|Year : 2019 | Volume
| Issue : 1 | Page : 36-53
Epidermal growth factor receptor-mutated non-small-cell lung cancer: A primer on contemporary management
Akhil Rajendra, Vanita Noronha, Amit Joshi, Vijay Maruti Patil, Nandini Menon, Kumar Prabhash
Department of Medical Oncology, Tata Memorial Hospital, Mumbai, Maharashtra, India
|Date of Web Publication||9-Sep-2019|
Department of Medical Oncology, Tata Memorial Hospital, Mumbai - 400 012, Maharashtra
Source of Support: None, Conflict of Interest: None
Non-small-cell lung cancer (NSCLC) constitutes 85% of patients diagnosed with lung cancer. In metastatic cases, its treatment classically consists of systemic cytotoxic chemotherapy, which resulted in a median overall survival of 7.9 months. However, over the last decade, improved understanding of driver mutations, especially identification of epidermal growth factor receptor (EGFR) mutation, has changed the treatment landscape of these patients. Our understanding of EGFR mutations has improved tremendously, and we now have three generations of EGFR tyrosine kinase inhibitors, have identified secondary resistance mutations, and have developed agents targeting these resistance mutations, making precision medicine a reality. We review these developments and try to propose an optimal approach toward the management of these patients with EGFR-mutated NSCLC.
Keywords: EGFR, LMIC, NSCLC, oral TKI
|How to cite this article:|
Rajendra A, Noronha V, Joshi A, Patil VM, Menon N, Prabhash K. Epidermal growth factor receptor-mutated non-small-cell lung cancer: A primer on contemporary management. Cancer Res Stat Treat 2019;2:36-53
|How to cite this URL:|
Rajendra A, Noronha V, Joshi A, Patil VM, Menon N, Prabhash K. Epidermal growth factor receptor-mutated non-small-cell lung cancer: A primer on contemporary management. Cancer Res Stat Treat [serial online] 2019 [cited 2021 May 6];2:36-53. Available from: https://www.crstonline.com/text.asp?2019/2/1/36/266465
| Introduction|| |
With an estimated 1.5 million deaths each year, lung cancer is the most common cause of cancer-related death worldwide. According to the GLOBOCAN report 2018, the estimated incidence of lung cancer in India was 67,795 in all ages and both sexes, and the crude incidence rate was 6.45/100,000, ranking third in cancer-related deaths with 63,475 deaths/year. Approximately 85% of patients with lung cancer have Non-small cell lung cancer (NSCLC), of which adenocarcinoma and squamous cell carcinoma are the most common subtypes. Tobacco smoking remains the dominant cause of all NSCLCs except in the case of adenocarcinoma which is associated with either fusion or mutation of the kinase genes such as epidermal growth factor receptor (EGFR), which are more commonly seen in light smokers and never smokers.
Treatment of advanced NSCLC historically comprised systemic cytotoxic chemotherapy which resulted in a median overall survival (OS) of 7.9 months. The success of imatinib in chronic myeloid leukemia has demonstrated the effectiveness of therapy which targets the critical genetic driver. An improved understanding of the molecular pathways that drive malignancy in NSCLC has led to the development of agents which specifically target these molecular pathways. This has changed the treatment landscape of patients with EGFR-mutant NSCLC and has paved the way for personalized, genotype-directed therapy.
Epidermal growth factor receptor Tumor growth and progression depends on cell surface receptors which control intracellular signaling, which regulates cell proliferation, apoptosis, angiogenesis, adhesion, and motility. EGFR (HER1 or erbB-1) tyrosine kinase is one such receptor. Other cell surface receptors include ALK, ROS1, Her2, MET, RET, and NTRK.
EGFR exists as a monomer, but needs dimerization to activate its tyrosine kinase activity. EGFR signaling begins with binding of cognate ligands (which include epidermal growth factor, transforming growth factor-α, and amphiregulin) to the receptor, resulting in homodimerization of two EGFRs or heterodimerization of EGFR with other family members (HER2, HER3, and HER4), activating a cascade of downstream signaling pathways (RAS-RAF-MEK-MAPK pathway, PI3K/PTEN/AKT pathway, and STAT pathway), resulting in cellular proliferation, differentiation, motility, survival, and angiogenesis.
