obtained from whole blood in 38 patients. RT-PCR demonstrated 65% sensitivity and 100% specificity for the detection of EML4–ALK fusion in the platelets.[38] This suggests that liquid biopsy has the potential to detect driver mutations in NSCLC and can be explored for diagnostic purposes. However, the technique needs further validation, especially because of the high rate of false-negative results, and this remains a subject for future research.

Role of next-generation sequencing in advanced metastatic non-small-cell lung cancer

Compared to the single-gene sequencing approach, NGS is rapidly becoming a part of clinical genomic testing. One of the key features of NGS is its ability to detect a wide range of genetic alterations, such as point mutations or insertions/deletions, gene rearrangements, and copy number variations. Thus, it has the potential to streamline genetic testing by using a single platform for data analysis.[39],[40] However, the type of mutations and gene rearrangements identified may vary based on the design of the NGS panel and assay protocol.[41]

Screening for brain metastasis

Patients with EGFR- or ALK-positive NSCLC have a high risk of developing brain metastasis; this dramatically influences the patients' quality of life (QoL) and their prognosis.[42] About 20% of the patients with NSCLC have brain metastasis at diagnosis, and about 40%–50% develop brain metastasis during the disease.[43] The most common symptoms of brain metastasis are headache, intracranial pressure, focal neurological signs, epileptic seizures, and neurocognitive deficits. NSCLC guidelines advocate screening patients with stage III NSCLC for brain metastasis, preferably by magnetic resonance imaging (MRI).[44],[45] A recent study by Schoenmaekers et al. recommended that screening for brain metastasis is essential in the workup of patients with stage III NSCLC, and MRI is superior to contrast-enhanced computed tomography (CT) for screening.[46]

Consensus

  • Positron emission tomography (PET)/CT scan and brain MRI at baseline are recommended
  • The tumor should be confirmed pathologically using a tissue biopsy
  • The histologic subtype should be established with adequate tissue for molecular testing
  • Non-squamous histology should be tested for the presence of all actionable mutations:


    • Molecular testing for EGFR, ALK, ROS, and BRAF is essential.
    • Simultaneously, it is preferable to check for MET exon 14 skipping, MET amplification, and NTRK, HER2, and RET mutations
    • PD-L1 testing is also recommended.


  • For squamous histology:


    • EGFR and ALK testing should be considered for never-smokers and small biopsy samples
    • Testing for ROS, BRAF, and MET exon 14 skipping should be considered in small biopsy specimens or tumors with mixed histology
    • PD-L1 testing is also recommended for all patients.


    • Testing should be conducted as part of broad molecular profiling (broad-panel NGS), wherever feasible
    • Liquid biopsy at baseline for molecular testing is recommended only if the tissue is limited or not accessible.



  First-Line Therapy Top


Which patients with advanced-stage non-small-cell lung cancer should be treated with only systemic chemotherapy?

Literature review

Platinum-based doublet chemotherapy has been shown to improve survival over best supportive care (BSC) in patients with a good performance status (PS) without impairing the QoL.[47],[48],[49],[50],[51],[52],[53] Addition of a third cytotoxic agent improves the response rate (odds ratio [OR]: 0.66, 95% confidence interval [CI] 0.58–0.75; P < 0.001) and toxicity without an increase in the 1-year survival (OR: 1.01, 95% CI, 0.85–1.21; P = 0.88).[54] The most recent meta-analysis on NSCLC indicated no significant difference in the overall survival (OS) (hazard ratio [HR]: 1.08, 95% CI, 0.96–1.21) and 1-year OS (relative risk [RR]: 0.97, 95% CI, 0.89–1.07) between carboplatin- and cisplatin-based chemotherapy doublets, despite a potentially higher objective response rate (ORR) for cisplatin (RR: 0.88, 95% CI, 0.78–0.99). Differences in drug-related toxicities were observed between carboplatin- and cisplatin-based chemotherapy for thrombocytopenia, anemia, neurotoxicity, and the risk of nausea/vomiting.[55] The study concluded that the small relative ORR benefit of cisplatin and the different toxicity profiles of carboplatin- and cisplatin-based chemotherapies should be considered in addition to the patients' symptoms, preferences, and comorbidities when selecting appropriate first-line therapy for NSCLC.

A pooled analysis of six randomized studies has shown that platinum-based doublets improved the ORR (OR: 3.243, 95% CI, 1.883–5.583) and 1-year survival rate (OR: 1.743, 95% CI, 1.203–2.525), with increased hematological toxicities compared to single-agent regimens in patients with a PS of 2.[56] For older patients and those with a PS of 2, single-agent vinorelbine and gemcitabine have been shown to improve the OS without compromising the QoL.[57],[58] In a phase III study comparing docetaxel with vinorelbine in older patients (aged ≥70 years) with PS ≥2, docetaxel significantly improved the progression-free survival (PFS median 5.5 vs. 3.1 months; P < 0.001), response rates (22.7% vs. 9.9%; P = 0.019), and the overall disease-related symptoms (OR: 1.86, 95% CI, 1.09–3.20) when compared to vinorelbine. The difference in the OS was not statistically significant (median: 14.3 vs. 9.9 months, HR for death: 0.78, 95% CI: 0.56–1.09). These data suggest that docetaxel should be considered a standard treatment option in this patient population.[59] A French Intergroup study (IFCT-0501) compared the monthly carboplatin + weekly paclitaxel regimen with single-agent vinorelbine or gemcitabine in older patients (aged 70–89 years) with a PS of 0–2 and reported a survival advantage with the combination therapy (median OS: 10.3 vs. 6.2 months; HR: 0.64, 95% CI, 0.52–0.78; P < 0.0001).[60] Lower doses of paclitaxel administered weekly along with carboplatin resulted in similar efficacy and lesser neurotoxicity.[61] Cisplatin-containing regimens are associated with more nephrotoxicity, nausea, and vomiting, whereas carboplatin combinations cause more severe thrombocytopenia. A retrospective analysis conducted on 293 older patients (aged ≥70 years) with advanced NSCLC and PS 0–2 has shown that two-drug combinations are better than single-agent therapy. In this study, patients who received systemic therapy had a better OS than those who received BSC (10.3 months [95% CI, 95% 7.80–12.80] vs. 1.9 months [95% CI, 1.12–2.68; P < 0.0001]). A study evaluated the role of platinum in the first-line treatment of older patients (aged >70 years) with advanced NSCLC and PS 0–1 and tested its efficacy in two phase-III studies (MILES 3 and MILES 4). In the MILES-3 study, patients with any tumor histology were randomly assigned 1:1 to receive either cisplatin/gemcitabine (Cis 60 mg/m2 on day 1, Gem 1000 mg/m2 on days 1 and 8) or Gem (1200 mg/m2 on days 1 and 8). In the MILES-4 study, patients with non-squamous histology were randomly assigned 1:1:1:1 to receive cisplatin/gemcitabine (Cis 60 mg/m2 on day 1, Gem 1000 mg/m2 on days 1 and 8), Gem (1200 mg/m2 dd1,8), cisplatin/pemetrexed (Cis 60 mg/m2 on day 1, Pem 500 mg/m2 on day 1),

or PEM (500 mg/m2 on day 1). In the joint analysis of these two studies, at a median follow-up of 2 years, the PFS (median: 4.6 vs. 3.0 months; HR, 0.76, 95% CI, 0.63–0.92; P = 0.005) and ORR (15.5% vs. 8.5%; P = 0.02) were found to be significantly greater in the cisplatin arms, and even though the OS was numerically superior in the cisplatin arms, the difference was not statistically significant (9.6 vs. 7.5 months; HR, 0.86; 95% CI, 0.70–1.05; P = 0.14). Thus, the addition of cisplatin to single-agent chemotherapy did not significantly prolong the overall survival in older patients.[62]

In all the studies comparing erlotinib to chemotherapy in older patients with advanced EGFR-mutated NSCLCs, the results favored the TKIs in terms of the cost/quality-adjusted life-years (QALY).[63],[64],[65],[66] In a European analysis, the Markov model studied three different health states (PFS, disease progression [post-first line of treatment], and death). Among the patients treated with different therapies, erlotinib was found to be the dominant strategy yielding cost savings of €7,807 in Spain, €17,311 in Italy, and €19,364 in France and a gain of 0.117 QALY. Erlotinib had a 100% probability of being cost-effective given the patients' willingness to pay a threshold of €90,000/QALY.[63]

Consensus

  • About 42.9% of the experts believe that in today's era, no patient should receive only chemotherapy in the first line in advanced NSCLC as there are better and more effective (targeted) treatments available
  • However, chemotherapy can be used if the results of molecular testing for actionable targets are awaited (agree – 71.4%)
  • For patients with PS 0–1, 4–6 cycles of platinum-based doublet chemotherapy should be offered
  • Carboplatin-based regimens should be used in patients in whom cisplatin is likely to be poorly tolerated. Weekly schedule of paclitaxel plus carboplatin may be considered (agree – 100%)
  • For patients with PS ≥2 and older patients, single-agent chemotherapy (vinorelbine, gemcitabine, pemetrexed, or docetaxel) may be appropriate (agree – 100%)
  • Carboplatin-based combinations may be considered for ineligible patients aged >70 years with PS 0–2 and adequate organ function (agree – 100%).


What are the treatment recommendations for non-squamous advanced metastatic non-small-cell lung cancer with no known driver mutation/rearrangement?

Literature review

In previously untreated advanced NSCLC, pemetrexed + platinum chemotherapy in the first-line setting offers a significant survival advantage, especially in tumors with non-squamous histology.[67] Addition of bevacizumab to the carboplatin + paclitaxel regimen results in high response rates, longer PFS (HR, 0.72, 95% CI, 0.66–0.79; P < 0.001), and improved OS (HR, 0.90, 95% CI, 0.81–0.99; P = 0.03) compared to carboplatin + paclitaxel alone in patients with non-squamous histology and PS 0–1; however, this is accompanied by increased adverse events (AEs) associated with bevacizumab.[68]

Recently, several clinical studies evaluating the efficacy of PD-1/PD-L1 inhibitors in combination with standard chemotherapy regimens have been published.[69],[70] The phase III IMpower150 study demonstrated that the addition of atezolizumab to bevacizumab, carboplatin, and paclitaxel in the first-line setting in patients with non-squamous metastatic NSCLC resulted in a significant improvement in the OS (P = 0.02) and PFS (P < 0.001), regardless of the status of PD-L1 expression and EGFR and ALK genetic alterations.[69] The results of the IMpower130 study add to the evidence that atezolizumab + carboplatin + nab-paclitaxel in the frontline setting in patients with metastatic nonsquamous NSCLC offers superior OS (P = 0.033 (decimal should be on the line)) and PFS (P < 0.0001 (decimal should be on the line)) compared to chemotherapy, regardless of the ALK and EGFR mutation status.[70] The subsequent confirmatory phase III KEYNOTE-024 study demonstrated that patients with PD-L1 ≥50% who received pembrolizumab + chemotherapy as the first-line treatment had superior PFS and OS compared to those who received platinum-doublet chemotherapy alone (P = 0.005), regardless of the EGFR and ALK mutation status.[22] About 81.2% of the patients treated with pembrolizumab in this study had tumors with non-squamous histology. The HR for disease progression or death in this subgroup was 0.55 (95% CI, 0.39–0.76). Severe (grade 3–5) treatment-related AEs (TEAEs) in patients treated with pembrolizumab were lower than in those treated with platinum-doublet chemotherapy (27% vs. 53%).[22] An extended follow-up of 25.2 months suggested a significant survival benefit with pembrolizumab in patients with PD-L1 ≥50% [Table 2].[71] In a recent phase III (KEYNOTE-189) study, for the treatment of non-squamous metastatic NSCLC without EGFR or ALK mutations, the addition of pembrolizumab to chemotherapy (cisplatin/carboplatin and pemetrexed) led to significantly prolonged PFS and improved OS relative to chemotherapy alone (P < 0.001). Importantly, improved OS was seen in all patients with PD-L1 expression, regardless of the expression level.
Table 2: Progression-free survival and overall survival data from clinical studies evaluating immune checkpoint inhibitor in the first-line treatment of non-squamous and squamous metastatic non-small-cell lung cancer

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Moreover, patients with non-squamous NSCLC suitable for the standard first-line chemotherapy benefitted from the addition of pembrolizumab. The benefit was greatest in patients with PD-L1 expression level ≥50 on the tumor cells.[72] After an extended follow-up of 18.7 months, first-line pembrolizumab + pemetrexed/platinum continued to show a substantial OS benefit in metastatic non-squamous NSCLC. The PFS was also significantly improved compared with chemotherapy alone. The median OS and PFS2 (disease progression after second-line therapy) were approximately doubled in the combination arm when compared to the chemotherapy-alone arm, suggesting that patients who use first-line immunotherapy as early as possible benefitted more, regardless of the PD-L1 tumor proportion score (TPS).[73] Another phase III (CheckMate 227) study, compared nivolumab + ipilimumab, nivolumab monotherapy, and chemotherapy in the first-line setting in patients with non-squamous and squamous NSCLCs [Table 2].[74]

Consensus

  • For patients with PD-L1 expression ≥50% or PD-L1 expression 1%–49% and no contraindication to immunotherapy, immunotherapy alone or in combination with chemotherapy can be prescribed (agree – 85.7% and 64.3%, respectively)
  • For those with 0% PD-L1 expression, chemotherapy or chemotherapy plus immunotherapy can be offered (agree – 100% and 50%, respectively)
  • Below are the commonly used chemotherapy regimens with or without immunotherapy:


    • Pemetrexed and platinum agent should be considered as the first-line option for patients with tumors of non-squamous histology without driver mutations (agree – 100%)
    • Bevacizumab in combination with paclitaxel-carboplatin may be offered to patients with tumors of non-squamous histology and PS 0–1 after the exclusion of contraindications (agree – 68%).


What are the treatment recommendations in squamous advanced metastatic non-small-cell lung cancer with no known driver mutation/rearrangement?

Literature review

Extrapolating from the success of adding pembrolizumab to first-line chemotherapy in non-squamous histology, the KEYNOTE-407 study compared carboplatin + paclitaxel or nab-paclitaxel with (n = 278) or without pembrolizumab (n = 281) in patients with squamous histology and any level of PD-L1 expression.[75] Carboplatin + paclitaxel or nab-paclitaxel was administered for four cycles, and pembrolizumab was given every 3 weeks for up to 35 cycles. At a median follow-up of 7.8 months, the pembrolizumab combination group showed significantly longer OS and PFS (P < 0.001) than the chemotherapy-alone group [Table 2]. All efficacy end points were improved with the addition of pembrolizumab to chemotherapy across all PD-L1 subgroups: PD-L1 <1% (63.2% vs. 40.4%), PD-L1 1%–49% (49.5% vs. 41.3%), and PD-L1 ≥50% (60.3% vs. 32.9%). The addition of pembrolizumab led to no significant increase in the overall rate of AEs (grade ≥3 in 69.8% vs. 68.2%).[75]

IMpower131, an ongoing phase III study, compared carboplatin + nab-paclitaxel in combination with atezolizumab (n = 343) with carboplatin + nab-paclitaxel alone (n = 340) regardless of the PD-L1 status. Chemotherapy was administered for 4 or 6 cycles, and atezolizumab was given every 3 weeks until disease progression or death. At the prespecified interim analysis, the addition of atezolizumab to chemotherapy improved the ORR and prolonged the PFS (P = 0.0001). The rate of grade ≥3 TEAEs was 68% in the atezolizumab + chemotherapy arm versus 56.9% in the chemotherapy-alone arm [Table 2].[76]

Consensus

  • For patients with PD-L1 expression ≥50% or PD-L1 expression 1%–49% and no contraindication to immunotherapy, immunotherapy alone or in combination with chemotherapy can be prescribed
  • For those with 0% PD-L1 expression, chemotherapy or chemotherapy plus immunotherapy can be offered
  • Below are some of the commonly used chemotherapy regimens with or without immunotherapy:
  • 4–6 cycles of platinum-doublet chemotherapy should be the standard of care for patients with squamous cell carcinoma (agree – 100%, disagree – 0%, and not sure – 0%)
  • Platinum + pemetrexed should not be used in patients with squamous cell carcinoma (agree – 85.71%, disagree – 14.29%, and not sure – 0%)
  • Bevacizumab should not be used in patients with squamous cell carcinoma because of the risk of severe bleeding (agree – 95.45%, disagree – 4.55%).


What are the treatment recommendations in advanced metastatic non-small-cell lung cancer (both squamous and non-squamous) with programmed death 1 tumor proportion score > 50% and no driver mutations?

Literature review

Herbst et al. reported the efficacy of pembrolizumab versus chemotherapy in patients with advanced NSCLC with PD-L1 TPS ≥50% (KEYNOTE-024), regardless of the EGFR mutation and ALK rearrangement status and presence of untreated brain metastasis. Pembrolizumab was associated with a significant improvement in the PFS (P < 0.001) and OS (P = 0.005) when compared with chemotherapy [Table 3]. In addition, pembrolizumab was found to be associated with a higher ORR and less frequent grade 3–5 treatment-related toxicities compared to chemotherapy (27% vs. 53%, respectively). Patients receiving pembrolizumab also experienced improved QoL and delayed deterioration of symptoms.[22] The updated data with a median follow-up of 25.2 months revealed longer OS in the pembrolizumab group than in the chemotherapy group.[71] Based on this study, pembrolizumab was approved as a first-line treatment option for patients with advanced NSCLC and PD-L1 expression on ≥50% of the tumor cells.[78] To assess the potential survival benefit of pembrolizumab in patients with PD-L1 expression ≥50% and 1%–49% in the first-line setting for advanced NSCLC, the KEYNOTE-042 study enrolled patients with PD-L1 expression ≥1%. Pembrolizumab showed significantly improved OS over chemotherapy in all three PD-L1 TPS populations [Table 3].[77]
Table 3: Key results of clinical studies with pembrolizumab as monotherapy in advanced non-small-cell lung cancer and their clinical implications

Click here to view


Consensus

  • For patients with PD-L1 expression ≥50% and no contraindication to immunotherapy, immunotherapy alone is recommended (agree – 85.7%); however, a combination of immunotherapy and chemotherapy can also be considered (agree – 64.3%).
s

What are the treatment recommendations in non-squamous advanced metastatic non-small-cell lung cancer with identified driver mutation/rearrangement?

Literature review

Testing for driver mutations is essential in patients with non-squamous NSCLC; irrespective of the PD-L1 expression level, these patients must be treated with targeted therapy. While immunotherapy offers significant clinical benefit in NSCLCs as a whole, this effect appears attenuated in the setting of EGFR-activating mutations. Tumors with EGFR mutations, in general, do not respond well to PD-1 or PD-L1 checkpoint inhibitors. A pooled analysis of phase III studies that compared ICIs, such as nivolumab, pembrolizumab, and atezolizumab with docetaxel, showed no OS benefit in the EGFR-mutant subgroup (HR 1.05, 95% CI, 0.70–1.55; P < 0.81); however, the ICIs significantly prolonged the OS compared to docetaxel in the wild-type EGFR subgroup (HR, 0.66, 95% CI, 0.58–0.76; P < 0.0001).[79] In a single-center analysis, the ORR with ICIs was found to be as low as 3.8% in patients with EGFR or ALK alterations. This suggests that ICIs do not function in a similar manner in patients with and without driver oncogenic mutations.[80] Therefore, it is important for patients harboring driver mutations to receive the appropriate targeted therapy first to achieve the best results.

Consensus

  • Patients with identified driver mutations should receive the appropriate targeted therapy first to achieve the best results
  • While immunotherapy offers significant clinical benefits in NSCLC, this effect appears attenuated in the presence of driver mutations and is therefore not recommended in this setting.


What are the treatment recommendations for advanced metastatic non-small-cell lung cancer with activating mutations in the epidermal growth factor receptor gene (exon 19 deletions and L858R mutation)?

Literature review

Data from six randomized clinical trials that compared the first-generation EGFR-TKIs (erlotinib and gefitinib) with platinum-doublet in EGFR mutation-positive patients demonstrated that EGFR-TKIs significantly prolonged the PFS compared to chemotherapy. However, no difference in the OS was reported in the entire patient population or the subgroups harboring exon 19 deletions and L858R mutation. In two separate head-to-head clinical studies, the LUX-Lung 3 and LUX-Lung 6, the second-generation EGFR-TKI, afatinib, has shown significant prolongation of PFS compared to chemotherapy.

