|REVIEW ARTICLE: GUIDELINES
|Year : 2021 | Volume
| 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)
Kumar Prabhash1, Amish Vora2, Sewanti Limaye3, Tarini Prasad Sahoo4, Ullas Batra5, Shekhar Patil6, Vijay M Patil1, Vanita Noronha1, Bharat Bhosale7, Nirmal Vivek Raut8, Narayanankutty Warrier9, Bharat Vaswani10, Govind Babu11, Adwaita Gore12, Nitesh Rohatgi13, Shailesh Bondarde14
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 Submission||24-Mar-2020|
|Date of Decision||16-May-2021|
|Date of Acceptance||10-Jun-2021|
|Date of Web Publication||30-Jun-2021|
Department of Medical Oncology, Tata Memorial Hospital, Dr. Ernest Borges Road, Homi Bhabha National Institute, Parel, Mumbai, Maharashtra
Source of Support: None, Conflict of Interest: None
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 2022 May 18];4:279-314. Available from: https://www.crstonline.com/text.asp?2021/4/2/279/320155
| Introduction|| |
Non-small-cell lung cancers (NSCLCs) constitute about 85% of all lung cancers. 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. 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 and the South Asian Journal of Cancer in 2019. 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|| |
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|| |
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?
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]. In patients with no known driver mutations, immunotherapy with checkpoint inhibitors has revolutionized the treatment. 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. In India, the incidence of EGFR mutations ranges from 24.8% to 48% and is more frequent in patients with adenocarcinomas.,, In women and non-smokers, the prevalence of EGFR mutations is reported to be as high as 50%. 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). Other uncommon mutations that may be clinically relevant are exon 20 insertions, which are typically intrinsically resistant to EGFR-TKIs, and exon 18 alterations. Mutations in the BRAF gene and ALK rearrangements have been reported to occur in 2%–2.4%,,,, and 4%–10%, 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%,, 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.
|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.,,, In patients with advanced NSCLC, overexpression of PD-L1 is predictive of clinical benefit with PD-1/PD-L1 inhibitors. 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.
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., 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.,, ROS1 gene rearrangements are rare and mutually exclusive with EGFR mutations and ALK rearrangements. ROS1 IHC may be used to screen for the presence of ROS1 mutations in patients with NSCLC. However, positive results on IHC should be confirmed using a molecular (RT-PCR) or cytogenetic (FISH) method [Table 1]. 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]. 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., 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.
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., 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., 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. Real-world data also suggest that ctDNA is suitable for an upfront EGFR mutation analysis when a tumor tissue sample is unavailable., 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. 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., However, the type of mutations and gene rearrangements identified may vary based on the design of the NGS panel and assay protocol.
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. About 20% of the patients with NSCLC have brain metastasis at diagnosis, and about 40%–50% develop brain metastasis during the disease. 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)., 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.
- 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|| |
Which patients with advanced-stage non-small-cell lung cancer should be treated with only systemic chemotherapy?
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.,,,,,, 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). 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. 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. 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., 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. 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). Lower doses of paclitaxel administered weekly along with carboplatin resulted in similar efficacy and lesser neurotoxicity. 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.
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).,,, 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.
- 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?
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. 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.
Recently, several clinical studies evaluating the efficacy of PD-1/PD-L1 inhibitors in combination with standard chemotherapy regimens have been published., 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. 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. 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. 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%). An extended follow-up of 25.2 months suggested a significant survival benefit with pembrolizumab in patients with PD-L1 ≥50% [Table 2]. 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. 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). 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].
- 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?
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. 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%).
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].
- 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?
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. The updated data with a median follow-up of 25.2 months revealed longer OS in the pembrolizumab group than in the chemotherapy group. 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. 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].
|Table 3: Key results of clinical studies with pembrolizumab as monotherapy in advanced non-small-cell lung cancer and their clinical implications|
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- 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%).
What are the treatment recommendations in non-squamous advanced metastatic non-small-cell lung cancer with identified driver mutation/rearrangement?
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). 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. Therefore, it is important for patients harboring driver mutations to receive the appropriate targeted therapy first to achieve the best results.
- 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)?
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). Four head-to-head studies, namely the WJOG 5108L, CTONG 0901, Lux Lung 7, and FLAURA, compared the efficacy of EGFR-TKIs.,,, 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). 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). 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. 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]. 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]. 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%). Moreover, osimertinib was well tolerated with fewer grade ≥3 AEs than the comparator arm (42% vs. 47%).
|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. Osimertinib has demonstrated better penetration of the blood–brain barrier (BBB) compared to gefitinib and afatinib in preclinical studies and promising intracranial efficacy in patients with advanced NSCLC.,, 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. 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%). 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]. 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]. 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. 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). 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%). Thus, the benefit of the combination of TKIs with chemotherapy or bevacizumab should be weighed against the increased risk of grade 3 AEs.