Targeting EGFR was initially attempted based on the observation that EGFR is expressed more abundantly in cancerous lung tissue than in the adjacent normal lung. Therapy with an EGFR-directed oral tyrosine kinase inhibitor (oral TKI) in patients progressing after chemotherapy resulted in a response rate of 12%–18% with a median progression-free survival (PFS) and median OS of 2.7 months and 8 months, respectively., It was observed that a significant clinical benefit was seen in a subset of 10%–30% of patients. Somatic activating mutations in the EGFR tyrosine kinase domain (exons 18, 19, and 21) were identified and were implicated in the enhanced response to gefitinib in the earlier studies.,
Epidermal growth factor receptor mutation
The EGFR gene is present on chromosome 7p11.2 and has 28 exons coding for the transmembrane receptor protein. Exons 18–24 code for the tyrosine kinase domain. Mutations in exons 18–21 have a therapeutic significance for NSCLC. There are three classes of mutations: Class I mutations include short in-frame deletions in exon 19, Class II mutations are single-nucleotide substitutions occurring in exons 18–21, and Class III mutations are in-frame duplications and/or insertions in exon 20. The most common mutations are in-frame deletions (Class I) in exon 19 and point mutations in exon 21 (L858R). Both are activating mutations associated with sensitivity to EGFR oral TKI.
Worldwide, the incidence of EGFR mutation is influenced by the ethnicity of the population, varying from 10% to 15% in North Americans and Europeans, 19% in African Americans, and 30% in East Asians.,,, EGFR mutation occurs more frequently in women and nonsmokers. In the Asian population, the incidence of EGFR mutation is higher, as shown by the PIONEER study conducted among patients from China, Hong Kong, India, Philippines, Taiwan, Thailand, and Vietnam, with an overall incidence of 51%, ranging from 22% to 62%. The incidence rate in Indian patients is approximately 20%–23%.,
| Anti-Epidermal Growth Factor Receptor Agents|| |
The concept of targeting EGFR is a rather old strategy proposed almost 30 years ago. The various options currently at our disposal include monoclonal antibodies, TKIs, immunotherapy, and antisense therapy. Only the first two classes of agents have stood the test of time.
First-generation tyrosine kinase inhibitor (gefitinib, erlotinib, and icotinib)
Until the 2000s, the standard of care for patients with metastatic NSCLC was a platinum-based doublet chemotherapy for patients with a good performance status (PS) and best supportive care for patients with a poor PS. The four commonly used chemotherapy regimens including cisplatin–gemcitabine, cisplatin–paclitaxel, carboplatin–paclitaxel, and cisplatin–docetaxel resulted in similar response rates and survival. In fact, the survival outcomes were rather disappointing with a response rate of 19% and median OS of 7.9 months.
The use of anti-EGFR agents began before the availability of assays to detect the mutation; therefore, the studies were conducted in a molecularly unselected population of NSCLC patients, and the results were rather disappointing. As evidenced in the TRIBUTE trial, erlotinib added to carboplatin and paclitaxel compared to carboplatin and paclitaxel with a placebo did not confer any form of survival advantage. However, there appeared to be an improvement in survival from the combination of erlotinib with carboplatin and paclitaxel in the patients who were never smokers. Later, when the EGFR mutation analyses were available, tumor DNA was sequenced from a subset of patients in the TRIBUTE trial, and the mutation status was correlated with the clinical data. In the EGFR mutation-positive patients, the use of erlotinib was associated with an increased response rate (53% vs. 21%) and delayed time to progression (8 months vs. 5 months). Lynch et al. also demonstrated a similar result, where they found that the increased clinical responsiveness of gefitinib was directly associated with the presence of a sensitizing EGFR mutation.
Gefitinib and erlotinib were the first-generation TKIs which were used in these trials. First-generation TKIs function by blocking the adenosine triphosphate (ATP)-binding sites in the EGFR receptor and thus inhibit the activation of the downstream signaling pathways.