Osimertinib is an oral third-generation EGFR-TKI that selectively and irreversibly inhibits both EGFR-sensitizing and the EGFR T790M resistance mutations while sparing the wild-type EGFR tyrosine kinase with superior penetration into the central nervous system (CNS).[81] Four head-to-head studies, namely the WJOG 5108L, CTONG 0901, Lux Lung 7, and FLAURA, compared the efficacy of EGFR-TKIs.[82],[83],[84],[85] In the WJOG 5108L and CTONG 0901 studies, gefitinib demonstrated efficacy comparable to that of erlotinib. In the WJOG 5108L study, the median PFS for gefitinib and erlotinib was 6.5 and 7.5 months, respectively (HR, 1.125, 95% CI, 0.940–1.347; P = 0.257), OS was 22.8 and 24.5 months, respectively (HR, 1.038, 95% CI, 0.833–1.294; P = 0.768), and the response rates were 45.9% and 44.1%, respectively. In EGFR mutation-positive patients, the median PFS was 8.3 months for gefitinib and 10.0 months for erlotinib (HR, 1.093, 95% CI, 0.879–1.358; P = 0.424).[82] In the Lux Lung 7 study that compared afatinib with gefitinib, afatinib was found to be superior to gefitinib in terms of PFS (median: 11.0 vs. 10.9 months; HR, 0.73, 95% CI, 0.57–0.95; P = 0.017) and time to treatment failure (median: 13.7 vs. 11.5 months; HR, 0.73, 95% CI, 0.58–0.92; P = 0.0073).[84] There was a trend toward improved OS with afatinib when compared to gefitinib (median: 27.9 vs. 24.5 months; HR, 0.86, 95% CI, 0.66–1.12; P = 0.258), but this did not reach statistical significance.[86] Although the incidence of grade 3–4 AEs was higher in the afatinib arm, the rates of AEs leading to treatment discontinuation were similar in both arms. In the phase III FLAURA study, conducted in patients with NSCLC harboring EGFR exon 19 deletions and L858R mutation, osimertinib demonstrated a significant improvement in the PFS (primary end point) relative to the first-generation EGFR-TKIs (erlotinib and gefitinib) [Table 4].[85] The PFS benefit was consistent across all subgroups, including patients harboring exon 19 deletions and L858R mutation, regardless of brain metastases. In a recently published update, patients receiving osimertinib have been found to have a significant OS benefit at 38.6 months translating to an absolute benefit of almost 7 months compared to the comparator group [Table 4].[92] At the end of 3 years, 28% of the patients were still receiving osimertinib. Despite a 31% cross over in the comparator arm, the OS benefit in the osimertinib arm was maintained. CNS progression was also significantly lower in patients treated with osimertinib (6% vs. 15%).[85] Moreover, osimertinib was well tolerated with fewer grade ≥3 AEs than the comparator arm (42% vs. 47%).[92]
Table 4: Key results of clinical studies of epidermal growth factor receptor tyrosine kinase inhibitors

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Patients with EGFR-mutated NSCLC have a much higher risk of developing CNS metastases.[42] Osimertinib has demonstrated better penetration of the blood–brain barrier (BBB) compared to gefitinib and afatinib in preclinical studies[93] and promising intracranial efficacy in patients with advanced NSCLC.[87],[94],[95] A recent preplanned subgroup analysis of the FLAURA study reported a CNS ORR of 91% with osimertinib in patients with ≥1 measurable brain metastasis; this greatly exceeds the ORR of 68% obtained with other EGFR-TKIs, and the benefit was observed regardless of previous brain irradiation.[87] After a median follow-up of 12.4 months, the median CNS PFS was not attained in the osimertinib arm (95% CI, 16.5 months–not reached [NR]) versus 13.9 months (95% CI, 8.3 months–NR) of standard EGFR-TKIs. However, a nominal significant difference was observed (HR, 0.48, 95% CI, 0.26–0.86, P = 0.014). In addition, of the five patients with suspected leptomeningeal metastases in the osimertinib group, complete responses were documented in four (80%).[87] ARCHER 1050, an open-label, phase III trial, compared the efficacy and safety of dacomitinib (a second-generation EGFR-TKI) with that of gefitinib as first-line therapy in patients with metastatic NSCLC harboring EGFR-activating mutations. A significantly longer OS was observed with dacomitinib compared to gefitinib (HR, 0.760; 95% CI, 0.582–0.993; two-sided P = 0.438); the median OS was 34.1 months (95% CI, 29.5–38.7 months) for dacomitinib and 26.8 months (95% CI, 23.7–32.1 months) for gefitinib [Table 4].[96] Results from the above studies suggest that osimertinib should be the new standard of care for patients with advanced metastatic NSCLC harboring EGFR-sensitizing mutation, as it not only provides the longest PFS but is also most effective against CNS metastasis and is quite tolerable.

To prevent or delay the emergence of acquired resistance to EGFR-TKIs and to prolong the OS, a combination of chemotherapy or antiangiogenic antibodies (such as bevacizumab or ramucirumab) with EGFR-TKIs may be used as an alternative treatment option. In the NEJ026 study, bevacizumab + erlotinib showed a longer median PFS than erlotinib alone [Table 4].[88] Recent data from the phase-III RELAY study have demonstrated superior PFS (P < 0.0001) and better duration of response (DoR) (median: 18.0 vs. 11.1 months) with erlotinib combined with the anti-vascular endothelial growth factor receptor 2 (VEGFR2) antibody, ramucirumab, compared to erlotinib alone. Patients with brain metastases were excluded from the study.[89] In another study, addition of pemetrexed and carboplatin chemotherapy to gefitinib significantly prolonged the PFS and OS (P < 0.001). Clinically relevant toxicities of grade ≥3 were higher in the carboplatin + gefitinib arm than in the gefitinib arm (51% vs. 25%, P < 0.001).[90] Further, the NEJ009 Japanese study, which evaluated the combination of gefitinib with and without carboplatin and pemetrexed chemotherapy as the first-line treatment for patients with EGFR-mutated NSCLC, demonstrated longer PFS and OS in the combination arm than in the gefitinib alone arm [Table 4]. However, the rate of TEAEs of grade ≥3 was higher in the combination arm than in the gefitinib arm (65.3% vs. 31.0%).[91] Thus, the benefit of the combination of TKIs with chemotherapy or bevacizumab should be weighed against the increased risk of grade 3 AEs.

Consensus

  • Patients with EGFR mutations should be treated with an EGFR-TKI (osimertinib, afatinib, dacomitinib, gefitinib, or erlotinib) in the first-line setting (agree – 92.9%). Osimertinib is the preferred option in the first line for EGFR-mutated advanced NSCLC due to the efficacy, safety, and CNS efficacy
  • Combination of EGFR-TKIs with chemotherapy or antiangiogenic agents could also be considered as an option in selected patients.


What are the treatment recommendations in patients with uncommon epidermal growth factor receptor mutations in the first-line setting?

Literature review

Exon 19 deletions and exon 21 L858R substitutions are the most common EGFR mutations reported in patients with NSCLC. Retrospective data suggest that rare mutations, except for Gly719Xaa (G719X) and Leu861Gln (L861Q) point mutations, have decreased responsiveness to erlotinib and gefitinib.[97],[98],[99],[100] In an analysis from the NEJ002 trial, gefitinib was found to be ineffective against both G719X and L861Q mutations.[101] However, in a post hoc analysis from the LUX-Lung 2, LUX-Lung 3, and LUX-Lung 6 studies, afatinib demonstrated high efficacy in patients with G719X, L861Q, and S768I mutations with a median PFS of 13.8 months (6.8–not estimable [NE]), 8.2 months (4.5–16.6), and 14.7 months (2.6–NE), respectively.[102] The objective response to EGFR-TKIs in patients with exon 20 insertions is poor.[102],[103],[104],[105] In another study by Tanaka et al. on patients harboring uncommon EGFR mutations (except exon 19 deletions and exon 21 L858R substitution), afatinib showed superior efficacy over the first-generation EGFR-TKIs with an ORR of 75% vs. 40% and PFS of 17.1 vs. 5.5 months (P = 0.0481).[106] Furthermore, patients with high-variant allele frequencies for the T790M mutation also do not respond to EGFR-TKIs. In the post hoc analysis from LUX-Lung 2, LUX-Lung 3, and LUX-Lung 6 studies, afatinib was found to be ineffective in patients harboring a T790M mutation.[102]

Osimertinib was also found to be effective in treating patients with uncommon EGFR mutations in an open-label, multicenter, phase-II, single-arm study that included 35 patients. A total of 77.8% of the patients harboring an L861Q mutation achieved a partial response with osimertinib, followed by 52.6% of the patients with a G719A/C/D/S/X mutation and 37.5% of the patients with an S768I mutation. At data cutoff (April 2018), the overall median PFS was 8.2 months (95% CI, 1.9–14.4) and the median DoR was 9.8 months (95% CI, 7.6–12.0). Osimertinib also showed substantial activity in patients with NSCLC harboring uncommon EGFR mutations with CNS activity.[107] In a multicenter, open-label, single-arm, phase II trial (KCSG-LU15-09) on patients with advanced NSCLC harboring EGFR mutations treated with osimertinib, the median PFS was 8.2 months (95% CI, 5.9–10.5 months) and the median OS was not reached.[108] In a case report, a patient with NSCLC harboring an H773L/V774M mutation in the exon 20 of the EGFR gene demonstrated sustained disease control with osimertinib, suggesting that patients with this mutation may clinically benefit from treatment with this TKI.[109]

Consensus

  • In addition to exon 19 deletions and L858R mutation, testing for uncommon mutations in the EGFR gene, such as de novo T790M mutation, other point mutations, duplications in exons 18–21, and exon 20 insertions, should be performed
  • For patients with specific point mutations such as G719X, S768I, and L861Q, afatinib may be preferred. Emerging data also support the role of osimertinib in patients harboring these uncommon mutations and it could therefore be considered in such patients
  • Chemotherapy along with, or followed by EGFR-TKIs are other reasonable options for patients with uncommon mutations
  • For patients with de novo T790M mutations, osimertinib may be the preferred treatment
  • For patients with exon 20 insertions, chemotherapy may be considered.


Should epidermal growth factor receptor-tyrosine kinase inhibitors be continued beyond disease progression in the first line?

Literature review

Some patients have rapid disease progression when an EGFR-TKI is discontinued after a prolonged course of treatment. Therefore, in certain situations, it may be reasonable to continue the use of an EGFR-TKI in the presence of disease progression as defined by Response Evaluation Criteria in Solid Tumors (RECIST) criteria. In a phase II study (ASPIRATION) investigating the continuation of erlotinib after disease progression on first-line erlotinib, an additional 3 months of PFS was observed. Of 208 patients enrolled, 176 had a PFS1 event, of which 93 continued erlotinib following progression. The median PFS1 and PFS2 for the 93 patients who continued erlotinib were 11.0 (95% CI, 9.2–11.1) and 14.1 (95% CI, 12.2–15.9) months, respectively.[110] The phase III study, IMPRESS, compared first-line gefitinib + chemotherapy (gefitinib + cisplatin/pemetrexed) with chemotherapy alone in patients with EGFR mutation-positive NSCLC who had progressed on first-line gefitinib. However, continuation of gefitinib + doublet chemotherapy at progression did not show any PFS or OS benefit when compared with continuation of chemotherapy alone.[63] In the LUX-Lung 7 study, afatinib and gefitinib were continued beyond RECIST-defined progression and the time to failure was significantly prolonged in the afatinib arm compared to the gefitinib arm (median: 13.7 vs. 11.5 months; HR, 0.73, 95% CI, 0.58–0.92; P = 0.0073).[84] Treatment of oligoprogressive disease and beyond-progression strategies are also applicable in EGFR-mutated NSCLC after the use of third-generation TKIs. In the FLAURA study, time to first subsequent treatment was 25.5 months in the osimertinib arm and 13.7 months in the comparator arm (HR = 0.478, P < 0.001). The PFS with osimertinib was significantly longer than that with standard EGFR-TKIs (18.9 vs. 10.2 months; 95% CI, 0.37–0.57; P < 0.001).[85] A multicenter study evaluated the post-progression (pp) outcomes of patients with NSCLC harboring the T790M mutation who were treated with osimertinib after a first/second-generation EGFR-TKI. Of the 144 patients evaluated, 50 (54.9%) received osimertinib following disease progression, of which 19 (20.9%) received adjunctive local ablative treatments (LATs) and 41 (45.1%) received switched therapy. The median ppPFS and ppOS in patients who received osimertinib were significantly longer than the median ppPFS and ppOS of those who received switched therapies (PFS: 6.4 vs. 4.7 months, HR, 0.57, 95% CI, 0.35–0.92; P = 0.0239 and OS: 11.3 vs. 7.8 months, HR, 0.57, 95% CI, 0.33–0.98; P = 0.0446). Improved ppPFS and ppOS were reported among patients who received osimertinib with or without LATs (median ppPFS: 6.4 and 5.7 months; HR, 0.90, 95% CI, 0.68–1.18, P = 0.4560, ppOS: 20.2 and 9.9 months, HR, 0.73, 95% CI, 0.52–1.03; P = 0.0748). Thus, maintaining osimertinib beyond progression with adjunctive LATs is an effective therapeutic option.[111] In a retrospective cohort study, patients who received osimertinib as a second-line treatment (following previous treatment failure with EGFR-TKI erlotinib) and those who continued the treatment even after disease progression demonstrated a prolonged survival beyond the initial progression event. A total of 76 patients progressed, with 47 continuing with osimertinib treatment. These patients exhibited a median PFS2 of 12.6 months. Continuation of osimertinib beyond progression was also associated with a longer OS compared to that for discontinuation (11.2 vs. 6.1 months; P = 0.02).[112]

Consensus

  • Continuation of single-agent EGFR-TKIs beyond progressive disease may be beneficial in some patients (e.g., in patients with an isolated site of progression which can be treated with local therapy and those with mild and asymptomatic progression) (agree – 95.24%, disagree – 4.76%, and not sure – 0%)
  • The addition of TKI to chemotherapy after progression on first-line TKI is otherwise not recommended. The TKI should be discontinued, and the patients should be offered chemotherapy (agree – 85%, disagree – 19%, and not sure – 5%).


What are the treatment recommendations for patients with advanced metastatic non-small-cell lung cancer with anaplastic lymphoma kinase rearrangements in the first line?

Literature review

Comparison of upfront crizotinib with chemotherapy in treatment-naïve ALK-positive NSCLC in the PROFILE 1014 study demonstrated superior PFS in the crizotinib arm than in the chemotherapy arm (median: 10.9 vs. 7.0 months; HR, 0.45; 95% CI, 0.35–0.60; P < 0.001). The ORRs were 74% and 45% in the crizotinib and chemotherapy arms, respectively (P < 0.001).[113] The final OS analysis of this study reported that better OS was achieved with crizotinib after adjustment for crossover (HR, 0.346, 95% bootstrap CI 0.081–0.718).[114] Recently, Nishio et al. reviewed two phase III clinical studies, PROFILE 1007 (NCT00932893) and PROFILE 1014 (NCT01154140). They reported that in Asian patients, the PFS nearly doubled (median; 13.6 vs. 7.0 months; P < 0.001) with the use of crizotinib as a first-line therapy compared to chemotherapy; the ORRs were 70% and 54% for crizotinib and chemotherapy, respectively. The study also demonstrated that crizotinib showed faster onset and longer duration of action, with fewer side effects.[115] Results of another phase III study (PROFILE 1029) reported significantly improved PFS and ORR with first-line crizotinib than chemotherapy in East Asian patients with ALK-positive advanced NSCLC (median PFS: 11.1 vs. 6.8 months, HR, 0.402, 95% CI, 0.286–0.565; P < 0.001 and ORR 87.5% vs. 45.6%; P < 0.001).[116] A phase III trial on 347 patients with ALK-positive NSCLC who had disease progression following treatment with platinum-based chemotherapy showed a dramatic improvement in the PFS of patients treated with crizotinib when compared to chemotherapy (pemetrexed or docetaxel) (7.7 vs. 3.0 months; HR, 0.49, 95% CI, 0.37–0.64; P < 0.001).[117] The treatment strategy of continuing crizotinib beyond disease progression has been supported by some retrospective studies as well, in which continued ALK inhibition with crizotinib was found to be associated with clinical benefits and prolonged OS.[118],[119] A recently published physicians' survey and retrospective chart review study from the United States of America demonstrated that the majority of physicians (75%) would add local therapy and resume crizotinib when a new isolated symptomatic lesion was observed in patients with ALK-positive NSCLC treated with crizotinib.[120]

Second-generation ALK inhibitors have shown promising efficacy in advanced ALK-positive NSCLCs. In a global phase III head-to-head study (ALEX), 303 patients with ALK-rearranged NSCLCs were randomly assigned to receive either alectinib or crizotinib in the first-line setting. The results of this study demonstrated that, at a median follow-up of 18 months, the median PFS was significantly longer with alectinib than with crizotinib (NR vs. 11.1 months), corresponding to a reduction in the relative risk of disease progression or death by 53% (P < 0.001). Furthermore, the ORR in the alectinib arm was higher than that in the crizotinib arm (82.9% vs. 75.5%). Unlike crizotinib, alectinib penetrates the CNS due to its lipophilic properties. Therefore, CNS progression was significantly lower among those who received alectinib when compared to the crizotinib-treated patients (12% vs. 45%; HR, 0.16, 95% CI, 0.10–0.28). Grade 3–5 toxicities were less frequent with alectinib than with crizotinib (41% vs. 50%).[121] An updated analysis of this study showed that after an additional 10 months of follow-up, treatment with alectinib continued to provide an improved PFS (median: 34.8 vs. 10.9 months; HR, 0.43, 95% CI, 0.32–0.58). In addition, in patients with baseline CNS metastases, alectinib was found to be associated with a significantly prolonged PFS (median: 27.7 vs. 7.4 months; HR, 0.35, 95% CI, 0.22–0.56).[122] The study by Gadgeel et al. also demonstrated that the superior PFS with alectinib remained consistent between patients with (HR 0.40, 95% CI, 0.25–0.64) and without (HR, 0.51, 95% CI, 0.33–0.80) CNS metastases, regardless of prior radiotherapy. Compared to crizotinib, treatment with alectinib also demonstrated superior CNS activity and significantly delayed CNS progression.[123] Finally, the recent phase III ALESIA study on 187 patients with ALK-positive NSCLC showed that the investigator-assessed PFS for patients receiving alectinib was significantly longer than that for those receiving crizotinib (median PFS, NR vs. 11.1 months; HR, 0.22, 95% CI, 0.13–0.38; P < 0.0001).[124]

Another second-generation ALK-TKI, brigatinib, showed superiority over crizotinib in the phase-III ALTA-1 L study (estimated 12-month PFS: 67% vs. 43%; HR, 0.49, 95% CI, 0.33–0.74; P < 0.001).[125] Ceritinib is another second-generation ALK-TKI. In treatment-naïve patients with advanced ALK-positive NSCLC, the ASCEND-4 study compared first-line ceritinib with chemotherapy.[126],[127] This study allowed patients with untreated as well as symptomatic brain metastasis to be accrued. Ceritinib achieved a significant and clinically meaningful improvement in the PFS and RR, and a similar trend was observed in the subset of patients with brain metastasis. Recently, lorlatinib, a highly potent and brain-penetrating third-generation ALK-TKI has shown promising antitumor activity in a phase II clinical study. Out of 30 patients with treatment-naïve ALK-positive NSCLC, 27 (90%) had an objective response to lorlatinib. Of the three patients with measurable baseline CNS lesions, intracranial response was observed in two.[128] These results led to the ongoing phase III study comparing the efficacy and safety of lorlatinib with that of crizotinib in the first-line setting in patients with advanced ALK-positive NSCLC.[129]

The CROWN trial (a global, randomized, phase III trial) was conducted in 296 patients with advanced ALK-positive NSCLC. The patients were randomized to receive either lorlatinib (n = 149) or crizotinib (n = 147). The patients who received lorlatinib had a longer PFS at 12 months (80% [95% CI, 73–86] vs. 35% [95% CI, 27–43]), better QoL (mean score: 64.6 ± 1.82 vs. 59.8 ± 1.90), a higher overall intracranial response (66% [95% CI, 49–80] vs. 20% [95% CI, 9–36]) in comparison to those who received crizotinib. However, a higher incidence of Grade 3 or 4 AEs (72% vs. 56%) was observed in patients receiving lorlatinib compared to the crizotinib-administered patients.[130]

Consensus

  • Patients with ALK rearrangements should be treated with first- or second-generation ALK inhibitors (crizotinib, alectinib, and ceritinib) upfront. Newer-generation ALK-TKIs with better PFS are preferred (agree – 64.3%).
  • In case chemotherapy is started before the results of ALK testing are available, chemotherapy may be continued for 4–6 cycles in responding patients. Switching to ALK inhibitors before completion of 4–6 cycles is a valid option
  • In carefully selected patients (e.g. in patients with an isolated site of progression which can be treated with local therapy, those with mild and asymptomatic progression), crizotinib may be continued beyond progression.