- 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?
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.,,, In an analysis from the NEJ002 trial, gefitinib was found to be ineffective against both G719X and L861Q mutations. 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. The objective response to EGFR-TKIs in patients with exon 20 insertions is poor.,,, 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). 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.
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. 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. 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.
- 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?
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. 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. 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). 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). 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. 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).
- 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?
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). 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). 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. 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). 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). 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., 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.
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%). 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). 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. 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).
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). 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., 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. 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.
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.
- 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?
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. 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. 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%. Furthermore, the ORR with crizotinib was 80% and the median PFS was 9.1 months in heavily pretreated patients in a retrospective study. Across all clinical studies on patients with ROS1-positive NSCLC, crizotinib treatment has been shown to be well tolerated.,, Noronha et al. reported that crizotinib resulted in durable disease control and prolonged PFS in five patients with ROS1-rearranged NSCLC in India. 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. 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%.
- 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|| |
What investigations (not treatment) are recommended at the time of disease progression on first-line tyrosine kinase inhibitors?
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. 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. Amplification of the MET oncogene has been associated with resistance to third-generation EGFR-TKIs in 5%–10% of the cases. 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. In some patients, resistance may be mediated by HER2 mutation/amplification. 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. Several studies have demonstrated the utility of the minimally invasive plasma ctDNA-based liquid biopsy for the detection of EGFR T790M mutation., 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., 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.
- 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|| |
Which patients should be offered maintenance therapy?
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. 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]. Having demonstrated an OS benefit in the second- and third-line settings for advanced NSCLC, 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. 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. 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]., Maintenance with pemetrexed and bevacizumab was thereafter tested in three major phase III studies.,, 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]., 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). 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. Improved PFS was reported with pemetrexed + bevacizumab maintenance therapy in patients with advanced NSCLC [Table 5].,
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.
- 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|| |
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?
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., 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.,,
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., Nivolumab, an anti-PD-1 antibody, was the first ICI approved for the second-line treatment of NSCLC. 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. 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. 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. 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.,,
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%., In the KEYNOTE-010 study, the OS was significantly prolonged with pembrolizumab when compared to docetaxel. 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. 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. The 3-year OS rate was 18.7% and 10% for atezolizumab and docetaxel, respectively. 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). 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). The INTEREST and TITAN 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. 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. 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.
- 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?
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. Docetaxel alone, or ramucirumab + docetaxel, or gemcitabine alone, or platinum-based chemotherapy can also be recommended.
- 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?
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.,,,,,,, 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.,,, 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. 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%). 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). 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). 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.
- 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?
While ALK inhibitors are highly active in patients with ALK-positive NSCLC, almost all patients inevitably develop resistance to these inhibitors. 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. 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. 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. 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). 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., 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). 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.
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. 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. 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. 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. 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. 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. 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.
- 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?
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. 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., 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. 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%). 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). 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.
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.
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., However, the addition of WBRT to focal treatment did not yield an OS benefit. 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. 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. 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. Patients with NSCLC harboring EGFR/ALK mutations have a higher incidence of brain metastases during the course of their disease. In such patients, treatment with targeted therapy has been shown to improve the outcomes.,,, 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). 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. 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. 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. 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. Another second-generation ALK inhibitor, brigatinib, has shown promising intracranial disease activity in clinical studies., 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. Among 39 patients with measurable brain lesions, the intracranial response rate was 78% (14/18) with brigatinib and 29% (6/21) with crizotinib. Therefore, brigatinib has better intracranial activity than crizotinib and is efficacious in the treatment of ALK-positive NSCLC with brain metastases.
- 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?
Oligometastatic disease in NSCLC refers to the presence of one to five metastatic lesions away from the primary tumor site. Patients with oligometastatic NSCLC do not always appear to have a widespread disseminated disease. 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.,, Surgical resection or definitive radiotherapy of intracranial and extracranial oligometastatic disease has been shown to have a positive effect on survival rates.,,,,,,
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. SRS and surgery have been shown to result in long-term survival in such patients.,, Use of targeted agents combined with ablative doses of radiation in the oligometastatic setting has resulted in promising outcomes., 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. 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.
- 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|| |
What is role of radiation in stage-IV non-small-cell lung cancer?
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. 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., 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.,, 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.,, 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. 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).
- 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?
Surgical resection remains the treatment of choice in patients with stage I–IIIA NSCLCs. 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. 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. 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). 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. 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. 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%. 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.
- 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?
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. 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.
- 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?
Patients with a PS of 3–4 can be offered BSC in the absence of documented EGFR mutations or ALK rearrangements. 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). 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). 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.
- 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].
| Conclusion|| |
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.
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Conflicts of interest
There are no conflicts of interest.
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[Table 1], [Table 2], [Table 3], [Table 4], [Table 5], [Table 6]