Four major trials support the use of gefitinib as a first-line agent in advanced metastatic NSCLC with EGFR mutation. The IPASS trial done in a population clinically enriched with nonsmokers or former light smokers and East Asian ethnicity conclusively proved the superiority of gefitinib compared to carboplatin and paclitaxel in the overall population and in the subgroup of EGFR mutation-positive patients, in terms of PFS (12-month PFS, 25% vs. 7%). However, the two groups had a similar OS (18.8 months vs. 17.4 months), which was attributed to the subsequent usage of TKI in the chemotherapy arm., First-SIGNAL, NEJ002, and WJTOG3405 all showed that the use of gefitinib as first-line therapy prolonged PFS with no apparent improvement in the OS. These trials are summarized in [Table 1].
|Table 1: Trials comparing gefitinib with chemotherapy in patients with advanced Non-small cell lung cancer|
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Our group conducted a Phase III trial in advanced EGFR-mutated Stage IIIB or IV lung adenocarcinoma, comparing gefitinib to the combination of carboplatin and pemetrexed followed by maintenance pemetrexed. The results of our trial similarly showed superiority of gefitinib over pemetrexed and carboplatin chemotherapy in terms of PFS (median PFS, 8.4 months vs. 5.6 months), with no improvement in OS., This was the first study which compared gefitinib to the then standard of care for nonsquamous NSCLC (carboplatin and pemetrexed followed by pemetrexed maintenance) proving the superiority of gefitinib over doublet chemotherapy in terms of PFS.
Erlotinib came into the therapeutic armamentarium with the Phase III BR.21 trial, in which metastatic NSCLC patients who had progressed on prior chemotherapy were assigned to erlotinib or to best supportive care. Erlotinib resulted in a response rate of 8.9% versus <1% with a median OS of 6.7 months compared to 4.7 months; hazard ratio (HR), 0.7; P < 0.001. Trials comparing erlotinib to chemotherapy as first-line therapy are summarized in [Table 2]. All the erlotinib trials, similar to the gefitinib trials, showed an improvement in PFS with no improvement in OS.
Icotinib is an oral selective EGFR TKI made in China. It is dosed at 125 mg three times a day. The CONVINCE trial, a Phase III, open-label, randomized trial conducted in 296 patients with Stage IIIB/IV lung adenocarcinoma with EGFR mutations in exons 19 or 21, recruited from 18 sites in China, compared icotinib to cisplatin with pemetrexed followed by pemetrexed maintenance in the first-line palliative setting. The median PFS was longer in the icotinib arm (11.2 vs. 7.9 months; HR: 0.61; 95% confidence interval [CI]: 0.43–0.87; P= 0.006). There was no significant difference in OS between the two groups; median OS was 30.5 months in the icotinib arm versus 32.1 months in the chemotherapy arm; P= 0.885.
For all the first-generation TKIs, the response to therapy did not differ according to the type of EGFR mutation.
Second-generation tyrosine kinase inhibitors
First-generation TKIs bind to and inhibit EGFR signaling in a reversible manner. Although first-generation TKIs result in a favorable and durable treatment response, eventually patients develop progressive disease within approximately a year of starting therapy. Thus, there was a need for the development of agents which could provide more long-term results. The most common mechanism of resistance to first-line TKI is the acquisition of mutation in exon 20, T790M mutation which was detected in approximately 50% of the patients with resistance. Second-generation TKIs, afatinib and dacomitinib, were considered capable of overcoming this mutation, because of the irreversible blockade of signaling from all relevant homodimers and heterodimers of the ErbB family of receptors.