What are the treatment recommendations for patients with advanced metastatic non-small-cell lung cancer harboring ROS proto-oncogene 1 receptor rearrangements in the first line?

Literature review

ROS1 inhibition by crizotinib has been extensively studied in patients with advanced ROS1-positive NSCLC. In an open-label study on 50 patients with ROS1 rearrangement, treatment with crizotinib elicited an ORR of 72% (3 complete and 33 partial responses; 95% CI, 58%–83%) and a median PFS of 19.2 months.[131] In an updated follow-up of more than 5 years among 53 patients with ROS1-positive NSCLC, a median PFS of 19.3 months (95% CI, 15.2–39.1) and OS of 51.4 months (95% CI, 29.3–NR) were observed.[132] Similar response rate was observed in a phase-II trial of crizotinib in 127 East-Asian patients with ROS1-positive NSCLC, with a median PFS of 15.9 months (95% CI, 12.9–24.0 months). A real-world study from China on 35 patients with ROS1-positive advanced NSCLC reported an improved median PFS (11 months; 95% CI, 7.8–14.2) and OS (41.0 months; 95% CI, 22.5–59.5) following treatment with crizotinib. The ORR was 71.4%.[133] Furthermore, the ORR with crizotinib was 80% and the median PFS was 9.1 months in heavily pretreated patients in a retrospective study.[134] Across all clinical studies on patients with ROS1-positive NSCLC, crizotinib treatment has been shown to be well tolerated.[132],[133],[134] Noronha et al. reported that crizotinib resulted in durable disease control and prolonged PFS in five patients with ROS1-rearranged NSCLC in India.[135] These findings suggest that targeting ROS1 is an effective treatment strategy in patients with ROS1-rearranged NSCLC. The second-generation ROS1 inhibitor, ceritinib, was evaluated in a Korean phase II study on 28 patients with advanced ROS1-rearranged NSCLC.[65] Among crizotinib-naive patients, the ORR was 67%, with a disease control rate of 87%. The median PFS was 9.3 months in the overall study population and 19.3 months in crizotinib-naïve patients. The median OS was 24 months. Five of eight patients with brain metastases experienced disease control; the intracranial ORR was 25%, with a disease control rate of 63%.[136]

Consensus

  • Patients with ROS1 rearrangements should be treated with crizotinib or newer ROS1-targeting agents in the upfront setting
  • In case chemotherapy is started before the results of ROS1 testing are available, chemotherapy may be continued for 4–6 cycles in responding patients. Switching to crizotinib or newer ROS1-TKI before completion of 4–6 cycles of chemotherapy is also a valid option
  • Lorlatinib is recommended as next-line treatment for patients who progress on first-line crizotinib
  • Chemotherapy remains an acceptable option for patients with ROS1 mutations who progress on first-line ROS1-targeting agents



  Diagnostic Options After Disease Progression on First-Line Treatment Top


What investigations (not treatment) are recommended at the time of disease progression on first-line tyrosine kinase inhibitors?

Literature review

Almost all patients with EGFR-mutated NSCLC who are treated with first- or second-generation EGFR-TKIs subsequently develop disease progression at a median interval of approximately 12 months.[137] In a study on 90 consecutive Indian patients with EGFR-mutation-positive NSCLC treated with first- or second-generation EGFR-TKIs, 52% developed a T790M mutation at progression.[138] Amplification of the MET oncogene has been associated with resistance to third-generation EGFR-TKIs in 5%–10% of the cases.[137] In addition, analyses of the tumor tissues have revealed the histological transformation of EGFR mutation-positive NSCLCs after first-line treatment into small cell lung cancers in approximately 5% of the cases.[139] In some patients, resistance may be mediated by HER2 mutation/amplification.[137] For patients with NSCLC (squamous and non-squamous) who have progressed on first-line chemotherapy and have not undergone any prior mutation testing, molecular testing should be considered. Based on the findings of different clinical trials (AURA II and AURA III), the Food and Drug Administration in the United States of America has approved osimertinib for patients with T790M-positive advanced NSCLC who have acquired resistance to first- or second-generation EGFR-TKIs.[140] Several studies have demonstrated the utility of the minimally invasive plasma ctDNA-based liquid biopsy for the detection of EGFR T790M mutation.[141],[142] Re-biopsy plays an important role in determining the potential mechanisms of resistance against EGFR-TKIs in patients with NSCLC. However, a re-biopsy may not always be feasible for the patients and physicians due to the inaccessibility of the tumor, deterioration of the patient's PS, or patient refusal. In such cases, liquid biopsy can be used as an alternative to tissue biopsy for the detection of the EGFR T790M mutation in the plasma to select patients suitable for receiving osimertinib.[140],[143] In fact, as per the guidelines of the National Comprehensive Cancer Network (NCCN), plasma-based testing for the T790M mutation should be considered at disease progression on EGFR-TKIs. In case the sensitivity of the testing method used for the detection of the T790M mutation from a liquid biopsy sample is low or if a patient tests negative for this mutation on liquid biopsy, re-biopsy and tissue-based testing is strongly recommended according to the NCCN guidelines. Practitioners may consider scheduling the biopsy concurrently with plasma testing. Tissue biopsy should be considered at the time of progression to rule out transformation to small cell lung cancer.[144]

Consensus

  • For patients with NSCLC (squamous/non-squamous) who have progressed after first-line chemotherapy and have not undergone any prior mutation testing, molecular testing should be considered
  • In patients with NSCLC, a re-biopsy is recommended at progression for determining the potential mechanisms of resistance to first-line EGFR-TKIs. If tissue re-biopsy is not feasible, liquid biopsy can be used as an alternative method
  • In case the liquid biopsy-based test is less sensitive at detecting the T790M mutation or if a patient tests negative for this mutation by liquid biopsy, a tissue-based testing with re-biopsied material is strongly recommended
  • Plasma testing and tissue biopsy should be scheduled concurrently.



  Maintenance Therapy Top


Which patients should be offered maintenance therapy?

Literature review

Maintenance therapy is the continued treatment of a tumor that has not progressed after initial induction chemotherapy and can be categorized as either switch maintenance or continuation maintenance.[145] In a large phase III study, switch maintenance therapy with pemetrexed after four cycles of non-pemetrexed containing platinum-based doublet (cisplatin or carboplatin plus gemcitabine, docetaxel, or paclitaxel) chemotherapy increased both the median PFS and OS compared to placebo. The benefit of pemetrexed was limited to patients with tumors of non-squamous histology [Table 5].[146] Having demonstrated an OS benefit in the second- and third-line settings for advanced NSCLC,[155] erlotinib was evaluated as a switch maintenance therapy in the SATURN study [Table 5]. The study reported a significantly longer median PFS with erlotinib when compared with placebo, including in the subgroup with EGFR-activating mutations.[147] However, the subsequent IUNO study comparing maintenance versus delayed erlotinib in patients without EGFR-activating mutations showed no OS or PFS benefit for maintenance erlotinib. This indicates that the likely benefit of maintenance erlotinib is limited to patients with EGFR-activating mutations.[156] In the PARAMOUNT study, continuous maintenance with pemetrexed in patients with non-squamous NSCLC demonstrated significant improvement in the PFS and OS compared to the placebo arm [Table 5].[148],[149] Maintenance with pemetrexed and bevacizumab was thereafter tested in three major phase III studies.[150],[151],[152] In the AVAPERL study, there was a 3.7-month improvement in the PFS in the pemetrexed + bevacizumab arm compared to the bevacizumab-alone arm, but the difference in the OS was not statistically significant [Table 5].[150],[151] In the updated analysis at a median follow-up of 14.8 months, patients randomized to the bevacizumab + pemetrexed arm had significantly improved PFS compared to those randomized to the bevacizumab-alone arm (7.4 vs. 3.7 months, HR, 0.57, 95% CI, 0.44–0.75; P < 0.0001). OS events occurred in 58% of all patients. The OS with bevacizumab + pemetrexed was numerically longer than that with bevacizumab (17.1 vs. 13.2 months, HR, 0.87 95% CI, 0.63–1.21; P = 0.29).[151] The PointBreak study assessed whether pemetrexed + carboplatin + bevacizumab followed by pemetrexed + bevacizumab (PemCBev) was superior to paclitaxel + carboplatin + bevacizumab followed by bevacizumab (PemCBev) in patients with advanced non-squamous NSCLC. Even though this study did not show a significant improvement in the OS and there was only a slight improvement in the PFS with the pemetrexed-containing regimen, it reported different toxicity profiles of the paclitaxel- and pemetrexed-containing regimens that may help in better treatment selection. Fatigue and thrombocytopenia were more frequent with the pemetrexed combination, while neutropenia, neuropathy, and alopecia occurred more frequently with the paclitaxel combination.[150] Improved PFS was reported with pemetrexed + bevacizumab maintenance therapy in patients with advanced NSCLC [Table 5].[153],[154]
Table 5: Summary of key maintenance studies

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Taken together, maintenance therapy, using either the switch or continuation approach, has been proven beneficial in patients with advanced NSCLC who have received up to four cycles of platinum-containing chemotherapy.

Consensus

  • Patients with NSCLC without driver mutations who have not received immunotherapy and have any response or stable disease after 4–6 cycles of first-line chemotherapy are appropriate candidates for maintenance chemotherapy using either the switch or continuation approach
  • Maintenance therapy with pemetrexed is preferred for tumors with non-squamous histology
  • Maintenance should be continued until progression or unacceptable AEs
  • For patients whose initial regimen included bevacizumab, this may be continued as maintenance treatment in the absence of unacceptable toxicity or disease progression
  • EGFR-TKIs should not be offered as maintenance therapy in patients with wild-type EGFR
  • Pemetrexed or bevacizumab maintenance should not be used for patients with squamous histology tumors.



  Second-Line Therapy Top


What is the treatment recommendation for patients with advanced metastatic non-small-cell lung cancer of squamous/non-squamous histology without driver mutations/rearrangements after progression on first-line chemotherapy?

Literature review

In a phase III study, 104 previously treated patients were randomized to receive either 100 mg/m2 or 75 mg/m2 of docetaxel every 3 weeks or BSC. Docetaxel at a dose of 75 mg/m2 was found to be superior to BSC in improving median OS (7.5 vs. 4.6 months; log-rank test, P = 0.010), pain control, and QoL.[157],[158] In a secondary analysis of head-to-head studies comparing pemetrexed with docetaxel, the OS was found to be significantly longer in patients with tumors of non-squamous histology who received pemetrexed (median OS: 9.3 vs. 8.0 months; HR, 0.78, 95% CI, 0.61–1.00; P = 0.047), with fewer Grade 3–4 AEs.[155],[159],[160]

Two phase III studies, comparing the oral triple TKI, nintedanib, which is an angiokinase inhibitor, and the anti-VEGFR2 monoclonal antibody, ramucirumab, both in combination with docetaxel versus docetaxel alone have demonstrated a significant survival advantage in favor of the combination arms in patients who progressed on platinum-based chemotherapy.[161],[162] Nivolumab, an anti-PD-1 antibody, was the first ICI approved for the second-line treatment of NSCLC.[163] In the CheckMate 057 study, compared to docetaxel, nivolumab significantly prolonged the OS in patients with NSCLC of non-squamous histology who progressed on first-line chemotherapy.[17] The median OS was 12.2 months (95% CI, 9.7–15.0) in the nivolumab arm and 9.4 months (95% CI, 8.1–10.7) in the docetaxel arm (HR, 0.73, 96% CI 0.59–0.89; P = 0.002). At 12 and 18 months, the OS rates were 51% (95% CI, 45–56) and 39% (95% CI, 34–45), respectively, with nivolumab and 39% (95% CI, 33–45) and 23% (95% CI, 19–28), respectively, with docetaxel.[17] However, patients with aggressive disease and low PD-L1 expression could be at risk of early death. Grade 3/4 TEAEs were reported in 10% and 54% of the patients in the nivolumab and docetaxel groups, respectively.[17] Another phase III study (CheckMate 017) comparing nivolumab with docetaxel was decisive in recommending immunotherapy for patients with previously treated advanced squamous NSCLC. These studies support the effectiveness of nivolumab in the second-line setting.[17],[31],[164]

In the KEYNOTE-001 and KEYNOTE-010 studies, another ICI, pembrolizumab, has shown promising efficacy in patients with advanced NSCLC who progressed on first-line chemotherapy and had PD-L1 expression ≥1%.[18],[19] In the KEYNOTE-010 study, the OS was significantly prolonged with pembrolizumab when compared to docetaxel.[18] In a recent update of this study, the 36-month OS rate was 26.4% (95% CI, 14.3–40.1) for untreated patients and 19.0% (95% CI, 15.0–23.4) for previously treated patients.[165] Atezolizumab is a humanized immunoglobulin G1 monoclonal antibody against PD-L1. The POPLAR study was designed to compare atezolizumab with docetaxel. It was observed that the median OS was 12.6 and 9.7 months (HR 0.73 95% CI, 0.53-0.99; P = 0.04) for atezolizumab and docetaxel, respectively.[166] The 3-year OS rate was 18.7% and 10% for atezolizumab and docetaxel, respectively.[167] In addition, OAK was a phase III study that enrolled 1225 pretreated patients with NSCLC who were randomized to receive either atezolizumab or docetaxel. The OS was prolonged in patients receiving atezolizumab, regardless of the PD-L1 expression. The median OS was 13.8 months in the atezolizumab arm and 9.6 months in the docetaxel arm (HR, 0.73, 95% CI, 0.62–0.87; P = 0.0003).[20] The 12- and 18-month OS rates were 55% and 40%, respectively, in the atezolizumab arm and 41% and 27%, respectively, in the docetaxel arm. In about 16% of the enrolled patients, at least 50% of the tumor cells or 10% of the tumor area stained positive for PD-L1. The median OS with atezolizumab versus docetaxel in this subgroup of patients was 20.5 months versus 8.9 months (HR, 0.41, 95% CI, 0.27–0.64). The OS was prolonged in the atezolizumab arm regardless of the NSCLC histology. The median OS in patients with non-squamous NSCLC was 15.6 months with atezolizumab and 11.2 months with docetaxel (HR, 0.73, 95% CI, 0.60–0.89; P = 0.0015).[20] The INTEREST[168] and TITAN[169] studies further demonstrated that EGFR-TKIs are not inferior to standard second-line chemotherapy (docetaxel or pemetrexed) for unselected patients with NSCLC. Despite these results, single-agent chemotherapy is the preferred treatment for patients with wild-type EGFR who progress on platinum-based doublet chemotherapy, especially in those who have derived clinical benefits from first-line chemotherapy. This was confirmed in TAILOR, a randomized controlled study that compared erlotinib with docetaxel in patients with NSCLC with wild-type EGFR who had progressed on first-line chemotherapy. The median PFS and OS were significantly better with docetaxel compared to erlotinib. In a subgroup analysis, the patients who failed to respond to the first-line platinum-based chemotherapy, and received docetaxel as second-line treatment, revealed significantly better (prolonged) PFS and OS compared to those patients receiving erlotinib.[170] Similar findings were demonstrated in the DELTA study, where erlotinib was found to be significantly inferior to docetaxel in terms of PFS (1.3 vs. 2.9 months; HR, 1.45, 95% CI, 1.09–1.94; P = 0.01) and ORR (5.6% vs. 20.0%, P < 0.01) in patients with EGFR wild-type NSCLC.[171] Moreover, a meta-analysis including data of 1605 patients with EGFR wild-type NSCLC from 11 studies demonstrated that chemotherapy was superior in terms of PFS (HR, 1.84, 95% CI, 1.35–2.52) and ORR (16.8 vs. 7.2%; RR, 1.11, 95% CI, 1.02–1.21) compared to EGFR-TKIs.[172]

Consensus

  • Patients with good PS should be offered second-line therapy (agree – 100%).
  • ICIs should be considered in the second-line setting, and the choice of immunotherapy should be based on PD-L1 expression levels
  • PD-L1 testing should be done using an approved diagnostic kit (agree – 100%).
  • For patients who are PD-L1 negative or whose PD-L1 status is not known, nivolumab or atezolizumab may be considered. For those with PD-L1 expression > 50%, either nivolumab, pembrolizumab, or atezolizumab may be considered (agree – 100%).
  • For those with rapid progression (<9 months from the start of first-line therapy) and those with progressive disease as the best response to first-line therapy, docetaxel + nintedanib/ramucirumab are acceptable options (agree – 100%)
  • For those who cannot afford the above treatments, single-agent docetaxel or pemetrexed (if not used in the first line) are preferred options (agree – 100%).


What are the treatment recommendations for patients with non-small-cell lung cancer of squamous histology having performance status of 2 without driver mutations/rearrangements after progression on first-line IO-based therapy?

Literature review

In patients with squamous cell carcinoma without driver mutations/rearrangements who were previously treated with systemic therapy and have a PS of 2, after progression on first-line IO-based therapy, docetaxel or gemcitabine or ramucirumab + docetaxel can be administered.[144] Docetaxel alone, or ramucirumab + docetaxel, or gemcitabine alone, or platinum-based chemotherapy can also be recommended.

Consensus

  • For patients with driver mutation/rearrangement-negative NSCLC who progress on first-line immunotherapy, chemotherapy with docetaxel or gemcitabine or combination of ramucirumab + docetaxel should be considered.


What are the treatment recommendations for patients with advanced metastatic non-small-cell lung cancer harboring epidermal growth factor receptor mutations after progression on first-line therapy?

Literature review

Clinical studies evaluating first-generation EGFR-TKIs in patients with EGFR mutation-positive NSCLC have shown that the OS remains the same regardless of whether EGFR-TKIs are given upfront or after progression on chemotherapy.[56],[57],[58],[60],[61],[67],[68],[173] Therefore, patients who are offered doublet chemotherapy in the first-line setting must be treated with an EGFR-TKI once there is disease progression on first-line chemotherapy. However, many patients with EGFR mutation-positive NSCLC eventually acquire resistance to EGFR-TKIs, which is most commonly mediated via the T790M mutation. To target these resistance mechanisms, third-generation EGFR-TKIs have been developed. Osimertinib is a third-generation, irreversible, oral EGFR-TKI that potently and selectively inhibits both EGFR-sensitizing mutations and EGFR T790M resistance mutation and has demonstrated efficacy in CNS metastases in patients with NSCLCs.[85],[89],[91],[174] In the AURA study, osimertinib demonstrated remarkable activity in patients with EGFR T790M mutations acquired because of prior treatment with EGFR-TKIs. Patients with EGFR T790M mutation had an ORR of 61%, whereas those without this mutation had an ORR of 21% (95% CI, 12–34). The median PFS for EGFR T790M-positive and -negative patients was 9.6 months (95% CI, 8.3–NR) and 2.8 months (955 CI, 2.1–ß4.3), respectively.[175] AURA3, a randomized phase III study that enrolled patients with EGFR T790M-positive NSCLC, showed longer PFS with osimertinib than with standard chemotherapy (pemetrexed + platinum) (10.1 vs. 4.4 months; HR, 0.3, 95% CI, 0.23–0.41; P < 0.001), with an absolute benefit of 5.7 months. Even in patients with CNS metastases, the PFS was longer in the osimertinib group than in the chemotherapy group (8.5 vs. 4.2 months; HR, 0.32, 95% CI, 0.21–0.49). In addition, osimertinib was associated with a lower rate of AEs of Grade ≥ 3 compared to standard chemotherapy (23% vs. 47%).[95] In the recently reported data from the AURA3 study on 419 patients randomized to receive either osimertinib (n = 279) or platinum-pemetrexed (n = 140), the median OS of the osimertinib group was found to be superior to that of the platinum-pemetrexed group (26.8 vs. 22.5 months; HR, 0.87, 95% CI, 0.67–1.12; P = 0.277). About 71% of the patients in the chemotherapy arm crossed over to osimertinib as a third-line treatment, while the remaining continued to receive chemotherapy. The median OS was significantly longer among patients who crossed over to osimertinib compared to those receiving platinum + pemetrexed (26.8 vs. 15.9 months; HR, 0.54, 95% CI, 0.18–1.60; P = 0.277).[176] Furthermore, a prospective observational study reported the incidence of the T790M mutation in patients who progressed on first-line EGFR-TKI. At progression, of the 90 patients, 47 (52.2%) had a T790M mutation, and almost all the patients with this mutation (n = 46) received osimertinib. At a median follow-up of 15 months, 19 (41.3%) patients had disease progression, including death in 13 (32.5%) patients. The ORR was 65.2% and median PFS was 12.4 months (standard deviation [SD] 1.03, 95% CI, 10.41–14.48).[138] According to the NCCN (2020) guidelines, for patients with advanced NCSLC harboring the EGFR T790M resistance mutation and progressing on osimertinib, continuing osimertinib has been recommended along with definitive local therapy.[144]

Consensus

  • Patients who progress on first-line EGFR-TKIs must be tested for the T790M mutation using either re-biopsy, cell block, or liquid biopsy (agree – 57.89%, disagree – 21.05%)
  • In patients with documented T790M mutation after treatment with first/second-generation TKIs, a third-generation EGFR-TKI such as osimertinib is recommended. In case of non-availability of osimertinib, chemotherapy is an acceptable option
  • Patients with EGFR-mutant NSCLC who are treated with combination chemotherapy in the first line should be offered EGFR-TKIs (osimertinib [preferred], afatinib, erlotinib, and gefitinib) in the second line if they are not already treated with EGFR-TKIs in the maintenance setting
  • Combination chemotherapy should be the preferred second-line treatment option in patients who are treated with EGFR-TKIs in the first line and whose T790M status is negative or unknown
  • Patients whose tumors transform to small cell lung cancer should be treated with appropriate chemotherapy
  • In patients who progress on third-generation TKIs, chemotherapy is an acceptable treatment option, although treatment directed toward actionable mutations should be considered pp, if testing done


What are the treatment recommendations for patients with non-small-cell lung cancer with anaplastic lymphoma kinase translocations after progression on first-line anaplastic lymphoma kinase inhibitor?