The LUX-Lung 3 and LUX-Lung 6 trials were open-label Phase III studies that compared afatinib with platinum-based doublet chemotherapy (pemetrexed/cisplatin and gemcitabine/cisplatin, respectively). Both showed significantly prolonged PFS in the afatinib arm. These results are summarized in [Table 3].
|Table 3: Trials comparing afatinib with chemotherapy or first-generation oral tyrosine kinase inhibitor in advanced NSCLC|
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Combined analysis of the LUX Lung 3 and LUX Lung 6 results was performed to determine the OS data. Analysis did not show an improvement in the OS with the use of afatinib over chemotherapy. However, subgroup analyses showed that, in patients with EGFR del19 mutation, afatinib significantly improved the OS compared to chemotherapy; this prolongation of OS did not occur in patients with EGFR L858R exon 21 mutation (HR: 0.41; 95% CI: 0.31–0.55; P= 0.02).
LUX-Lung 7, a Phase IIb trial, comparing afatinib with gefitinib as first-line treatment, showed a very modest prolongation of PFS of 11 months versus 10.9 months (HR: 0.73; 95% CI: 0.57–0.95; P= 0.017) and a prolonged time to treatment failure (13.7 months vs. 11.5 months). Serious treatment-related adverse events occurred in 11% of patients in the afatinib arm compared to 4% in the gefitinib arm. Common Grade 3 or 4 toxicities with afatinib included diarrhea, rash, acne, and liver enzyme elevation. Increased side effects in afatinib have been attributed to the narrow therapeutic window and inhibition of wild-type EGFR.
Dacomitinib is another second generation TKI approved for use in patients with NSCLC with EGFR mutation. Evidence for its use comes from the ARCHER 1050 study, an open-label Phase III study conducted in seven countries (China, Hong Kong, Japan, South Korea, Poland, Italy, and Spain), in which 452 EGFR-mutant newly diagnosed advanced NSCLC patients were randomized 1:1 to dacomitinib or gefitinib. The median PFS was 14.7 months in the dacomitinib arm and 9.2 months in the gefitinib arm; HR, 0.59; 95% CI, 0.47–0.74; P < 0.0001. Treatment-related serious adverse events were reported in 9% of patients receiving dacomitinib compared to 4% in the gefitinib arm. The updated OS results showed a survival advantage for dacomitinib; 34.1 months versus 26.8 months; HR, 0.76; 95% CI, 0.582–0.993; P= 0.044. Despite these promising results, the global adoption of the use of dacomitinib seems to be limited, perhaps due to the increased toxicity of dacomitinib, the exclusion of patients with brain metastases in ARCHER 1050, and the emergence of the third-generation TKI, osimertinib.
Acquired resistance to first- and second-generation tyrosine kinase inhibitors
Most patients who are treated with oral EGFR TKIs develop resistance, limiting their long-term efficacy. The three mechanisms of acquired resistance include target gene modification, alternative pathway activation, and histological or phenotypic transformation. T790M mutation, which substitutes methionine for threonine at amino acid position 790, has been reported in 50% of EGFR-mutant patients with equal prevalence following the use of both first- and second-generation oral TKIs. This mutation leads to an enhanced affinity for ATP, thus hindering the competitive EGFR inhibitors. One potential strategy to overcome this was the development of second-generation TKIs which were irreversible inhibitors. However, these second-generation TKIs, both afatinib and dacomitinib, led to improvement in response rates of <10% and an improvement in PFS of approximately 5 months (afatinib: <1 month and dacomitinib: 5 months) over first-generation TKIs. With a view to improving efficacy, third-generation TKIs such as osimertinib, rociletinib, and olmutinib were designed which could specifically target T790M.
Third-generation oral tyrosine kinase inhibitor
Osimertinib was the first agent that was effective against the T790M mutation. In addition to inhibition of T790M mutation, it also inhibits EGFR-sensitizing mutations. In the Phase I/II AURA1 trial, osimertinib (80 mg once daily) administered to patients who had progressed on an EGFR TKI and who were T790M mutation positive led to an objective response rate of 62% (95% CI: 54–68) with a median PFS of 12.3 months (95% CI: 9.5–13.8). In addition, AURA3, a Phase III trial, was conducted in 419 patients with T790M-positive advanced NSCLC who had progressed after first-line EGFR TKI therapy and who were then randomized to osimertinib or chemotherapy consisting of a platinum–pemetrexed doublet. The PFS in the osimertinib arm was significantly longer at 10.1 months compared to 4.4 months in the chemotherapy arm; HR, 0.30; 95% CI, 0.23–0.41. Osimertinib also seems to have superior efficacy in terms of better PFS among patients with central nervous system (CNS) metastases, thus substantiating its ability to cross the blood–brain barrier as proven in the preclinical trials. These results culminated in the accelerated approval of osimertinib for use in patients who had progressed on first-line TKI with acquired T790M mutation.