Literature review

While ALK inhibitors are highly active in patients with ALK-positive NSCLC, almost all patients inevitably develop resistance to these inhibitors.[177] Second- and third-generation ALK inhibitors (ceritinib, alectinib, and brigatinib) have been designed to overcome this resistance by increasing the potency and selectivity of the drugs for ALK fusion proteins.[178] In the global, phase III study, ASCEND-5, ceritinib significantly improved the PFS and ORR compared to chemotherapy in patients with ALK-rearranged NSCLC, who had previously progressed on crizotinib and platinum-based chemotherapy. Although no improvement in the OS was noted for those assigned to receive ceritinib, the OS data were immature.[127] In the phase-II study, ASCEND-9, ceritinib was used as a second-line treatment after disease progression on alectinib. The ORR, median PFS, and 1-year OS were found to be 25%, 3.7 months, and 75.6%, respectively.[179] In the phase III study, ASCEND-5, 29 Japanese patients had previously received crizotinib or platinum-based treatment. Of these, 11 patients subsequently received ceritinib and 18 received chemotherapy (pemetrexed or docetaxel). Compared to chemotherapy, ceritinib resulted in a better ORR (54.5% vs. 0%) and median PFS (9.8 vs. 1.6 months; HR, 0.17, 95% CI, 0.05–0.61) but no significant improvement in the OS (23.9 vs. 22.8 months, HR, 0.88, 95% CI, 0.27–2.82).[180] Two phase-II studies evaluated the efficacy and safety of alectinib in patients with ALK-positive NSCLC who had progressed on platinum-based chemotherapy or crizotinib.[181],[182] A pooled analysis of these two studies demonstrated an ORR of 51.3%, a disease control rate of 78.8%, and a median DoR of 14.9 months. The median PFS was 8.3 months (95% CI, 7.0–11.3) and median OS was 26.0 months (95% CI, 21.4–NE).[183] The phase III study, ALUR, compared alectinib with chemotherapy in patients with ALK-positive metastatic NSCLC whose disease had progressed after platinum-based chemotherapy and after crizotinib. The median PFS was significantly longer with alectinib than with chemotherapy, as assessed by both, the investigators (9.6 vs. 1.4 months; HR, 0.15, 95% CI, 0.08–0.29; P < 0.001) and an independent review committee (7.1 vs. 1.6 months; HR, 0.32, 95% CI, 0.17–0.59; P < 0.001). The CNS ORR (54.2% vs. 0%, P < 0.00) was also significantly higher with alectinib than with chemotherapy. No significant differences were reported in the OS between the two arms.[184]

Lorlatinib, a third-generation inhibitor of ALK and ROS1 tyrosine kinases, can easily cross the BBB. The efficacy of lorlatinib was confirmed in a global, phase II study on 276 patients with ALK- or ROS1-positive advanced NSCLC. Of the 30 patients who had not previously received treatment, 27 achieved an objective response; 2 out of 3 patients with brain metastases also showed an objective response. The ORR in 198 patients who had previously received at least one ALK inhibitor was 47.0%, and the ORR for 81 patients with brain metastases was 63.0%. In each subgroup, 59 patients who had previously received only crizotinib had an ORR of 69.5%, and in 111 of those who had received more than 2 ALK-TKIs, the ORR was 38.7%. The study demonstrated that lorlatinib has great potential for use as first- and second-line treatment in patients with brain metastases. Lorlatinib was found to be effective not only against ALK mutations but also against ROS1 mutations.[128] In a study on 12 Asian patients with ALK or ROS1 mutations who had progressed on ALK-TKIs, lorlatinib showed an ORR of 64% and a median PFS of 6.5 months. Of the three patients with intracranial metastases, one achieved a complete response, while the remaining two showed partial responses.[185] Brigatinib, a second-generation ALK inhibitor, also demonstrated superior efficacy over crizotinib in the ALTA-1L phase III study in patients with advanced ALK-positive NSCLC who had not previously received an ALK inhibitor.[125] The patients treated with brigatinib demonstrated higher median 12-month PFS (67% vs. 43%; HR, 0.49, 95% CI, 0.33–0.74; P < 0.001), higher ORR (71% vs. 60%), and a higher intracranial response rate (78% vs. 29%) than those treated with crizotinib; however, the OS data were immature.[125] A study also reported that brigatinib was effective not only against ALK-mutant NSCLCs but also against EGFR-mutant NSCLCs, especially those with the C797S and T790M mutations produced by EGFR-TKIs.[186] Thus, in addition to being used after disease progression on crizotinib, brigatinib has the potential to be used as a fourth-generation EGFR-TKI. In the AP26113 (ALTA) study involving 222 patients with crizotinib-refractory ALK-positive NSCLC, brigatinib at a dose of 180 mg once daily (with a 7-day lead-in period at 90 mg in 110 patients) was associated with high systemic and CNS response rates and a median PFS of 16.7 months.[187] Overall, these data suggest that brigatinib has significant penetration into the CNS, regardless of prior treatment with crizotinib. In addition, a study by Gainor et al. reported the resistance pattern in ALK-positive NSCLC patients, wherein minority of patients (approximately 20%) developed ALK resistance mutations on receiving crizotinib, and the mutations were also observed in around 50% of the patients progressing on second-generation ALK inhibitors.[188]

Consensus

  • Patients who progress on newer ALK inhibitors (alectinib, ceritinib) should be considered for second-line therapy with lorlatinib or systemic chemotherapy
  • Patients with ALK-positive NSCLC who progress on crizotinib should be considered for second-line therapy with newer ALK inhibitors (alectinib, ceritinib, and lorlatinib)


What are the treatment recommendations for patients with non-small-cell lung cancer with brain metastases?

Literature review

Brain metastases are common in patients with lung cancer. The treatment of brain metastases is crucial for symptom control and improving the survival. Whole-brain radiotherapy (WBRT) along with steroids has been the cornerstone of this treatment.[189] In routine clinical practice, prognostic indices such as recursive partitioning analysis (RPA) and graded prognostic assessment (GPA) help to categorize the patients into cohorts based on expected survivals. Patients in RPA Class III have poorer survival than those in RPA Class I. Their indices are based on the Karnofsky performance status score, age, number of brain metastases, and presence of active extracranial disease.[189],[190] WBRT traditionally is believed to improve QoL, disease-free survival, and OS. Contrary to popular practice, WBRT with steroids did not demonstrate a survival benefit when compared to steroids alone.[191] Apart from this, a randomized phase III Alliance study compared stereotactic radiosurgery (SRS) alone with SRS + WBRT in patients with 1–3 brain metastases using a primary neurocognitive endpoint, defined as a decline from baseline in any 6 cognitive tests at 3 months. The decline was significantly more frequent after SRS + WBRT than after SRS alone (88% vs. 61.9%) (Class I), with more deterioration in immediate recall (30.4% vs. 8.2%), delayed recall (51.1% vs. 19.7%), and verbal fluency (18.6% vs. 1.9%).[192] A recent meta-analysis of two randomized controlled studies compared SRS alone with WBRT + SRS in patients with NSCLC with 1–4 brain metastases stratified by GPA (<2 vs. ≥2). SRS + WBRT did not show a survival benefit over SRS alone (GPA < 2: HR, 0.93, 95% CI, 0.61–1.40; P = 0.71), (GPA ≥2: HR, 1.28, 95% CI, 0.58–2.80; P = 0.54). SRS + WBRT improved the brain tumor recurrence free-time in both the subgroups (GPA <2: HR, 5.46, 95% CI, 2.09–14.22; P = 0.0005 and GPA ≥2: HR, 4.24, 95% CI, 2.24–8.04; P < 0.00001).[193] However, the applicability of the results of these studies is limited by the small sample size, and the inclusion of patients with very small volume disease, and less than or equal to four brain metastases. Nevertheless, WBRT remains a management option for patients with more than 4 brain metastases and/or location/size that render SRS or surgery difficult.[194]

A recent meta-analysis of 54 published studies evaluating the effectiveness of WBRT alone or in combination with radiosurgery in adults with newly diagnosed brain metastases reported improved OS, neurological function, and symptom control (as compared to standard care) with the use of a higher radiation dose of 30 Gy in 10 fractions when compared to the lower biologically effective doses. However, data showed worse neurocognitive outcomes and no difference in OS with the use of the combination of radiosurgery and WBRT.[195]

In patients with a solitary brain metastasis, surgery is recommended if feasible; if surgery is not feasible because the tumor is in the eloquent area, focal treatment alone or with WBRT is recommended.[196],[197] However, the addition of WBRT to focal treatment did not yield an OS benefit.[198] To decrease local recurrences at resection cavities, depending on the volume of the cavity and residual disease, high-dose focal radiotherapy has been shown to be effective.[199] Recently, a secondary analysis of the EORTC 22952 study that randomized patients to receive SRS or surgery with or without adjuvant WBRT reported that early control was better with SRS, although the relative benefit decreased with time.[200] Currently, there is no definitive evidence regarding the effectiveness and safety of surgery versus SRS in patients with a solitary brain metastasis, and the decision must be made on a case-by-case basis.[201] Patients with NSCLC harboring EGFR/ALK mutations have a higher incidence of brain metastases during the course of their disease.[42] In such patients, treatment with targeted therapy has been shown to improve the outcomes.[202],[203],[204],[205] A combined analysis of 81 patients with brain metastases from the LUX-Lung 3 and LUX-Lung 6 studies demonstrated a significantly improved PFS with afatinib compared to chemotherapy (8.2 vs. 5.4 months; HR, 0.50; P = 0.0297).[204] In the FLAURA study, the median PFS was significantly longer with osimertinib than with standard EGFR-TKIs (18.9 vs. 10.2 months; HR, 0.46, 95% CI, 0.37–0.57; P < 0.001). In this study, both systemic and intracranial efficacies were measured. Osimertinib showed greater efficacy than erlotinib and gefitinib in the CNS. Osimertinib is the only EGFR-TKI to show significant intracranial efficacy. In the FLAURA study, osimertinib was found to be efficacious in patients with and without CNS metastases, and fewer new CNS lesions were observed in the osimertinib group compared to the erlotinib and gefitinib groups.[85] In the phase III ALEX study, in patients with measurable CNS lesions at baseline, the CNS response rate was 81% in the alectinib arm and 50% in the crizotinib arm.[121] Crizotinib has been shown to control intracranial disease in patients with ALK-rearranged NSCLC. In a pooled analysis, the intracranial disease control rate was 56% among patients with untreated asymptomatic brain metastases as opposed to 62% among patients with previously treated brain metastases.[205] A retrospective analysis of 94 patients with ALK-rearranged NSCLC with brain metastases treated with ceritinib in the multicenter phase I ASCEND-1 study showed a median time to intracranial response of 6.1 weeks. The rate of intracranial disease control was 79% in ALK-inhibitor-naïve patients and 61% in those pretreated with ALK inhibitors. There was no difference in the intracranial response in patients with and without prior radiotherapy.[206] Another second-generation ALK inhibitor, brigatinib, has shown promising intracranial disease activity in clinical studies.[125],[187] ALTA was a randomized phase II study in which patients with ALK-positive NSCLC with baseline brain metastases received varying doses of brigatinib. The intracranial response rate among patients with measurable brain metastases ranged between 46% and 67% (n = 59). The median intracranial PFS was 14.6–18.4 months. Another phase III study enrolled ALK-inhibitor-naïve patients with advanced ALK-positive NSCLC to receive brigatinib or crizotinib.[125] Among 39 patients with measurable brain lesions, the intracranial response rate was 78% (14/18) with brigatinib and 29% (6/21) with crizotinib.[125] Therefore, brigatinib has better intracranial activity than crizotinib and is efficacious in the treatment of ALK-positive NSCLC with brain metastases.

Consensus

  • Treatment of patients with brain metastases depends on their age and the PS
  • RPA Class I and II patients with more than three brain metastases may be treated with WBRT
  • SRS may be a reasonable option in carefully selected patients with limited disease
  • In RPA Class III patients, best supportive care is recommended
  • Patients with a solitary brain metastasis may be treated with either surgical resection or SRS/stereotactic radiotherapy
  • Single large symptomatic metastasis should be treated with surgery
  • SRS/stereotactic radiotherapy is a reasonable alternative to surgery for small (<3 cm) and inaccessible tumors
  • RPA Class I and II patients with 1–3 small brain metastases (<3 cm) should be treated with SRS or stereotactic radiotherapy alone rather than with SRS + WBRT
  • WBRT is a reasonable option in patients who are not eligible for surgery or whose lesions are too large for radiosurgery
  • Patients treated with surgical resection or stereotactic radiosurgery should undergo a follow-up magnetic resonance imaging every 3 months
  • Dexamethasone is recommended for patients with symptomatic brain metastases
  • For patients with symptomatic metastases, radiotherapy should be preferred
  • In patients with druggable oncogenic driver mutations and asymptomatic brain metastases, TKIs (osimertinib among EGFR-TKIs and alectinib or ceritinib among ALK inhibitors) may help control the brain disease and defer WBRT
  • Patients with EGFR mutation-positive NSCLC with brain metastases who progress on first- and second-generation EGFR-TKIs may benefit from osimertinib along with definitive local therapy
  • Patients with ALK-positive NSCLC with brain metastases who progress on crizotinib may benefit from alectinib or ceritinib along with definitive local therapy
  • Patients should undergo follow-up imaging by MRI/CT every 3 months.


What are the treatment recommendations for patients with advanced metastatic non-small-cell lung cancer with oligometastatic disease?

Literature review

Oligometastatic disease in NSCLC refers to the presence of one to five metastatic lesions away from the primary tumor site.[207] Patients with oligometastatic NSCLC do not always appear to have a widespread disseminated disease.[208] Appropriately selected patients can be treated with metastasis-directed surgical or ablative procedures. Identification of such patients is of utmost importance. Factors associated with improved OS in oligometastatic disease include metachronous metastases, better PS, limited nodal disease, presence of an EGFR mutation, and metastases limited to one organ.[209],[210],[211] Surgical resection or definitive radiotherapy of intracranial and extracranial oligometastatic disease has been shown to have a positive effect on survival rates.[212],[213],[214],[215],[216],[217],[218]

In patients who have more than one pulmonary site of cancer, it can sometimes be difficult to distinguish between a second primary tumor and metastasis. The International Association for the Study of Lung Cancer Staging and Prognostic Factors Committee (IASLC) performed a systematic review to develop clinical and pathological criteria to identify two foci as separate primary lung cancers versus a metastasis. The IASLC recommended a careful review by a multidisciplinary tumor board, and the pursuit of radical therapy, such as that for a synchronous second primary tumor, when possible.[219] SRS and surgery have been shown to result in long-term survival in such patients.[218],[220],[221] Use of targeted agents combined with ablative doses of radiation in the oligometastatic setting has resulted in promising outcomes.[217],[222] A meta-analysis of 21 studies on 924 patients with synchronous oligometastatic NSCLC selected specifically to investigate the outcomes of patients receiving radiotherapy to the primary tumor, with or without local consolidative treatment to metastatic disease, showed a median pooled OS of 20.4 months and PFS of 12 months.[223] Patients who received thoracic radiation to the primary tumor had significantly better OS (HR, 0.44, 95% CI, 0.32–0.6, P < 0.001) and PFS (HR, 0.42, 95% CI, 0.33–0.55, P < 0.001). In addition, analysis of the data from four studies on the comparison of radiotherapy to the primary tumor versus no treatment showed significantly improved OS and PFS in favor of radiotherapy to the primary tumor.[223]

Consensus

  • Patients with stage IV NSCLC with synchronous or metachronous oligometastasis may benefit from surgery and/or radiotherapy. Metachronous oligometastasis has a better prognosis than synchronous oligometastasis
  • Every attempt must be made to biopsy the second primary tumor in the lung, and it may be treated with radical intent, if possible.
  • For patients with oligometastatic recurrence or progression while receiving targeted therapy, stereotactic body radiation therapy to the progressing sites may be considered (agree – 42.86%, disagree – 57.14%, and not sure – 0%).



  Others Top


What is role of radiation in stage-IV non-small-cell lung cancer?

Literature review

For patients with metastatic NSCLC, radiation therapy is recommended for local palliation or prevention of symptoms, such as pain, bleeding, and obstruction. Definitive local therapy to isolated or limited metastatic sites (oligometastases) (including but not limited to the brain, lungs, and adrenal gland) can achieve prolonged survival in a small proportion of well-selected patients with good PS who have also received radical therapy to the intrathoracic disease.[209] Definitive radiation therapy to oligometastases (the term “limited number” has not been universally defined but clinical studies have included patients with up to three to five metastases), particularly stereotactic ablative radiotherapy (SABR), is an appropriate option if it can be delivered safely to the involved sites.[224],[225] In two randomized phase II studies, significantly improved PFS was observed for local consolidative therapy (radiotherapy or surgery) to oligometastatic lesions compared to maintenance systemic therapy or observation for patients not progressing on systemic therapy.[226],[227],[228] In the setting of progression at limited number of sites on a given line of systemic therapy (oligoprogression), local ablative therapy to the oligoprogressive sites may extend the duration of benefit of the current line of systemic therapy. When treating oligometastatic/oligoprogressive lesions, if SABR is not feasible, other dose-intensive–accelerated/hypofractionated conformal radiation therapy regimens may be used.

The dose and fractionation of palliative radiation therapy should be individualized based on the goals of care, symptoms, PS, and logistical considerations. Shorter courses of radiation therapy are preferred for patients with poor PS and/or shorter life expectancy because they provide pain relief to a similar extent as the longer courses, although there is a higher potential need for repeat treatment.[229],[230],[231] For palliation of thoracic symptoms, higher-dose/longer-course thoracic radiation therapy (e.g., ≥30 Gy in 10 fractions) has been shown to demonstrate modestly improved survival and symptoms, particularly in patients with good PS. When higher doses (>30 Gy) are warranted, technologies to reduce normal tissue radiation (such as three-dimensional conformal radiotherapy [3D-CRT] including intensity-modulated radiotherapy [IMRT] or proton therapy as appropriate) may be used. A meta-analysis which assessed the therapeutic effect of WBRT on brain metastases from NSCLC in patients stratified by GPA reported that SRS + WBRT did not show a survival benefit over SRS alone (GPA <2; HR, 0.93, 95% CI, 0.61–1.40; P = 0.71, and GPA ≥ 2; HR, 1.28, 95% CI, 0.58–2.80; P = 0.54). However, SRS + WBRT improved the brain tumor recurrence-free time in both the subgroups (GPA <2 and GPA ≥2), with similar grade 3/4 late radiation toxicities.[193] Lim et al. randomized 105 patients with NSCLC with 1–4 asymptomatic brain metastases and a PS of 0–1 to receive SRS followed by chemotherapy or upfront chemotherapy alone. SRS + chemotherapy did not improve the OS compared to upfront chemotherapy alone (14.6 vs. 15.3 months, P = 0.418). There was no significant difference between the groups in terms of time to symptomatic progression of brain metastases (26.5% vs. 18.4%) and overall CNS disease progression (9.4 vs. 6.6 months, P = 0.248).[232]

Consensus

  • For patients with metastatic NSCLC, radiation therapy is recommended for local palliation or prevention of symptoms, such as pain, bleeding, and obstruction
  • Definitive radiation therapy to oligometastases (up to 3–5 metastases), particularly SABR, is an appropriate option if it can be delivered safely to the involved sites
  • The dose and fractionation of palliative radiation therapy should be individualized based on the goals of care, symptoms, PS, and logistical considerations
  • Shorter courses of radiation therapy are preferred for patients with poor PS and/or shorter life expectancy because they provide pain relief to a similar extent as the longer courses, although there is a higher potential need for repeat treatment
  • For palliation of thoracic symptoms, higher-dose/longer-course thoracic radiation therapy is recommended, particularly in patients with good PS
  • When higher doses are warranted, technologies to reduce normal tissue radiation may be used (3D-CRT along with IMRT or proton therapy as appropriate).


What is role of surgery in stage-IV non--small-cell lung cancer?

Literature review

Surgical resection remains the treatment of choice in patients with stage I–IIIA NSCLCs.[233] Surgery has a limited role in advanced stage-IV NSCLCs. A retrospective review of data from April 1989 to December 2010 identified 46 patients with stage-IV NSCLC who underwent surgical resection for primary lung cancer in Japan. The results suggest that surgical treatment can extend the survival in patients with stage IV NSCLC if they can tolerate surgery.[234] Although this approach has been used only in few patients, it could be advantageous for patients with oligometastasis. In a narrative review of the literature on surgical intervention in the multimodality management of stage IV NSCLC, it was reported that surgical resection could confer excellent 5-year survival that is heavily influenced by the presence of mediastinal nodal disease.[235] Another prospective randomized study has shown that in stage IV NSCLC, patients with less than three metastatic lesions who received first-line systemic therapy, surgical treatment, or local radiotherapy had significantly longer PFS compared to those who received maintenance therapy (11.9 vs. 3.9 months, P = 0.005).[226] In one study, patients with stage IV NSCLC who underwent surgical procedures as a part of multimodality treatment had a significantly prolonged median OS (9.4–28 months), depending on the inclusion of chemotherapy and radiotherapy, compared to those who received non-surgical treatments (2–10 months). Despite this survival benefit, the inclusion of surgery in treatment regimens decreased from 2004 to 2012 in California, in the United States of America.[236] For patients with advanced NSCLC who do not respond to surgery, chemotherapy is the first-line treatment of choice as evidenced in different studies. In a phase II trial, chemotherapy-naive patients with Stage IIIB, IV or recurrent metastatic NSCLC were treated with S-1, cisplatin, and bevacizumab. S-1 plus cisplatin along with bevacizumab showed an improved PFS, OS, and ORR of 7.3 months (95% CI, 5.9–8.7), 21.4 months (95% CI, 14.7–NR), and 64%, respectively.[237] Chemotherapy with afatinib plus docetaxel was found to be safe and effective in patients with advanced non-squamous NSCLC with brain metastases, with a median PFS of 2.92 months (95% CI, 1.38–4.48) and a 6-month OS of 80%.[238] Another study demonstrated improved efficacy of carboplatin plus paclitaxel in the treatment of patients with advanced NSCLC over conventional chemotherapy with an ORR of 69.7% and median PFS of 6.3 months.[239]

Consensus

  • Surgery has a very limited role in the treatment of advanced stage IV NSCLC
  • Surgical treatment can be offered to patients with stage IV NSCLC if they can tolerate surgery and have oligometastasis at accessible sites and have received first-line systemic therapy


What is the ideal interval for follow-up/scans after initial response to treatment?

Literature review

When the patient is started on targeted therapy, initial response assessment can be done after 2 cycles and thereafter every 2–4 cycles with a CT imaging with or without contrast of the known sites; the patient can be followed up once every 6–12 weeks. The timing of CT imaging is determined by the practicing physician.[173] When the patient is on initial systemic therapy, response assessment can be done after 2 cycles and thereafter every 2–4 cycles with CT imaging with or without contrast of the known sites; the patient can be followed up once every 6–12 weeks. The timing of CT imaging is determined by the practicing physician.[173]

Consensus

  • When the patient is on initial therapy, response assessment can be done after 2 cycles and thereafter every 2–4 cycles with CT imaging with or without contrast of the known sites; the patient can be followed up once every 6–12 weeks.


What is the role of best supportive care in advanced metastatic non-small-cell lung cancer?

Literature review

Patients with a PS of 3–4 can be offered BSC in the absence of documented EGFR mutations or ALK rearrangements.[240] Among patients with NSCLC, BSC is known to improve the QoL and prolong survival. A randomized study of 151 patients with newly diagnosed metastatic NSCLC showed that early implementation of palliative care along with standard oncologic care improved the median survival of patients compared to standard oncologic care alone (11.6 vs. 8.9 months, P = 0.02).[241] Compared to the standard-care group, the intervention group had a better QoL (98.0 vs. 91.5; P = 0.03) and lower rates of depression (16% vs. 38%, P = 0.01).[241] Another study showed that in patients with newly diagnosed incurable lung cancer, timely palliative care referral in addition to the usual care can result in improved QoL and lower depression rates compared to usual care alone.[242]

Consensus

  • Patients with a PS of 3–4 can be offered BSC in the absence of driver mutations
  • Timely palliative care referral in patients with newly diagnosed incurable lung cancer can result in improved QoL and lower depression rates compared with usual care.


The guidelines are summarized in [Table 6].
Table 6: Summary of guidelines/recommendations

Click here to view



  Conclusion Top


Molecular testing is a crucial step to be considered for patients with NSCLC (squamous/non-squamous) who have progressed on first-line chemotherapy and have not undergone any prior mutation testing. For progression on first-line immunotherapy in driver mutation/rearrangement-negative NSCLC, single-agent chemotherapy with docetaxel or gemcitabine or combination of ramucirumab + docetaxel should be considered. Patients with progression on newer ALK inhibitors (alectinib, ceritinib) should be considered for second-line therapy with lorlatinib or systemic chemotherapy. Maintenance therapy with pemetrexed is preferred for non-squamous NSCLC and should not be used in tumors of squamous histology.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
  References Top

1.
Duma N, Santana-Davila R, Molina JR. Non-small cell lung cancer: Epidemiology, screening, diagnosis, and treatment. Mayo Clin Proc 2019;94:1623-40.  Back to cited text no. 1
    
2.
Yuan M, Huang LL, Chen JH, Wu J, Xu Q. The emerging treatment landscape of targeted therapy in non-small-cell lung cancer. Signal Transduct Target Ther 2019;4:61.  Back to cited text no. 2
    
3.
Under the Aegis of Lung Cancer Consortium Asia (LCCA), Indian Cooperative Oncology Network (ICON), Indian Society of Medical and Pediatric Oncology (ISMPO), Molecular Oncology Society (MOS) and Association of Physicians of India API). Indian consensus statement for treatment of advanced non small cell lung cancer: First line, maintenance, and second line. Indian J Cancer 2017;54:89-103.  Back to cited text no. 3
    
4.
Prabhash K. Treatment of advanced nonsmall cell lung cancer: First line, maintenance and second line-Indian consensus statement update. South Asian J Cancer 2019;8:1-17.  Back to cited text no. 4
[PUBMED]  [Full text]  
5.
Guo Y, Cao R, Zhang X, Huang L, Sun L, Zhao J, et al. Recent progress in rare oncogenic drivers and targeted therapy for non-small cell lung cancer. Onco Targets Ther 2019;12:10343-60.  Back to cited text no. 5
    
6.
Paliwal P, Rajappa S, Santa A, Mohan M, Murthy S, Lavanya N. Clinical profile and outcomes of patients with Stage IV adenocarcinoma of lung: A tertiary cancer center experience. Indian J Cancer 2017;54:197-202.  Back to cited text no. 6
[PUBMED]  [Full text]  
7.
Singh V, Guleria P, Malik PS, Mohan A, Thulkar S, Pandey RM, et al. Epidermal growth factor receptor (EGFR), KRAS, and BRAF mutations in lung adenocarcinomas: A study from India. Curr Probl Cancer 2019;43:391-401.  Back to cited text no. 7
    
8.
Kasana BA, Dar WR, Aziz SA, Lone AR, Sofi NU, Dar IA, et al. Epidermal growth factor receptor mutation in adenocarcinoma lung in a North Indian population: Prevalence and relation with different clinical variables. Indian J Med Paediatr Oncol 2016;37:189-95.  Back to cited text no. 8
[PUBMED]  [Full text]  
9.
Chatterjee K, Ray A, Chattopadhyay B. Incidence and characteristics of Epidermal Growth Factor Receptor (EGFR) mutation in non-small-cell lung cancer (Adenocarcinoma histology): A report of 106 patients from Kolkata. Indian J Cancer 2017;54:305-7.  Back to cited text no. 9
[PUBMED]  [Full text]  
10.
Yu HA, Suzawa K, Jordan E, Zehir A, Ni A, Kim R, et al. Concurrent alterations in EGFR-mutant lung cancers associated with resistance to EGFR kinase inhibitors and characterization of MTOR as a mediator of resistance. Clin Cancer Res 2018;24:3108-18.  Back to cited text no. 10
    
11.
Lin Q, Zhang H, Ding H, Qian J, Lizaso A, Lin J, et al. The association between BRAF mutation class and clinical features in BRAF-mutant Chinese non-small cell lung cancer patients. J Transl Med 2019;17:298.  Back to cited text no. 11
    
12.
Chatterjee K, Bhowmik R, Chattopadhyay B. Regional reporting of the incidence of Anaplastic Lymphoma Kinase mutation in 379 non-small-cell lung cancer patients from Kolkata: Using immunohistochemistry as the diagnostic modality in a significant subset. South Asian J Cancer 2017;6:169-70.  Back to cited text no. 12
[PUBMED]  [Full text]  
13.
Murthy SS, Rajappa SJ, Gundimeda SD, Mallavarapu KM, Ayyagari S, Yalavarthi P, et al. Anaplastic lymphoma kinase status in lung cancers: An immunohistochemistry and fluorescence in situ hybridization study from a tertiary cancer center in India. Indian J Cancer 2017;54:231-5.  Back to cited text no. 13
[PUBMED]  [Full text]  
14.
Joshi A, Pande N, Noronha V, Patil V, Kumar R, Chougule A, et al. ROS1 mutation non-small cell lung cancer-access to optimal treatment and outcomes. Ecancermedicalscience 2019;13:900.  Back to cited text no. 14
    
15.
Jain J, Chinta D, Jayaraman U, Pathak N, Kaur M, Chatterjee S, et al. Determination of ROS1 positivity by immunohistochemistry in a multicentric cohort of 426 nonsmallcell lung cancer cases in India. Cancer Res Stat Treat 2019;2:16-20.  Back to cited text no. 15
  [Full text]  
16.
Vallonthaiel AG, Malik PS, Singh V, Kumar V, Kumar S, Sharma MC, et al. Clinicopathologic correlation of programmed death ligand-1 expression in non-small cell lung carcinomas: A report from India. Ann Diagn Pathol 2017;31:56-61.  Back to cited text no. 16
    
17.
Borghaei H, Paz-Ares L, Horn L, Spigel DR, Steins M, Ready NE, et al. Nivolumab versus docetaxel in advanced nonsquamous non-small-cell lung cancer. N Engl J Med 2015;373:1627-39.  Back to cited text no. 17
    
18.
Garon EB, Rizvi NA, Hui R, Leighl N, Balmanoukian AS, Eder JP, et al. Pembrolizumab for the treatment of non-small-cell lung cancer. N Engl J Med 2015;372:2018-28.  Back to cited text no. 18
    
19.
Herbst RS, Baas P, Kim DW, Felip E, Pérez-Gracia JL, Han JY, et al. Pembrolizumab versus docetaxel for previously treated, PD-L1-positive, advanced non-small-cell lung cancer (KEYNOTE-010): A randomised controlled trial. Lancet 2016;387:1540-50.  Back to cited text no. 19
    
20.
Rittmeyer A, Barlesi F, Waterkamp D, Park K, Ciardiello F, von Pawel J, et al. Atezolizumab versus docetaxel in patients with previously treated non-small-cell lung cancer (OAK): A phase 3, open-label, multicentre randomised controlled trial. Lancet 2017;389:255-65.  Back to cited text no. 20
    
21.
Ancevski Hunter K, Socinski MA, Villaruz LC. PD-L1 testing in guiding patient selection for PD-1/PD-L1 inhibitor therapy in lung cancer. Mol Diagn Ther 2018;22:1-10.  Back to cited text no. 21
    
22.
Reck M, Rodríguez-Abreu D, Robinson AG, Hui R, Csőszi T, Fül&#s246;p A, et al. Pembrolizumab versus chemotherapy for PD-L1-positive non-small-cell lung cancer. N Engl J Med 2016;375:1823-33.  Back to cited text no. 22
    
23.
Xu Q, Zhu Y, Bai Y, Wei X, Zheng X, Mao M, et al. Detection of epidermal growth factor receptor mutation in lung cancer by droplet digital polymerase chain reaction. Onco Targets Ther 2015;8:1533-41.  Back to cited text no. 23
    
24.
Raja T, Warrier NK. Epidermal growth factor receptor mutation testing: From conventional to real-time diagnosis of lung cancer. Indian J Cancer 2017;54:S9-14.  Back to cited text no. 24
    
25.
Park HS, Lee JK, Kim DW, Kulig K, Kim TM, Lee SH, et al. Immunohistochemical screening for anaplastic lymphoma kinase (ALK) rearrangement in advanced non-small cell lung cancer patients. Lung Cancer 2012;77:288-92.  Back to cited text no. 25
    
26.
Paik JH, Choe G, Kim H, Choe JY, Lee HJ, Lee CT, et al. Screening of anaplastic lymphoma kinase rearrangement by immunohistochemistry in non-small cell lung cancer: Correlation with fluorescence in situ hybridization. J Thorac Oncol 2011;6:466-72.  Back to cited text no. 26
    
27.
Luk PP, Selinger CI, Mahar A, Cooper WA. Biomarkers for ALK and ROS1 in lung cancer: Immunohistochemistry and fluorescent in situ hybridization. Arch Pathol Lab Med 2018;142:922-8.  Back to cited text no. 27
    
28.
Lin JJ, Ritterhouse LL, Ali SM, Bailey M, Schrock AB, Gainor JF, et al. ROS1 fusions rarely overlap with other oncogenic drivers in non-small cell lung cancer. J Thorac Oncol 2017;12:872-7.  Back to cited text no. 28
    
29.
Bubendorf L, Büttner R, Al-Dayel F, Dietel M, Elmberger G, Kerr K, et al. Testing for ROS1 in non-small cell lung cancer: A review with recommendations. Virchows Arch 2016;469:489-503.  Back to cited text no. 29
    
30.
Lindeman NI, Cagle PT, Aisner DL, Arcila ME, Beasley MB, Bernicker EH, et al. Updated molecular testing guideline for the selection of lung cancer patients for treatment with targeted tyrosine kinase inhibitors: Guideline from the College of American Pathologists, the International Association for the Study of Lung Cancer, and the Association for Molecular Pathology. Arch Pathol Lab Med 2018;142:321-46.  Back to cited text no. 30
    
31.
Brahmer J, Reckamp KL, Baas P, Crinò L, Eberhardt WE, Poddubskaya E, et al. Nivolumab versus docetaxel in advanced squamous-cell non-small-cell lung cancer. N Engl J Med 2015;373:123-35.  Back to cited text no. 31
    
32.
Taus Á, Camacho L, Rocha P, Hardy-Werbin M, Pijuan L, Piquer G, et al. Dynamics of EGFR mutation load in plasma for prediction of treatment response and disease progression in patients with EGFR-mutant lung adenocarcinoma. Clin Lung Cancer 2018;19:387-94.e2.  Back to cited text no. 32
    
33.
Marrugo-Ramírez J, Mir M, Samitier J. Blood-based cancer biomarkers in liquid biopsy: A promising non-invasive alternative to tissue biopsy. Int J Mol Sci 2018;19:2877.  Back to cited text no. 33
    
34.
Park CK, Kim JE, Kim MS, Kho BG, Park HY, Kim TO, et al. Feasibility of liquid biopsy using plasma and platelets for detection of anaplastic lymphoma kinase rearrangements in non-small cell lung cancer. J Cancer Res Clin Oncol 2019;145:2071-82.  Back to cited text no. 34
    
35.
Douillard JY, Ostoros G, Cobo M, Ciuleanu T, Cole R, McWalter G, et al. Gefitinib treatment in EGFR mutated caucasian NSCLC: Circulating-free tumor DNA as a surrogate for determination of EGFR status. J Thorac Oncol 2014;9:1345-53.  Back to cited text no. 35
    
36.
Denis MG, Lafourcade MP, Le Garff G, Dayen C, Falchero L, Thomas P, et al. Circulating free tumor-derived DNA to detect EGFR mutations in patients with advanced NSCLC: French subset analysis of the ASSESS study. J Thorac Dis 2019;11:1370-8.  Back to cited text no. 36
    
37.
Reck M, Hagiwara K, Han B, Tjulandin S, Grohé C, Yokoi T, et al. ctDNA determination of EGFR mutation status in European and Japanese patients with advanced NSCLC: The ASSESS study. J Thorac Oncol 2016;11:1682-9.  Back to cited text no. 37
    
38.
Nilsson RJ, Karachaliou N, Berenguer J, Gimenez-Capitan A, Schellen P, Teixido C, et al. Rearranged EML4-ALK fusion transcripts sequester in circulating blood platelets and enable blood-based crizotinib response monitoring in non-small-cell lung cancer. Oncotarget 2016;7:1066-75.  Back to cited text no. 38
    
39.
Mehrad M, Roy S, Bittar HT, Dacic S. Next-generation sequencing approach to non-small cell lung carcinoma yields more actionable alterations. Arch Pathol Lab Med 2018;142:353-7.  Back to cited text no. 39
    
40.
Cao L, Long L, Li M, Yang H, Deng P, Mao X, et al. The utilization of next-generation sequencing to detect somatic mutations and predict clinical prognosis of Chinese non-small cell lung cancer patients. Onco Targets Ther 2018;11:2637-46.  Back to cited text no. 40
    
41.
Jennings LJ, Arcila ME, Corless C, Kamel-Reid S, Lubin IM, Pfeifer J, et al. Guidelines for Validation of Next-Generation Sequencing-Based Oncology Panels: A Joint Consensus Recommendation of the Association for Molecular Pathology and College of American Pathologists. J Mol Diagn 2017;19:341-65.  Back to cited text no. 41
    
42.
Rangachari D, Yamaguchi N, VanderLaan PA, Folch E, Mahadevan A, Floyd SR, et al. Brain metastases in patients with EGFR-mutated or ALK-rearranged non-small-cell lung cancers. Lung Cancer 2015;88:108-11.  Back to cited text no. 42
    
43.
Preusser M, Winkler F, Valiente M, Manegold C, Moyal E, Widhalm G, et al. Recent advances in the biology and treatment of brain metastases of non-small cell lung cancer: Summary of a multidisciplinary roundtable discussion. ESMO Open 2018;3:e000262.  Back to cited text no. 43
    
44.
Postmus PE, Kerr KM, Oudkerk M, Senan S, Waller DA, Vansteenkiste J, et al. Early and locally advanced non-small-cell lung cancer (NSCLC): ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol 2017;28:v1-21.  Back to cited text no. 44
    
45.
NICE. Clinical Guidelines Team. Lung Cancer: Diagnosis and Management (Update); Evidence Reviews for the Clinical and Cost Effectiveness of Routine MRI or CT of the Brain in the Management of People with Lung Cancer Prior to Therapy with Curative Intent; 2019. Available from: https://www.nice.org.uk/guidance/ng122/evidence/evidence-review-b-clinical-and-costeffectiveness- of-routine-mri-or-ct-of-the-brain-in-the-management -of-people-with-lung-cancer-prior-to-therapy -with-curative-intent-pdf-6722112207. [Last accessed on 2020 Feb 04].  Back to cited text no. 45
    
46.
Schoenmaekers J, Hofman P, Bootsma G, Westenend M, de Booij M, Schreurs W, et al. Screening for brain metastases in patients with stage III non-small-cell lung cancer, magnetic resonance imaging or computed tomography? A prospective study. Eur J Cancer 2019;115:88-96.  Back to cited text no. 46
    
47.
Danson S, Middleton MR, O'Byrne KJ, Clemons M, Ranson M, Hassan J, et al. Phase III trial of gemcitabine and carboplatin versus mitomycin, ifosfamide, and cisplatin or mitomycin, vinblastine, and cisplatin in patients with advanced nonsmall cell lung carcinoma. Cancer 2003;98:542-53.  Back to cited text no. 47
    
48.
Ohe Y, Ohashi Y, Kubota K, Tamura T, Nakagawa K, Negoro S, et al. Randomized phase III study of cisplatin plus irinotecan versus carboplatin plus paclitaxel, cisplatin plus gemcitabine, and cisplatin plus vinorelbine for advanced non-small-cell lung cancer: Four-Arm Cooperative Study in Japan. Ann Oncol 2007;18:317-23.  Back to cited text no. 48
    