The FLAURA trial was a Phase III trial, were 556 patients with previously untreated advanced adenocarcinoma lung with EGFR sensitizing mutation (exon 19 deletion or L858R) and good performance status(PS 0 or 1), were randomized to osimertinib or standard of care TKI (gefitinib or erlotinib). The median PFS was longer in the osimertinib-treated patients compared to the standard EGFR TKIs (18.9 months vs. 10.2 months; HR: 0.46; 95% CI: 0.37–0.57; P < 0.001). Grade 3 or 4 toxicities were also fewer in the patients treated with osimertinib compared to the standard EGFR TKI (34% vs. 45%). The 18-month OS was 83% in patients treated with osimertinib versus 71% in patients treated with standard oral TKI (HR: 0.63; 95% CI: 0.45–0.88; P= 0.007), which did not reach the level of statistical significance for the interim analysis (significance level set at P < 0.0015). A recent press release stated that osimertinib led to a statistically significant benefit in OS in the FLAURA trial; the details are not available currently and we await the presentation and publication of these data.
Third-generation tyrosine kinase inhibitor resistance
Despite the improved efficacy of third-generation TKIs, patients eventually progress, and new resistance mechanisms have been identified. These include HER2 amplification, c-MET amplification, KRAS G12S mutation, histological transformation to small cell, EGFR L718Q mutation, and C797S mutation. Among these, C797S is the most common mutation associated with resistance to osimertinib. Osimertinib and rociletinib bind covalently to the cysteine residue of the ATP-binding socket of EGFR. C797S mutation, where cysteine is replaced by serine, functions by altering the covalent anchor point for binding of the third-generation TKI.,
Prior treatment modality and genetic background have important implications for cancers that have acquired the C797S mutation. In case of the patients treated with third-generation TKI upfront, C797 mutation may develop in the absence of T790M mutation. For patients who received a first-line TKI upfront followed by third-generation TKI (on development of T790M mutation), the T790M and C797S mutation can have two different configurations. If both the mutations are in trans, combination of first- and third-generation TKI can restore EGFR inhibition, whereas if both the mutations are in cis, the cells will be refractory to any of the available EGFR TKIs.
Fourth-generation tyrosine kinase inhibitor
The emergence of C797S mutation led to the need for EGFR-targeted agents which could bypass this mutation. This culminated in the development of EAI045, a fourth-generation oral TKI which is an allosteric TKI and binds at a site away from the ATP-binding site and inhibits T790M. However, this medication has been found to be effective only when combined with cetuximab. Clinical efficacy of this compound is unknown currently.
| Combination Strategies With Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitor|| |
Oral TKIs prolong PFS, but do not seem to impact the OS. In an attempt to improve outcomes, various combination strategies have been tested, including the combination of oral TKI with chemotherapy and with vascular endothelial growth factor (VEGF) inhibitors.