49.
Scagliotti GV, Kortsik C, Dark GG, Price A, Manegold C, Rosell R, et al. Pemetrexed combined with oxaliplatin or carboplatin as first-line treatment in advanced non-small cell lung cancer: A multicenter, randomized, phase II trial. Clin Cancer Res 2005;11:690-6.  Back to cited text no. 49
    
50.
Scagliotti GV, Parikh P, von Pawel J, Biesma B, Vansteenkiste J, Manegold C, et al. Phase III study comparing cisplatin plus gemcitabine with cisplatin plus pemetrexed in chemotherapy-naive patients with advanced-stage non-small-cell lung cancer. J Clin Oncol 2008;26:3543-51.  Back to cited text no. 50
    
51.
Schiller JH, Harrington D, Belani CP, Langer C, Sandler A, Krook J, et al. Comparison of four chemotherapy regimens for advanced non-small-cell lung cancer. N Engl J Med 2002;346:92-8.  Back to cited text no. 51
    
52.
Socinski MA, Bondarenko I, Karaseva NA, Makhson AM, Vynnychenko I, Okamoto I, et al. Weekly nab-paclitaxel in combination with carboplatin versus solvent-based paclitaxel plus carboplatin as first-line therapy in patients with advanced non-small-cell lung cancer: Final results of a phase III trial. J Clin Oncol 2012;30:2055-62.  Back to cited text no. 52
    
53.
NSCLC Meta-Analyses Collaborative Group. Chemotherapy in addition to supportive care improves survival in advanced non-small-cell lung cancer: A systematic review and meta-analysis of individual patient data from 16 randomized controlled trials. J Clin Oncol 2008;26:4617-25.  Back to cited text no. 53
    
54.
Delbaldo C, Michiels S, Syz N, Soria JC, Le Chevalier T, Pignon JP. Benefits of adding a drug to a single-agent or a 2-agent chemotherapy regimen in advanced non-small-cell lung cancer: A meta-analysis. JAMA 2004;292:470-84.  Back to cited text no. 54
    
55.
Griesinger F, Korol EE, Kayaniyil S, Varol N, Ebner T, Goring SM. Efficacy and safety of first-line carboplatin-versus cisplatin-based chemotherapy for non-small cell lung cancer: A meta-analysis. Lung Cancer 2019;135:196-204.  Back to cited text no. 55
    
56.
Bronte G, Rolfo C, Passiglia F, Rizzo S, Gil-Bazo I, Fiorentino E, et al. What can platinum offer yet in the treatment of PS2 NSCLC patients? A systematic review and meta-analysis. Crit Rev Oncol Hematol 2015;95:306-17.  Back to cited text no. 56
    
57.
Effects of vinorelbine on quality of life and survival of elderly patients with advanced non-small-cell lung cancer. The Elderly Lung Cancer Vinorelbine Italian Study Group. J Natl Cancer Inst 1999;91:66-72.  Back to cited text no. 57
    
58.
Gridelli C, Perrone F, Gallo C, Cigolari S, Rossi A, Piantedosi F, et al. Chemotherapy for elderly patients with advanced non-small-cell lung cancer: The Multicenter Italian Lung Cancer in the Elderly Study (MILES) phase III randomized trial. J Natl Cancer Inst 2003;95:362-72.  Back to cited text no. 58
    
59.
Kudoh S, Takeda K, Nakagawa K, Takada M, Katakami N, Matsui K, et al. Phase III study of docetaxel compared with vinorelbine in elderly patients with advanced non-small-cell lung cancer: Results of the West Japan Thoracic Oncology Group Trial (WJTOG 9904). J Clin Oncol 2006;24:3657-63.  Back to cited text no. 59
    
60.
Quoix E, Zalcman G, Oster JP, Westeel V, Pichon E, Lavolé A, et al. Carboplatin and weekly paclitaxel doublet chemotherapy compared with monotherapy in elderly patients with advanced non-small-cell lung cancer: IFCT-0501 randomised, phase 3 trial. Lancet 2011;378:1079-88.  Back to cited text no. 60
    
61.
Schuette W, Blankenburg T, Guschall W, Dittrich I, Schroeder M, Schweisfurth H, et al. Multicenter randomized trial for stage IIIB/IV non-small-cell lung cancer using every-3-week versus weekly paclitaxel/carboplatin. Clin Lung Cancer 2006;7:338-43.  Back to cited text no. 61
    
62.
Gridelli C, Morabito A, Cavanna L, Luciani A, Maione P, Bonanno L, et al. Cisplatin-based first-line treatment of elderly patients with advanced non-small-cell lung cancer: Joint analysis of MILES-3 and MILES-4 phase III trials. J Clin Oncol 2018;36:2585-92.  Back to cited text no. 62
    
63.
Vergnenegre A, Massuti B, de Marinis F, Carcereny E, Felip E, Do P, et al. Economic analysis of first-line treatment with erlotinib in an EGFR-mutated population with advanced NSCLC. J Thorac Oncol 2016;11:801-7.  Back to cited text no. 63
    
64.
Schremser K, Rogowski WH, Adler-Reichel S, Tufman AL, Huber RM, Stollenwerk B. Cost-effectiveness of an individualized first-line treatment strategy offering erlotinib based on EGFR mutation testing in advanced lung adenocarcinoma patients in Germany. Pharmacoeconomics 2015;33:1215-28.  Back to cited text no. 64
    
65.
Khan I, Morris S, Hackshaw A, Lee SM. Cost-effectiveness of first-line erlotinib in patients with advanced non-small-cell lung cancer unsuitable for chemotherapy. BMJ Open 2015;5:e006733.  Back to cited text no. 65
    
66.
Nguyen CTT, Petrelli F, Scuri S, Nguyen BT, Grappasonni I. A systematic review of pharmacoeconomic evaluations of erlotinib in the first-line treatment of advanced non-small cell lung cancer. Eur J Health Econ 2019;20:763-77.  Back to cited text no. 66
    
67.
Li M, Zhang Q, Fu P, Li P, Peng A, Zhang G, et al. Pemetrexed plus platinum as the first-line treatment option for advanced non-small cell lung cancer: A meta-analysis of randomized controlled trials. PLoS One 2012;7:e37229.  Back to cited text no. 67
    
68.
Soria JC, Mauguen A, Reck M, Sandler AB, Saijo N, Johnson DH, et al. Systematic review and meta-analysis of randomised, phase II/III trials adding bevacizumab to platinum-based chemotherapy as first-line treatment in patients with advanced non-small-cell lung cancer. Ann Oncol 2013;24:20-30.  Back to cited text no. 68
    
69.
Socinski MA, Jotte RM, Cappuzzo F, Orlandi F, Stroyakovskiy D, Nogami N, et al. Atezolizumab for first-line treatment of metastatic nonsquamous NSCLC. N Engl J Med 2018;378:2288-301.  Back to cited text no. 69
    
70.
West H, McCleod M, Hussein M, Morabito A, Rittmeyer A, Conter HJ, et al. Atezolizumab in combination with carboplatin plus nab-paclitaxel chemotherapy compared with chemotherapy alone as first-line treatment for metastatic non-squamous non-small-cell lung cancer (IMpower130): A multicentre, randomised, open-label, phase 3 trial. Lancet Oncol 2019;20:924-37.  Back to cited text no. 70
    
71.
Reck M, Rodríguez-Abreu D, Robinson AG, Hui R, Csőszi T, Fülöp A, et al. Updated analysis of KEYNOTE-024: Pembrolizumab versus platinum-based chemotherapy for advanced non-small-cell lung cancer With PD-L1 tumor proportion score of 50% or greater. J Clin Oncol 2019;37:537-46.  Back to cited text no. 71
    
72.
Gandhi L, Rodríguez-Abreu D, Gadgeel S, Esteban E, Felip E, De Angelis F, et al. Pembrolizumab plus chemotherapy in metastatic non-small-cell lung cancer. N Engl J Med 2018;378:2078-92.  Back to cited text no. 72
    
73.
Gadgeel S, Garassino M, Esteban E, Speranza G, Felip E, Hochmair M, et al. Updated OS and progression after the next line of therapy (PFS2) with pembrolizumab (pembro) plus chemo with pemetrexed and platinum vs placebo plus chemo for metastatic nonsquamous NSCLC. J Clin Oncol 2019;37:abstr 9013.  Back to cited text no. 73
    
74.
Hellmann MD, Paz-Ares L, Bernabe Caro R, Zurawski B, Kim SW, Carcereny Costa E, et al. Nivolumab plus ipilimumab in advanced non-small-cell lung cancer. N Engl J Med 2019;381:2020-31.  Back to cited text no. 74
    
75.
Paz-Ares L, Luft A, Vicente D, Tafreshi A, Gümüş M, Mazières J, et al. Pembrolizumab plus chemotherapy for squamous non-small-cell lung Cancer. N Engl J Med 2018;379:2040-51.  Back to cited text no. 75
    
76.
Jotte R, Cappuzzo F, Vynnychenko I, Stroyakovskiy D, Abreu D, Hussein M, et al. IMpower131: Primary PFS and safety analysis of a randomized phase III study of atezolizumab+carboplatin+paclitaxel or Nab-paclitaxel vs carboplatin+Nab-paclitaxel as 1L therapy in advanced squamous NSCLC. J Clin Oncol 2018;36:18_suppl.  Back to cited text no. 76
    
77.
Mok TS, Wu YL, Kudaba I, Kowalski DM, Cho BC, Turna HZ, et al. Pembrolizumab versus chemotherapy for previously untreated, PD-L1-expressing, locally advanced or metastatic non-small-cell lung cancer (KEYNOTE-042): A randomised, open-label, controlled, phase 3 trial. Lancet 2019;393:1819-30.  Back to cited text no. 77
    
78.
Pai-Scherf L, Blumenthal GM, Li H, Subramaniam S, Mishra-Kalyani PS, He K, et al. FDA Approval summary: Pembrolizumab for treatment of metastatic non-small cell lung cancer: First-line therapy and beyond. Oncologist 2017;22:1392-9.  Back to cited text no. 78
    
79.
Lee CK, Man J, Lord S, Links M, Gebski V, Mok T, et al. Checkpoint inhibitors in metastatic EGFR-mutated non-small cell lung cancer-A meta-analysis. J Thorac Oncol 2017;12:403-7.  Back to cited text no. 79
    
80.
Gainor JF, Shaw AT, Sequist LV, Fu X, Azzoli CG, Piotrowska Z, et al. EGFR mutations and ALK rearrangements are associated with low response rates to PD-1 pathway blockade in non-small cell lung cancer: A retrospective analysis. Clin Cancer Res 2016;22:4585-93.  Back to cited text no. 80
    
81.
Cross DA, Ashton SE, Ghiorghiu S, Eberlein C, Nebhan CA, Spitzler PJ, et al. AZD9291, an irreversible EGFR TKI, overcomes T790M-mediated resistance to EGFR inhibitors in lung cancer. Cancer Discov 2014;4:1046-61.  Back to cited text no. 81
    
82.
Urata Y, Katakami N, Morita S, Kaji R, Yoshioka H, Seto T, et al. Randomized phase III study comparing gefitinib with erlotinib in patients with previously treated advanced lung adenocarcinoma: WJOG 5108L. J Clin Oncol 2016;34:3248-57.  Back to cited text no. 82
    
83.
Yang JJ, Zhou Q, Yan HH, Zhang XC, Chen HJ, Tu HY, et al. A phase III randomised controlled trial of erlotinib vs gefitinib in advanced non-small cell lung cancer with EGFR mutations. Br J Cancer 2017;116:568-74.  Back to cited text no. 83
    
84.
Park K, Tan EH, O'Byrne K, Zhang L, Boyer M, Mok T, et al. Afatinib versus gefitinib as first-line treatment of patients with EGFR mutation-positive non-small-cell lung cancer (LUX-Lung 7): A phase 2B, open-label, randomised controlled trial. Lancet Oncol 2016;17:577-89.  Back to cited text no. 84
    
85.
Soria JC, Ohe Y, Vansteenkiste J, Reungwetwattana T, Chewaskulyong B, Lee KH, et al. Osimertinib in Untreated EGFR-Mutated Advanced Non-Small-Cell Lung Cancer. N Engl J Med 2018;378:113-25.  Back to cited text no. 85
    
86.
Paz-Ares L, Tan EH, O'Byrne K, Zhang L, Hirsh V, Boyer M, et al. Afatinib versus gefitinib in patients with EGFR mutation-positive advanced non-small-cell lung cancer: Overall survival data from the phase IIb LUX-Lung 7 trial. Ann Oncol 2017;28:270-7.  Back to cited text no. 86
    
87.
Reungwetwattana T, Nakagawa K, Cho BC, Cobo M, Cho EK, Bertolini A, et al. CNS response to osimertinib versus standard epidermal growth factor receptor tyrosine kinase inhibitors in patients with untreated EGFR-mutated advanced non-small-cell lung cancer. J Clin Oncol 2018:JCO2018783118.   Back to cited text no. 87
    
88.
Saito H, Fukuhara T, Furuya N, Watanabe K, Sugawara S, Iwasawa S, et al. Erlotinib plus bevacizumab versus erlotinib alone in patients with EGFR-positive advanced non-squamous non-small-cell lung cancer (NEJ026): Interim analysis of an open-label, randomised, multicentre, phase 3 trial. Lancet Oncol 2019;20:625-35.  Back to cited text no. 88
    
89.
Nakagawa K, Garon EB, Seto T, Nishio M, Ponce Aix S, Paz-Ares L, et al. Ramucirumab plus erlotinib in patients with untreated, EGFR-mutated, advanced non-small-cell lung cancer (RELAY): A randomised, double-blind, placebo-controlled, phase 3 trial. Lancet Oncol 2019;20:1655-69.  Back to cited text no. 89
    
90.
Noronha V, Patil VM, Joshi A, Menon N, Chougule A, Mahajan A, et al. Gefitinib versus gefitinib plus pemetrexed and carboplatin chemotherapy in EGFR-mutated lung cancer. J Clin Oncol 2020;38:124-36.  Back to cited text no. 90
    
91.
Hosomi Y, Morita S, Sugawara S, Kato T, Fukuhara T, Gemma A, et al. Gefitinib alone versus gefitinib plus chemotherapy for non-small-cell lung cancer with mutated epidermal growth factor receptor: NEJ009 study. J Clin Oncol 2020;38:115-23.  Back to cited text no. 91
    
92.
Ramalingam SS, Vansteenkiste J, Planchard D, Cho BC, Gray JE, Ohe Y, et al. Overall survival with osimertinib in untreated, EGFR-mutated advanced NSCLC. N Engl J Med 2020;382:41-50.  Back to cited text no. 92
    
93.
Ballard P, Yates JW, Yang Z, Kim DW, Yang JC, Cantarini M, et al. Preclinical Comparison of Osimertinib with Other EGFR-TKIs in EGFR-Mutant NSCLC Brain Metastases Models, and Early Evidence of Clinical Brain Metastases Activity. Clin Cancer Res 2016;22:5130-40.  Back to cited text no. 93
    
94.
Xing P, Mu Y, Hao X, Wang Y, Li J. Data from real world to evaluate the efficacy of osimertinib in non-small cell lung cancer patients with central nervous system metastasis. Clin Transl Oncol 2019;21:1424-31.  Back to cited text no. 94
    
95.
Mok TS, Wu YL, Ahn MJ, Garassino MC, Kim HR, Ramalingam SS, et al. Osimertinib or platinum-pemetrexed in EGFR T790M-positive lung cancer. N Engl J Med 2017;376:629-40.  Back to cited text no. 95
    
96.
Mok TS, Cheng Y, Zhou X, Lee KH, Nakagawa K, Niho S, et al. Improvement in overall survival in a randomized study that compared dacomitinib with gefitinib in patients with advanced non-small-cell lung cancer and EGFR-activating mutations. J Clin Oncol 2018;36:2244-50.  Back to cited text no. 96
    
97.
Arrieta O, Cardona AF, Corrales L, Campos-Parra AD, Sánchez-Reyes R, Amieva-Rivera E, et al. The impact of common and rare EGFR mutations in response to EGFR tyrosine kinase inhibitors and platinum-based chemotherapy in patients with non-small cell lung cancer. Lung Cancer 2015;87:169-75.  Back to cited text no. 97
    
98.
Baek JH, Sun JM, Min YJ, Cho EK, Cho BC, Kim JH, et al. Efficacy of EGFR tyrosine kinase inhibitors in patients with EGFR-mutated non-small cell lung cancer except both exon 19 deletion and exon 21 L858R: A retrospective analysis in Korea. Lung Cancer 2015;87:148-54.  Back to cited text no. 98
    
99.
Keam B, Kim DW, Park JH, Lee JO, Kim TM, Lee SH, et al. Rare and complex mutations of epidermal growth factor receptor, and efficacy of tyrosine kinase inhibitor in patients with non-small cell lung cancer. Int J Clin Oncol 2014;19:594-600.  Back to cited text no. 99
    
100.
Lohinai Z, Hoda MA, Fabian K, Ostoros G, Raso E, Barbai T, et al. Distinct epidemiology and clinical consequence of classic versus rare EGFR mutations in lung adenocarcinoma. J Thorac Oncol 2015;10:738-46.  Back to cited text no. 100
    
101.
Watanabe S, Minegishi Y, Yoshizawa H, Maemondo M, Inoue A, Sugawara S, et al. Effectiveness of gefitinib against non-small-cell lung cancer with the uncommon EGFR mutations G719X and L861Q. J Thorac Oncol 2014;9:189-94.  Back to cited text no. 101
    
102.
Yang JC, Sequist LV, Geater SL, Tsai CM, Mok TS, Schuler M, et al. Clinical activity of afatinib in patients with advanced non-small-cell lung cancer harbouring uncommon EGFR mutations: A combined post-hoc analysis of LUX-Lung 2, LUX-Lung 3, and LUX-Lung 6. Lancet Oncol 2015;16:830-8.  Back to cited text no. 102
    
103.
De Pas T, Toffalorio F, Manzotti M, Fumagalli C, Spitaleri G, Catania C, et al. Activity of epidermal growth factor receptor-tyrosine kinase inhibitors in patients with non-small cell lung cancer harboring rare epidermal growth factor receptor mutations. J Thorac Oncol 2011;6:1895-901.  Back to cited text no. 103
    
104.
Sequist LV, Martins RG, Spigel D, Grunberg SM, Spira A, Jänne PA, et al. First-line gefitinib in patients with advanced non-small-cell lung cancer harboring somatic EGFR mutations. J Clin Oncol 2008;26:2442-9.  Back to cited text no. 104
    
105.
Wu JY, Yu CJ, Chang YC, Yang CH, Shih JY, Yang PC. Effectiveness of tyrosine kinase inhibitors on “uncommon” epidermal growth factor receptor mutations of unknown clinical significance in non-small cell lung cancer. Clin Cancer Res 2011;17:3812-21.  Back to cited text no. 105
    
106.
Tanaka I, Morise M, Kodama Y, Matsui A, Ozawa N, Ozone S, et al. Potential for afatinib as an optimal treatment for advanced non-small cell lung carcinoma in patients with uncommon EGFR mutations. Lung Cancer 2019;127:169-71.  Back to cited text no. 106
    
107.
Cho J, Sun J, Lee S, Ahn J, Park K, Park K, et al. An open-label, multicenter, phase II single arm trial of osimertinib in NSCLC patients with uncommon EGFR mutation (KCSG-LU15-09). J Thorac Oncol 2018;13:S344.  Back to cited text no. 107
    
108.
Cho JH, Lim SH, An HJ, Kim KH, Park KU, Kang EJ, et al. Osimertinib for patients with non-small-cell lung cancer harboring uncommon EGFR mutations: A multicenter, open-label, phase II trial (KCSG-LU15-09). J Clin Oncol 2020;38:488-95.  Back to cited text no. 108
    
109.
Yang M, Tong X, Xu X, Zheng E, Ni J, Li J, et al. Case report: Osimertinib achieved remarkable and sustained disease control in an advanced non-small-cell lung cancer harboring EGFR H773L/V774M mutation complex. Lung Cancer 2018;121:1-4.  Back to cited text no. 109
    
110.
Park K, Yu CJ, Kim SW, Lin MC, Sriuranpong V, Tsai CM, et al. First-line erlotinib therapy until and beyond response evaluation criteria in solid tumors progression in Asian patients with epidermal growth factor receptor mutation-positive non-small-cell lung cancer: The ASPIRATION study. JAMA Oncol 2016;2:305-12.  Back to cited text no. 110
    
111.
Cortellini A, Leonetti A, Catino A, Pizzutillo P, Ricciuti B, De Giglio A, et al. Osimertinib beyond disease progression in T790M EGFR-positive NSCLC patients: A multicenter study of clinicians' attitudes. Clin Transl Oncol 2020;22:844-51.  Back to cited text no. 111
    
112.
Le X, Puri S, Negrao MV, Nilsson MB, Robichaux J, Boyle T, et al. Landscape of EGFR-dependent and -independent resistance mechanisms to osimertinib and continuation therapy beyond progression in EGFR-mutant NSCLC. Clin Cancer Res 2018;24:6195-203.  Back to cited text no. 112
    
113.
Solomon BJ, Mok T, Kim DW, Wu YL, Nakagawa K, Mekhail T, et al. First-line crizotinib versus chemotherapy in ALK-positive lung cancer. N Engl J Med 2014;371:2167-77.  Back to cited text no. 113
    
114.
Solomon BJ, Kim DW, Wu YL, Nakagawa K, Mekhail T, Felip E, et al. Final overall survival analysis from a study comparing first-line crizotinib versus chemotherapy in ALK-mutation-positive non-small-cell lung cancer. J Clin Oncol 2018;36:2251-8.  Back to cited text no. 114
    
115.
Nishio M, Kim DW, Wu YL, Nakagawa K, Solomon BJ, Shaw AT, et al. Crizotinib versus chemotherapy in Asian patients with ALK-positive advanced non-small cell lung cancer. Cancer Res Treat 2018;50:691-700.  Back to cited text no. 115
    
116.
Wu YL, Lu S, Lu Y, Zhou J, Shi YK, Sriuranpong V, et al. Results of PROFILE 1029, a phase III comparison of first-line crizotinib versus chemotherapy in East Asian patients with ALK-positive advanced non-small cell lung cancer. J Thorac Oncol 2018;13:1539-48.  Back to cited text no. 116
    
117.
Shaw AT, Kim DW, Nakagawa K, Seto T, Crinó L, Ahn MJ, et al. Crizotinib versus chemotherapy in advanced ALK-positive lung cancer. N Engl J Med 2013;368:2385-94.  Back to cited text no. 117
    
118.
Ou SH, Jänne PA, Bartlett CH, Tang Y, Kim DW, Otterson GA, et al. Clinical benefit of continuing ALK inhibition with crizotinib beyond initial disease progression in patients with advanced ALK-positive NSCLC. Ann Oncol 2014;25:415-22.  Back to cited text no. 118
    
119.
Hong X, Chen Q, Ding L, Liang Y, Zhou N, Fang W, et al. Clinical benefit of continuing crizotinib therapy after initial disease progression in Chinese patients with advanced ALK-rearranged non-small-cell lung cancer. Oncotarget 2017;8:41631-40.  Back to cited text no. 119
    
120.
Bendaly E, Dalal AA, Culver K, Galebach P, Bocharova I, Foster R, et al. Monitoring for and characterizing crizotinib progression: A chart review of ALK-positive non-small cell lung cancer patients. Adv Ther 2017;34:1673-85.  Back to cited text no. 120
    
121.
Peters S, Camidge DR, Shaw AT, Gadgeel S, Ahn JS, Kim DW, et al. Alectinib versus crizotinib in untreated ALK-positive non-small-cell lung cancer. N Engl J Med 2017;377:829-38.  Back to cited text no. 121
    
122.
Camidge DR, Dziadziuszko R, Peters S, Mok T, Noe J, Nowicka M, et al. Updated efficacy and safety data and impact of the EML4-ALK fusion variant on the efficacy of alectinib in untreated ALK-positive advanced non-small cell lung cancer in the global phase III ALEX study. J Thorac Oncol 2019;14:1233-43.  Back to cited text no. 122
    
123.
Gadgeel S, Peters S, Mok T, Shaw AT, Kim DW, Ou SI, et al. Alectinib versus crizotinib in treatment-naive anaplastic lymphoma kinase-positive (ALK+) non-small-cell lung cancer: CNS efficacy results from the ALEX study. Ann Oncol 2018;29:2214-22.  Back to cited text no. 123
    
124.
Zhou C, Kim SW, Reungwetwattana T, Zhou J, Zhang Y, He J, et al. Alectinib versus crizotinib in untreated Asian patients with anaplastic lymphoma kinase-positive non-small-cell lung cancer (ALESIA): A randomised phase 3 study. Lancet Respir Med 2019;7:437-46.  Back to cited text no. 124
    
125.
Camidge DR, Kim HR, Ahn MJ, Yang JC, Han JY, Lee JS, et al. Brigatinib versus crizotinib in ALK-positive non-small-cell lung cancer. N Engl J Med 2018;379:2027-39.  Back to cited text no. 125
    
126.
Soria JC, Tan DSW, Chiari R, Wu YL, Paz-Ares L, Wolf J, et al. First-line ceritinib versus platinum-based chemotherapy in advanced ALK-rearranged non-small-cell lung cancer (ASCEND-4): A randomised, open-label, phase 3 study. Lancet 2017;389:917-29.  Back to cited text no. 126
    
127.
Shaw AT, Kim TM, Crinò L, Gridelli C, Kiura K, Liu G, et al. Ceritinib versus chemotherapy in patients with ALK-rearranged non-small-cell lung cancer previously given chemotherapy and crizotinib (ASCEND-5): A randomised, controlled, open-label, phase 3 trial. Lancet Oncol 2017;18:874-86.  Back to cited text no. 127
    
128.
Solomon BJ, Besse B, Bauer TM, Felip E, Soo RA, Camidge DR, et al. Lorlatinib in patients with ALK-positive non-small-cell lung cancer: Results from a global phase 2 study. Lancet Oncol 2018;19:1654-67.  Back to cited text no. 128
    
129.
A study of Lorlatinib Versus Crizotinib in First Line Treatment of Patients with ALK-Positive NSCLC (NCT03052608). Available from: https://clinicaltrials.gov/ct2/show/NCT03052608. [Last accessed on 16 May 2021].  Back to cited text no. 129
    
130.
Shaw AT, Bauer TM, de Marinis F, Felip E, Goto Y, Liu G, et al. First-line lorlatinib or crizotinib in advanced ALK-positive lung cancer. N Engl J Med 2020;383:2018-29.  Back to cited text no. 130
    
131.
Shaw AT, Ou SH, Bang YJ, Camidge DR, Solomon BJ, Salgia R, et al. Crizotinib in ROS1-rearranged non-small-cell lung cancer. N Engl J Med 2014;371:1963-71.  Back to cited text no. 131
    
132.
Shaw AT, Riely GJ, Bang YJ, Kim DW, Camidge DR, Solomon BJ, et al. Crizotinib in ROS1-rearranged advanced non-small-cell lung cancer (NSCLC): Updated results, including overall survival, from PROFILE 1001. Ann Oncol 2019;30:1121-6.  Back to cited text no. 132
    
133.
Liu C, Yu H, Chang J, Chen H, Li Y, Zhao W, et al. Crizotinib in Chinese patients with ROS1-rearranged advanced non-'small-cell lung cancer in routine clinical practice. Target Oncol 2019;14:315-23.  Back to cited text no. 133
    
134.
Mazières J, Zalcman G, Crinò L, Biondani P, Barlesi F, Filleron T, et al. Crizotinib therapy for advanced lung adenocarcinoma and a ROS1 rearrangement: Results from the EUROS1 cohort. J Clin Oncol 2015;33:992-9.  Back to cited text no. 134
    
135.
Noronha V, Chandrakanth MV, Joshi AP, Patil V, Chougule A, Mahajan A, et al. ROS1 rearranged nonsmall cell lung cancer and crizotinib: An Indian experience. Indian J Cancer 2017;54:436-8.  Back to cited text no. 135
[PUBMED]  [Full text]  
136.
Lim SM, Kim HR, Lee JS, Lee KH, Lee YG, Min YJ, et al. Open-label, multicenter, phase II study of ceritinib in patients with non-small-cell lung cancer harboring ROS1 rearrangement. J Clin Oncol 2017;35:2613-8.  Back to cited text no. 136
    
137.
Nagano T, Tachihara M, Nishimura Y. Mechanism of resistance to epidermal growth factor receptor-tyrosine kinase inhibitors and a potential treatment strategy. Cells 2018;7:212.   Back to cited text no. 137
    
138.
Jaiswal R, Pinninti R, Mohan M, Santa A, Boyella P, Nambaru L, et al. T790M mutation and clinical outcomes with osimertinib in patients with epidermal growth factor receptor-mutant nonsmall cell lung cancer. Indian J Med Paediatr Oncol 2019;40:73-8.  Back to cited text no. 138
  [Full text]  
139.
Oser MG, Niederst MJ, Sequist LV, Engelman JA. Transformation from non-small-cell lung cancer to small-cell lung cancer: Molecular drivers and cells of origin. Lancet Oncol 2015;16:e165-72.  Back to cited text no. 139
    
140.
Wu SG, Shih JY. Management of acquired resistance to EGFR TKI-targeted therapy in advanced non-small cell lung cancer. Mol Cancer 2018;17:38.  Back to cited text no. 140
    
141.
Thress KS, Brant R, Carr TH, Dearden S, Jenkins S, Brown H, et al. EGFR mutation detection in ctDNA from NSCLC patient plasma: A cross-platform comparison of leading technologies to support the clinical development of AZD9291. Lung Cancer 2015;90:509-15.  Back to cited text no. 141
    
142.
Oxnard GR, Thress KS, Alden RS, Lawrance R, Paweletz CP, Cantarini M, et al. Association between plasma genotyping and outcomes of treatment with osimertinib (AZD9291) in advanced non-small-cell lung cancer. J Clin Oncol 2016;34:3375-82.  Back to cited text no. 142
    
143.
Zhou J, Zhao C, Zhao J, Wang Q, Chu X, Li J, et al. Re-biopsy and liquid biopsy for patients with non-small cell lung cancer after EGFR-tyrosine kinase inhibitor failure. Thorac Cancer 2019;10:957-65.  Back to cited text no. 143
    
144.
NCCN. NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines): Non-Small Cell Lung Cancer, Version 12020. Available online at: https://www.nccn.org/login?ReturnURL=https://www.nccn.org/professionals/physician_gls/pdf/nscl.pdf. [Last accessed on 2021 Jun15].  Back to cited text no. 144
    
145.
Freidlin B, Little RF, Korn EL. Design issues in randomized clinical trials of maintenance therapies. J Natl Cancer Inst 2015;107:djv225.  Back to cited text no. 145
    
146.
Ciuleanu T, Brodowicz T, Zielinski C, Kim JH, Krzakowski M, Laack E, et al. Maintenance pemetrexed plus best supportive care versus placebo plus best supportive care for non-small-cell lung cancer: A randomised, double-blind, phase 3 study. Lancet 2009;374:1432-40.  Back to cited text no. 146
    
147.
Cappuzzo F, Ciuleanu T, Stelmakh L, Cicenas S, Szczésna A, Juhász E, et al. Erlotinib as maintenance treatment in advanced non-small-cell lung cancer: A multicentre, randomised, placebo-controlled phase 3 study. Lancet Oncol 2010;11:521-9.  Back to cited text no. 147
    
148.
Paz-Ares L, de Marinis F, Dediu M, Thomas M, Pujol JL, Bidoli P, et al. Maintenance therapy with pemetrexed plus best supportive care versus placebo plus best supportive care after induction therapy with pemetrexed plus cisplatin for advanced non-squamous non-small-cell lung cancer (PARAMOUNT): A double-blind, phase 3, randomised controlled trial. Lancet Oncol 2012;13:247-55.  Back to cited text no. 148
    
149.
Paz-Ares LG, de Marinis F, Dediu M, Thomas M, Pujol JL, Bidoli P, et al. PARAMOUNT: Final overall survival results of the phase III study of maintenance pemetrexed versus placebo immediately after induction treatment with pemetrexed plus cisplatin for advanced nonsquamous non-small-cell lung cancer. J Clin Oncol 2013;31:2895-902.  Back to cited text no. 149
    
150.
Barlesi F, Scherpereel A, Gorbunova V, Gervais R, Vikström A, Chouaid C, et al. Maintenance bevacizumab-pemetrexed after first-line cisplatin-pemetrexed-bevacizumab for advanced nonsquamous nonsmall-cell lung cancer: Updated survival analysis of the AVAPERL (MO22089) randomized phase III trial. Ann Oncol 2014;25:1044-52.  Back to cited text no. 150
    
151.
Barlesi F, Scherpereel A, Rittmeyer A, Pazzola A, Ferrer Tur N, Kim JH, et al. Randomized phase III trial of maintenance bevacizumab with or without pemetrexed after first-line induction with bevacizumab, cisplatin, and pemetrexed in advanced nonsquamous non-small-cell lung cancer: AVAPERL (MO22089). J Clin Oncol 2013;31:3004-11.  Back to cited text no. 151
    
152.
Patel JD, Socinski MA, Garon EB, Reynolds CH, Spigel DR, Olsen MR, et al. PointBreak: A randomized phase III study of pemetrexed plus carboplatin and bevacizumab followed by maintenance pemetrexed and bevacizumab versus paclitaxel plus carboplatin and bevacizumab followed by maintenance bevacizumab in patients with stage IIIB or IV nonsquamous non-small-cell lung cancer. J Clin Oncol 2013;31:4349-57.  Back to cited text no. 152
    
153.
Tsutani Y, Miyata Y, Masuda T, Fujitaka K, Doi M, Awaya Y, et al. Multicenter phase II study on cisplatin, pemetrexed, and bevacizumab followed by maintenance with pemetrexed and bevacizumab for patients with advanced or recurrent nonsquamous non-small cell lung cancer: MAP study. BMC Cancer 2018;18:1231.  Back to cited text no. 153
    
154.
Shan F, Zhang B, Sun L, Xie L, Shen M, Ruan S. The role of combination maintenance with pemetrexed and bevacizumab for advanced stage nonsquamous non-small cell lung cancer: A systematic review and meta-analysis. Biomed Res Int 2018;2018:5839081.  Back to cited text no. 154
    
155.
Hanna N, Shepherd FA, Fossella FV, Pereira JR, De Marinis F, von Pawel J, et al. Randomized phase III trial of pemetrexed versus docetaxel in patients with non-small-cell lung cancer previously treated with chemotherapy. J Clin Oncol 2004;22:1589-97.  Back to cited text no. 155
    
156.
Cicenas S, Geater SL, Petrov P, Hotko Y, Hooper G, Xia F, et al. Maintenance erlotinib versus erlotinib at disease progression in patients with advanced non-small-cell lung cancer who have not progressed following platinum-based chemotherapy (IUNO study). Lung Cancer 2016;102:30-7.  Back to cited text no. 156
    
157.
Shepherd FA, Dancey J, Ramlau R, Mattson K, Gralla R, O'Rourke M, et al. Prospective randomized trial of docetaxel versus best supportive care in patients with non-small-cell lung cancer previously treated with platinum-based chemotherapy. J Clin Oncol 2000;18:2095-103.  Back to cited text no. 157
    
158.
Dancey J, Shepherd FA, Gralla RJ, Kim YS. Quality of life assessment of second-line docetaxel versus best supportive care in patients with non-small-cell lung cancer previously treated with platinum-based chemotherapy: Results of a prospective, randomized phase III trial. Lung Cancer 2004;43:183-94.  Back to cited text no. 158
    
159.
Pujol JL, Paul S, Chouaki N, Peterson P, Moore P, Berry DA, et al. Survival without common toxicity criteria grade — toxicity for pemetrexed compared with docetaxel in previously treated patients with advanced non-small cell lung cancer (NSCLC): A risk-benefit analysis. J Thorac Oncol 2007;2:397-401.  Back to cited text no. 159
    
160.
Scagliotti G, Hanna N, Fossella F, Sugarman K, Blatter J, Peterson P, et al. The differential efficacy of pemetrexed according to NSCLC histology: A review of two Phase III studies. Oncologist 2009;14:253-63.  Back to cited text no. 160
    
161.
Reck M, Kaiser R, Mellemgaard A, Douillard JY, Orlov S, Krzakowski M, et al. Docetaxel plus nintedanib versus docetaxel plus placebo in patients with previously treated non-small-cell lung cancer (LUME-Lung 1): A phase 3, double-blind, randomised controlled trial. Lancet Oncol 2014;15:143-55.  Back to cited text no. 161
    
162.
Garon EB, Ciuleanu TE, Arrieta O, Prabhash K, Syrigos KN, Goksel T, et al. Ramucirumab plus docetaxel versus placebo plus docetaxel for second-line treatment of stage IV non-small-cell lung cancer after disease progression on platinum-based therapy (REVEL): A multicentre, double-blind, randomised phase 3 trial. Lancet 2014;384:665-73.  Back to cited text no. 162
    
163.
Aguiar PN Jr., De Mello RA, Barreto CM, Perry LA, Penny-Dimri J, Tadokoro H, et al. Immune checkpoint inhibitors for advanced non-small cell lung cancer: Emerging sequencing for new treatment targets. ESMO Open 2017;2:e000200.  Back to cited text no. 163
    
164.
Vokes EE, Ready N, Felip E, Horn L, Burgio MA, Antonia SJ, et al. Nivolumab versus docetaxel in previously treated advanced non-small-cell lung cancer (CheckMate 017 and CheckMate 057): 3-year update and outcomes in patients with liver metastases. Ann Oncol 2018;29:959-65.  Back to cited text no. 164
    
165.
Leighl NB, Hellmann MD, Hui R, Carcereny E, Felip E, Ahn MJ, et al. Pembrolizumab in patients with advanced non-small-cell lung cancer (KEYNOTE-001): 3-year results from an open-label, phase 1 study. Lancet Respir Med 2019;7:347-57.  Back to cited text no. 165
    
166.
Fehrenbacher L, Spira A, Ballinger M, Kowanetz M, Vansteenkiste J, Mazieres J, et al. Atezolizumab versus docetaxel for patients with previously treated non-small-cell lung cancer (POPLAR): A multicentre, open-label, phase 2 randomised controlled trial. Lancet 2016;387:1837-46.  Back to cited text no. 166
    
167.
Mazières J, Park K, Lewanski C, Gadgeel S, Fehrenbacher L, Rittmeyer A, et al. 3-Year survival and duration of response in randomized phase II study of atezolizumab (atezo) vs docetaxel (doc) in 2L+NSCLC (POPLAR). J Thorac Oncol 2018;13:S1-139.  Back to cited text no. 167
    
168.
Kim ES, Hirsh V, Mok T, Socinski MA, Gervais R, Wu YL, et al. Gefitinib versus docetaxel in previously treated non-small-cell lung cancer (INTEREST): A randomised phase III trial. Lancet 2008;372:1809-18.  Back to cited text no. 168
    
169.
Ciuleanu T, Stelmakh L, Cicenas S, Miliauskas S, Grigorescu AC, Hillenbach C, et al. Efficacy and safety of erlotinib versus chemotherapy in second-line treatment of patients with advanced, non-small-cell lung cancer with poor prognosis (TITAN): A randomised multicentre, open-label, phase 3 study. Lancet Oncol 2012;13:300-8.  Back to cited text no. 169
    
170.
Garassino MC, Martelli O, Broggini M, Farina G, Veronese S, Rulli E, et al. Erlotinib versus docetaxel as second-line treatment of patients with advanced non-small-cell lung cancer and wild-type EGFR tumours (TAILOR): A randomised controlled trial. Lancet Oncol 2013;14:981-8.  Back to cited text no. 170
    
171.
Kawaguchi T, Ando M, Asami K, Okano Y, Fukuda M, Nakagawa H, et al. Randomized phase III trial of erlotinib versus docetaxel as second- or third-line therapy in patients with advanced non-small-cell lung cancer: Docetaxel and Erlotinib Lung Cancer Trial (DELTA). J Clin Oncol 2014;32:1902-8.  Back to cited text no. 171
    
172.
Lee JK, Hahn S, Kim DW, Suh KJ, Keam B, Kim TM, et al. Epidermal growth factor receptor tyrosine kinase inhibitors vs conventional chemotherapy in non-small cell lung cancer harboring wild-type epidermal growth factor receptor: A meta-analysis. JAMA 2014;311:1430-7.  Back to cited text no. 172
    
173.
Langer CJ, Gadgeel SM, Borghaei H, Papadimitrakopoulou VA, Patnaik A, Powell SF, et al. Carboplatin and pemetrexed with or without pembrolizumab for advanced, non-squamous non-small-cell lung cancer: A randomised, phase 2 cohort of the open-label KEYNOTE-021 study. Lancet Oncol 2016;17:1497-508.  Back to cited text no. 173
    