Epidermal growth factor receptor tyrosine kinase inhibitor with chemotherapy There are two approaches to combine oral TKIs with chemotherapy: the concurrent approach and the intercalated approach. In the concurrent approach, chemotherapy and oral TKI are administered at the same time. In the intercalated approach, chemotherapy and TKI are administered at different time periods to ensure a pharmacodynamic separation. The earlier trials (INTACT 1, INTACT 2, TALENT, and TRIBUTE) which were performed using the concurrent approach showed that the concurrent administration of chemotherapy and TKI did not result in a survival advantage; however, these trials were conducted in a molecularly unselected patient population, because they were started prior to routine EGFR testing.,, The intercalated approach (FASTACT 2), in which erlotinib was administered from day 15 to day 28 orally along with gemcitabine (1250 mg/m 2 intravenously on day 1 and day 8) and carboplatin (dosed at area under the curve 5 intravenously on day 1) or cisplatin (75 mg/m 2 intravenously on day 1) every 4 weeks, led to a survival advantage of 11.2 months. A randomized Phase II trial by Cheng et al. compared the combination of gefitinib and pemetrexed with gefitinib alone in EGFR-mutant advanced NSCLC. There was a significant prolongation of the PFS (15.8 months vs. 10.9 months; HR: 0.68, 95% CI: 0.48–0.96, P= 0.014). Recently, the NEJ009 trial (reported only in abstract form), a Phase III trial done in 345 Japanese patients with PS 0 or 1 (patients with brain metastases were permitted) who were randomized to gefitinib with pemetrexed and carboplatin chemotherapy or to gefitinib alone, showed a significant improvement in the median PFS (20.9 months vs. 11.2 months; HR: 0.494; 95% CI: 0.390–0.623; P < 0.001) and in median OS (52.2 months vs. 38.8 months; HR: 0.695; 95% CI: 0.520–0.927; P= 0.013) in the combination arm compared to the gefitinib-alone arm. Similarly, a Phase III trial conducted by our group at the Tata Memorial Hospital in Mumbai, Maharashtra, India, in 350 Indian patients with PS 0–2 (patients with brain metastases were allowed and 21% of the patients were PS 2) comparing gefitinib plus chemotherapy (pemetrexed + carboplatin) to gefitinib alone, showed an improvement in the median PFS (16 months vs. 8 months; HR: 0.51; 95% CI: 0.39–0.66; P < 0.001) and the median OS (not reached vs. 17 months; HR: 0.45; 95% CI: 0.31–0.65; P < 0.001). At the time of progressive disease, patients with PS of 0–2 were similar in both the arms (68% in the gefitinib + chemotherapy arm vs. 66% in the gefitinib arm). Thus, there are now two Phase III studies, both of which prove that the combination of oral TKI with chemotherapy prolongs both PFS and OS; therefore, the combination of pemetrexed with carboplatin and gefitinib could represent the new standard first-line therapy option for EGFR-mutant advanced NSCLC. These results are summarized in [Table 4].
|Table 4: Trials comparing tyrosine kinase inhibitor + chemotherapy combination with chemotherapy alone or tyrosine kinase inhibitor alone in advanced NSCLC|
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Epidermal growth factor receptor tyrosine kinase inhibitor with bevacizumab
Tumor angiogenesis plays a key role in both local tumor growth and in the development of distant metastases. The VEGF is a potent and specific mitogen which targets the endothelial cells to improve the vascular permeability. Bevacizumab is a humanized anti-angiogenic monoclonal antibody developed against VEGF. The role of bevacizumab in the management of NSCLC was established in the Phase III Eastern Cooperative Oncology Group (ECOG) 4599 and AVAiL trials, which showed that addition of bevacizumab to chemotherapy resulted in an increase in the response rate and prolongation of PFS., EGFR and VEGF share a common downstream pathway implicating an increased upregulation of VEGF as a possible explanation of resistance to EGFR blockade. Preclinical data on lung cancer models showed that the combination of erlotinib and bevacizumab resulted in a good response. The BeTa trial, a Phase III trial comparing the combination of erlotinib with bevacizumab to erlotinib alone in the second-line setting for NSCLC (not selected for EGFR mutation status), showed similar OS; 9.3 months in the bevacizumab group and 9.2 months in the erlotinib group; HR, 0.97; 95% CI, 0.8–1.18; P= 0.7583. The PFS in the bevacizumab group was longer at 3.4 months compared to the control erlotinib group at 1.7 months; HR, 0.62; 95% CI, 0.52–0.75. A post hoc analysis showed a substantially prolonged PFS with the erlotinib–bevacizumab combination in comparison to erlotinib alone (17.1 months vs. 9.7 months) for EGFR mutation-positive NSCLC., Subsequently, the JO25567 trial, an open-label phase II trial from Japan in EGFR mutation-positive NSCLC, showed an improvement in the PFS in the erlotinib plus bevacizumab arm compared to the erlotinib alone arm (16 months vs. 9.7 months; HR: 0.54; 95% CI: 0.36–0.79; P= 0.0015). Rash (25%), hypertension (60%), and proteinuria (8%) were the predominant Grade 3 and 4 adverse events that occurred in the combination arm. The interim analysis of NEJ026, a Phase III trial performed in Japan, showed a PFS benefit (16.9 months vs. 13.3 months; HR: 0.605; 95% CI: 0.417–0.877; P= 0.016). These results are summarised in [Table 5].