174.
Wu YL, Ahn MJ, Garassino MC, Han JY, Katakami N, Kim HR, et al. CNS efficacy of osimertinib in patients with T790M-positive advanced non-small-cell lung cancer: Data from a randomized phase III trial (AURA3). J Clin Oncol 2018;36:2702-9.  Back to cited text no. 174
    
175.
Jänne PA, Yang JC, Kim DW, Planchard D, Ohe Y, Ramalingam SS, et al. AZD9291 in EGFR inhibitor-resistant non-small-cell lung cancer. N Engl J Med 2015;372:1689-99.  Back to cited text no. 175
    
176.
Wu Y, Mok T, Han J, Ahn M, Delmonte A, Ramalingam S, et al. Overall survival (OS) from the AURA3 phase III study: Osimertinib vs platinum-pemetrexed (plt-pem) in patients (pts) with EGFR T790M advanced non-small cell lung cancer (NSCLC) and progression on a prior EGFR-tyrosine kinase inhibitor (TKI). Ann Oncol 2019;30:ix158.  Back to cited text no. 176
    
177.
Shaw AT, Engelman JA. Ceritinib in ALK-rearranged non-small-cell lung cancer. N Engl J Med 2014;370:2537-9.  Back to cited text no. 177
    
178.
Sharma GG, Mota I, Mologni L, Patrucco E, Gambacorti-Passerini C, Chiarle R. Tumor resistance against ALK targeted therapy-where it comes from and where it goes. Cancers (Basel) 2018;10:62.  Back to cited text no. 178
    
179.
Hida T, Seto T, Horinouchi H, Maemondo M, Takeda M, Hotta K, et al. Phase II study of ceritinib in alectinib-pretreated patients with anaplastic lymphoma kinase-rearranged metastatic non-small-cell lung cancer in Japan: ASCEND-9. Cancer Sci 2018;109:2863-72.  Back to cited text no. 179
    
180.
Kiura K, Imamura F, Kagamu H, Matsumoto S, Hida T, Nakagawa K, et al. Phase 3 study of ceritinib vs chemotherapy in ALK-rearranged NSCLC patients previously treated with chemotherapy and crizotinib (ASCEND-5): Japanese subset. Jpn J Clin Oncol 2018;48:367-75.  Back to cited text no. 180
    
181.
Ou SH, Ahn JS, De Petris L, Govindan R, Yang JC, Hughes B, et al. Alectinib in crizotinib-refractory ALK-rearranged non-small-cell lung cancer: A phase II global study. J Clin Oncol 2016;34:661-8.  Back to cited text no. 181
    
182.
Shaw AT, Gandhi L, Gadgeel S, Riely GJ, Cetnar J, West H, et al. Alectinib in ALK-positive, crizotinib-resistant, non-small-cell lung cancer: A single-group, multicentre, phase 2 trial. Lancet Oncol 2016;17:234-42.  Back to cited text no. 182
    
183.
Yang JC, Ou SI, De Petris L, Gadgeel S, Gandhi L, Kim DW, et al. Pooled systemic efficacy and safety data from the pivotal phase II studies (NP28673 and NP28761) of alectinib in ALK-positive non-small cell lung cancer. J Thorac Oncol 2017;12:1552-60.  Back to cited text no. 183
    
184.
Novello S, Mazières J, Oh IJ, de Castro J, Migliorino MR, Helland Å, et al. Alectinib versus chemotherapy in crizotinib-pretreated anaplastic lymphoma kinase (ALK)-positive non-small-cell lung cancer: Results from the phase III ALUR study. Ann Oncol 2018;29:1409-16.  Back to cited text no. 184
    
185.
Lee J, Sun JM, Lee SH, Ahn JS, Park K, Choi Y, et al. Efficacy and safety of lorlatinib in Korean non-small-cell lung cancer patients with ALK or ROS1 rearrangement whose disease failed to respond to a previous tyrosine kinase inhibitor. Clin Lung Cancer 2019;20:215-21.  Back to cited text no. 185
    
186.
Uchibori K, Inase N, Araki M, Kamada M, Sato S, Okuno Y, et al. Brigatinib combined with anti-EGFR antibody overcomes osimertinib resistance in EGFR-mutated non-small-cell lung cancer. Nat Commun 2017;8:14768.  Back to cited text no. 186
    
187.
Camidge DR, Kim DW, Tiseo M, Langer CJ, Ahn MJ, Shaw AT, et al. Exploratory analysis of brigatinib activity in patients with anaplastic lymphoma kinase-positive non-small-cell lung cancer and brain metastases in two clinical trials. J Clin Oncol 2018;36:2693-701.  Back to cited text no. 187
    
188.
Gainor JF, Dardaei L, Yoda S, Friboulet L, Leshchiner I, Katayama R, et al. Molecular mechanisms of resistance to first- and second-generation ALK inhibitors in ALK-rearranged lung cancer. Cancer Discov 2016;6:1118-33.  Back to cited text no. 188
    
189.
Barton R. Inoperable brain metastases from non-small cell lung cancer: What part does whole brain radiotherapy play in standard treatment? Thorax 2008;63:1-2.  Back to cited text no. 189
    
190.
Suh JH, Kotecha R, Chao ST, Ahluwalia MS, Sahgal A, Chang EL. Current approaches to the management of brain metastases. Nat Rev Clin Oncol 2020;17:279-99.  Back to cited text no. 190
    
191.
Mulvenna P, Nankivell M, Barton R, Faivre-Finn C, Wilson P, McColl E, et al. Dexamethasone and supportive care with or without whole brain radiotherapy in treating patients with non-small cell lung cancer with brain metastases unsuitable for resection or stereotactic radiotherapy (QUARTZ): Results from a phase 3, non-inferiority, randomised trial. Lancet 2016;388:2004-14.  Back to cited text no. 191
    
192.
Brown PD, Jaeckle K, Ballman KV, Farace E, Cerhan JH, Anderson SK, et al. Effect of radiosurgery alone vs radiosurgery with whole brain radiation therapy on cognitive function in patients with 1 to 3 brain metastases: A randomized clinical trial. JAMA 2016;316:401-9.  Back to cited text no. 192
    
193.
Qie S, Li Y, Shi HY, Yuan L, Su L, Zhang X. Stereotactic radiosurgery (SRS) alone versus whole brain radiotherapy plus SRS in patients with 1 to 4 brain metastases from non-small cell lung cancer stratified by the graded prognostic assessment: A meta-analysis (PRISMA) of randomized control trials. Medicine (Baltimore) 2018;97:e11777.  Back to cited text no. 193
    
194.
Nieder C, Guckenberger M, Gaspar LE, Rusthoven CG, De Ruysscher D, Sahgal A, et al. Management of patients with brain metastases from non-small cell lung cancer and adverse prognostic features: Multi-national radiation treatment recommendations are heterogeneous. Radiat Oncol 2019;14:33.  Back to cited text no. 194
    
195.
Tsao MN, Xu W, Wong RK, Lloyd N, Laperriere N, Sahgal A, et al. Whole brain radiotherapy for the treatment of newly diagnosed multiple brain metastases. Cochrane Database Syst Rev 2018;1:CD003869.  Back to cited text no. 195
    
196.
Mintz A, Perry J, Spithoff K, Chambers A, Laperriere N. Management of single brain metastasis: A practice guideline. Curr Oncol 2007;14:131-43.  Back to cited text no. 196
    
197.
Qin H, Wang C, Jiang Y, Zhang X, Zhang Y, Ruan Z. Patients with single brain metastasis from non-small cell lung cancer equally benefit from stereotactic radiosurgery and surgery: A systematic review. Med Sci Monit 2015;21:144-52.  Back to cited text no. 197
    
198.
Soon YY, Tham IW, Lim KH, Koh WY, Lu JJ. Surgery or radiosurgery plus whole brain radiotherapy versus surgery or radiosurgery alone for brain metastases. Cochrane Database Syst Rev 2014;2014:CD009454.   Back to cited text no. 198
    
199.
Kim CS, Jeter MD. Radiation Therapy, Early Stage Non-Small Cell Lung Cancer. Treasure Island, FL: StatPearls; 2020.  Back to cited text no. 199
    
200.
Churilla TM, Chowdhury IH, Handorf E, Collette L, Collette S, Dong Y, et al. Comparison of local control of brain metastases with stereotactic radiosurgery vs surgical resection: A Secondary analysis of a randomized clinical trial. JAMA Oncol 2019;5:243-7.  Back to cited text no. 200
    
201.
Fuentes R, Osorio D, Expósito Hernandez J, Simancas-Racines D, Martinez-Zapata MJ, Bonfill Cosp X. Surgery versus stereotactic radiotherapy for people with single or solitary brain metastasis. Cochrane Database Syst Rev 2018;8:CD012086.  Back to cited text no. 201
    
202.
Watanabe S, Hayashi H, Nakagawa K. Is afatinib a treatment option for brain metastases in patients with EGFR mutation-positive non-small cell lung cancer? Ann Transl Med 2016;4:225.  Back to cited text no. 202
    
203.
Zhang J, Yu J, Sun X, Meng X. Epidermal growth factor receptor tyrosine kinase inhibitors in the treatment of central nerve system metastases from non-small cell lung cancer. Cancer Lett 2014;351:6-12.  Back to cited text no. 203
    
204.
Schuler M, Wu YL, Hirsh V, O'Byrne K, Yamamoto N, Mok T, et al. First-line afatinib versus chemotherapy in patients with non-small cell lung cancer and common epidermal growth factor receptor gene mutations and brain metastases. J Thorac Oncol 2016;11:380-90.  Back to cited text no. 204
    
205.
Costa DB, Shaw AT, Ou SH, Solomon BJ, Riely GJ, Ahn MJ, et al. Clinical experience with crizotinib in patients with advanced ALK-rearranged non-small-cell lung cancer and brain metastases. J Clin Oncol 2015;33:1881-8.  Back to cited text no. 205
    
206.
Kim DW, Mehra R, Tan DS, Felip E, Chow LQ, Camidge DR, et al. Activity and safety of ceritinib in patients with ALK-rearranged non-small-cell lung cancer (ASCEND-1): Updated results from the multicentre, open-label, phase 1 trial. Lancet Oncol 2016;17:452-63.  Back to cited text no. 206
    
207.
Palma DA, Salama JK, Lo SS, Senan S, Treasure T, Govindan R, et al. The oligometastatic state-separating truth from wishful thinking. Nat Rev Clin Oncol 2014;11:549-57.  Back to cited text no. 207
    
208.
Mehta N, Mauer AM, Hellman S, Haraf DJ, Cohen EE, Vokes EE, et al. Analysis of further disease progression in metastatic non-small cell lung cancer: Implications for locoregional treatment. Int J Oncol 2004;25:1677-83.  Back to cited text no. 208
    
209.
Ashworth AB, Senan S, Palma DA, Riquet M, Ahn YC, Ricardi U, et al. An individual patient data metaanalysis of outcomes and prognostic factors after treatment of oligometastatic non-small-cell lung cancer. Clin Lung Cancer 2014;15:346-55.  Back to cited text no. 209
    
210.
Parikh RB, Cronin AM, Kozono DE, Oxnard GR, Mak RH, Jackman DM, et al. Definitive primary therapy in patients presenting with oligometastatic non-small cell lung cancer. Int J Radiat Oncol Biol Phys 2014;89:880-7.  Back to cited text no. 210
    
211.
Hendriks LE, Derks JL, Postmus PE, Damhuis RA, Houben RM, Troost EG, et al. Single organ metastatic disease and local disease status, prognostic factors for overall survival in stage IV non-small cell lung cancer: Results from a population-based study. Eur J Cancer 2015;51:2534-44.  Back to cited text no. 211
    
212.
Agolli L, Valeriani M, Nicosia L, Bracci S, De Sanctis V, Minniti G, et al. Stereotactic ablative body radiotherapy (SABR) in pulmonary oligometastatic/oligorecurrent non-small cell lung cancer patients: A new therapeutic approach. Anticancer Res 2015;35:6239-45.  Back to cited text no. 212
    
213.
Collaud S, Stahel R, Inci I, Hillinger S, Schneiter D, Kestenholz P, et al. Survival of patients treated surgically for synchronous single-organ metastatic NSCLC and advanced pathologic TN stage. Lung Cancer 2012;78:234-8.  Back to cited text no. 213
    
214.
De Rose F, Cozzi L, Navarria P, Ascolese AM, Clerici E, Infante M, et al. Clinical outcome of stereotactic ablative body radiotherapy for lung metastatic lesions in non-small cell lung cancer oligometastatic patients. Clin Oncol (R Coll Radiol) 2016;28:13-20.  Back to cited text no. 214
    
215.
Gray PJ, Mak RH, Yeap BY, Cryer SK, Pinnell NE, Christianson LW, et al. Aggressive therapy for patients with non-small cell lung carcinoma and synchronous brain-only oligometastatic disease is associated with long-term survival. Lung Cancer 2014;85:239-44.  Back to cited text no. 215
    
216.
Hu C, Chang EL, Hassenbusch SJ 3rd, Allen PK, Woo SY, Mahajan A, et al. Nonsmall cell lung cancer presenting with synchronous solitary brain metastasis. Cancer 2006;106:1998-2004.  Back to cited text no. 216
    
217.
Iyengar P, Kavanagh BD, Wardak Z, Smith I, Ahn C, Gerber DE, et al. Phase II trial of stereotactic body radiation therapy combined with erlotinib for patients with limited but progressive metastatic non-small-cell lung cancer. J Clin Oncol 2014;32:3824-30.  Back to cited text no. 217
    
218.
Tönnies M, Pfannschmidt J, Bauer TT, Kollmeier J, Tönnies S, Kaiser D. Metastasectomy for synchronous solitary non-small cell lung cancer metastases. Ann Thorac Surg 2014;98:249-56.  Back to cited text no. 218
    
219.
Detterbeck FC, Franklin WA, Nicholson AG, Girard N, Arenberg DA, Travis WD, et al. The IASLC Lung Cancer Staging Project: Background Data and Proposed Criteria to Distinguish Separate Primary Lung Cancers from Metastatic Foci in Patients with Two Lung Tumors in the Forthcoming Eighth Edition of the TNM Classification for Lung Cancer. J Thorac Oncol 2016;11:651-65.  Back to cited text no. 219
    
220.
Chang JY, Liu YH, Zhu Z, Welsh JW, Gomez DR, Komaki R, et al. Stereotactic ablative radiotherapy: A potentially curable approach to early stage multiple primary lung cancer. Cancer 2013;119:3402-10.  Back to cited text no. 220
    
221.
Griffioen G, Lagerwaard F, Haasbeek C, Smit E, Slotman B, Senan S. Treatment of multiple primary lung cancers using stereotactic radiotherapy, either with or without surgery. Radiother Oncol 2013;107:403-8.  Back to cited text no. 221
    
222.
Weickhardt AJ, Scheier B, Burke JM, Gan G, Lu X, Bunn PA Jr., et al. Local ablative therapy of oligoprogressive disease prolongs disease control by tyrosine kinase inhibitors in oncogene-addicted non-small-cell lung cancer. J Thorac Oncol 2012;7:1807-14.  Back to cited text no. 222
    
223.
Petrelli F, Ghidini A, Cabiddu M, Tomasello G, De Stefani A, Bruschieri L, et al. Addition of radiotherapy to the primary tumour in oligometastatic NSCLC: A systematic review and meta-analysis. Lung Cancer 2018;126:194-200.  Back to cited text no. 223
    
224.
Milano MT, Katz AW, Okunieff P. Patterns of recurrence after curative-intent radiation for oligometastases confined to one organ. Am J Clin Oncol 2010;33:157-63.  Back to cited text no. 224
    
225.
Salama JK, Chmura SJ, Mehta N, Yenice KM, Stadler WM, Vokes EE, et al. An initial report of a radiation dose-escalation trial in patients with one to five sites of metastatic disease. Clin Cancer Res 2008;14:5255-9.  Back to cited text no. 225
    
226.
Gomez DR, Blumenschein GR Jr, Lee JJ, Hernandez M, Ye R, Camidge DR, et al. Local consolidative therapy versus maintenance therapy or observation for patients with oligometastatic non-small-cell lung cancer without progression after first-line systemic therapy: A multicentre, randomised, controlled, phase 2 study. Lancet Oncol 2016;17:1672-82.  Back to cited text no. 226
    
227.
Iyengar P, Wardak Z, Gerber DE, Tumati V, Ahn C, Hughes RS, et al. Consolidative radiotherapy for limited metastatic non-small-cell lung cancer: A phase 2 randomized clinical trial. JAMA Oncol 2018;4:e173501.  Back to cited text no. 227
    
228.
Gomez DR, Tang C, Zhang J, Blumenschein GR Jr., Hernandez M, Lee JJ, et al. Local consolidative therapy vs. maintenance therapy or observation for patients with oligometastatic non-small-cell lung cancer: Long-term results of a multi-institutional, phase II, randomized study. J Clin Oncol 2019;37:1558-65.  Back to cited text no. 228
    
229.
Chow E, Harris K, Fan G, Tsao M, Sze WM. Palliative radiotherapy trials for bone metastases: A systematic review. J Clin Oncol 2007;25:1423-36.  Back to cited text no. 229
    
230.
Lutz S, Berk L, Chang E, Chow E, Hahn C, Hoskin P, et al. Palliative radiotherapy for bone metastases: An ASTRO evidence-based guideline. Int J Radiat Oncol Biol Phys 2011;79:965-76.  Back to cited text no. 230
    
231.
Cross CK, Berman S, Buswell L, Johnson B, Baldini EH. Prospective study of palliative hypofractionated radiotherapy (8.5 Gyx2) for patients with symptomatic non-small-cell lung cancer. Int J Radiat Oncol Biol Phys 2004;58:1098-105.  Back to cited text no. 231
    
232.
Lim SH, Lee JY, Lee MY, Kim HS, Lee J, Sun JM, et al. A randomized phase III trial of stereotactic radiosurgery (SRS) versus observation for patients with asymptomatic cerebral oligo-metastases in non-small-cell lung cancer. Ann Oncol 2015;26:762-8.  Back to cited text no. 232
    
233.
Lackey A, Donington JS. Surgical management of lung cancer. Semin Intervent Radiol 2013;30:133-40.  Back to cited text no. 233
    
234.
Kawano D, Takeo S, Katsura M, Tsukamoto S, Masuyama E, Nakaji Y. Surgical treatment of stage IV non-small cell lung cancer. Interact Cardiovasc Thorac Surg 2012;14:167-70.  Back to cited text no. 234
    
235.
David EA, Clark JM, Cooke DT, Melnikow J, Kelly K, Canter RJ. The role of thoracic surgery in the therapeutic management of metastatic non-small cell lung cancer. J Thorac Oncol 2017;12:1636-45.  Back to cited text no. 235
    
236.
David EA, Canter RJ, Chen Y, Cooke DT, Cress RD. Surgical management of advanced non-small cell lung cancer is decreasing but is associated with improved survival. Ann Thorac Surg 2016;102:1101-9.  Back to cited text no. 236
    
237.
Miyanaga A, Kubota K, Hosomi Y, Okuma Y, Minato K, Fujimoto S, et al. Phase II trial of S-1 plus cisplatin combined with bevacizumab for advanced non-squamous non-small cell lung cancer (TCOG LC-1202). Jpn J Clin Oncol 2019;49:749-54.  Back to cited text no. 237
    
238.
Jiang Q, Zhang NL, Ma DY, Tan BX, Hu X, Fang XD. Efficacy and safety of apatinib plus docetaxel as the second or above line treatment in advanced nonsquamous NSCLC: A multi center prospective study. Medicine (Baltimore) 2019;98:e16065.  Back to cited text no. 238
    
239.
Fukuizumi A, Minegishi Y, Omori M, Atsumi K, Takano N, Hisakane K, et al. Weekly paclitaxel in combination with carboplatin for advanced non-small-cell lung cancer complicated by idiopathic interstitial pneumonias: A single-arm phase II study. Int J Clin Oncol 2019;24:1543-8.  Back to cited text no. 239
    
240.
Madrid E, Barros M, Urrútia G, Roqué I, Pérez B, Vargas P, et al. Taxanes for advanced non-small cell lung cancer. Cochrane Database Syst Rev 2018;2018:CD013075.  Back to cited text no. 240
    
241.
Temel JS, Greer JA, Muzikansky A, Gallagher ER, Admane S, Jackson VA, et al. Early palliative care for patients with metastatic non-small-cell lung cancer. N Engl J Med 2010;363:733-42.  Back to cited text no. 241
    
242.
Temel JS, Greer JA, El-Jawahri A, Pirl WF, Park ER, Jackson VA, et al. Effects of early integrated palliative care in patients with lung and GI cancer: A randomized clinical trial. J Clin Oncol 2017;35:834-41.  Back to cited text no. 242
    


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