|Table 5: Trials comparing oral tyrosine kinase inhibitor + bevacizumab with oral tyrosine kinase inhibitor alone in advanced NSCLC|
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Epidermal growth factor receptor tyrosine kinase inhibitor with ramucirumab
Ramucirumab is a recombinant immunoglobulin which binds with high affinity to the extracellular domain of VEGF receptor-2, preventing the binding of VEGF-A, C, and D. Ramucirumab was used in combination with docetaxel in the second-line setting in the REVEL study and led to an improvement in the OS and PFS by 1.4 and 1.5 months, respectively. In the recently presented RELAY trial, ramucirumab combined with erlotinib was compared to erlotinib alone. 449 patients were randomized to both arms (RAM + E: 224 and E alone: 225). Patients with CNS metastases were not permitted. There was a significant improvement in the PFS in the RAM + E arm compared to the E alone arm; 19.4 versus 12.4 months; HR, 0.591; 95% CI, 0.461–0.760; P < 0.0001. OS data were immature.
Immunotherapy in epidermal growth factor receptor-mutant NSCLC
Immune checkpoint inhibitors that target the programmed death-1 (PD-1) and programmed death ligand-1 (PD-L1) have shown survival benefits over chemotherapy in advanced NSCLC in several Phase III trials. Pooled analysis of five clinical trials (Checkmate 017, Checkmate 057, Keynote 010, OAK, and POPLAR) showed that prolongation of the OS conferred by the use of immune checkpoint inhibitors was not evident in the EGFR-mutant subgroup (HR: 1.11; 95% CI: 0.8–1.53; P= 0.54) compared to the EGFR wild-type subgroup (HR: 0.67; 95% CI: 0.6–0.75; P < 0.001).,,,,, This could be explained by the low PD-1/PD-L1 expression, low tumor mutation burden, and the uninflamed tumor microenvironment seen in EGFR-mutant patients.,,,
Resistance mutations present at baseline
Although the presence of EGFR-sensitizing mutations predicts increased responsiveness to oral EGFR TKIs, not all tumors with an EGFR mutation are associated with an enhanced response. Tumors that fail to respond to EGFR TKIs tend to have genetic alterations affecting a downstream pathway or an additional genetic alteration which relieves the tumor of its dependence on the EGFR signaling pathway.
Exon 20 insertion mutations
One mechanism which confers primary resistance is the presence of insertion point mutations in exon 20 of the EGFR gene. Exon 20 insertion mutations are heterogeneous at the molecular level, but are characterized by in-frame insertions or duplications between 3 and 21 base pairs clustered between amino acid positions 762–774 of the EGFR proteins. The insertion mutation includes D770_N771(ins NPG), D770_(insSVQ), and D770_(ins G) N771T; the most common mutation is D770_N771(ins NPG) (25.5%). The incidence of this mutation ranges from 4% to 10% of all observed EGFR mutations in NSCLC.,,, Retrospective data published by our group from the Tata Memorial Hospital, Mumbai, describing the types of EGFR mutations in 580 patients with NSCLC, reported the incidence of exon 20 insertion mutation to be 3.4%.
Exon 20 mutation results in the inward movement of the C-Helix, which results in the constitutive activation of the EGFR receptor. However, despite the constitutive activation, its affinity to EGFR TKI is decreased leading to de novo resistance. With the exception of A763_Y764insFQEA mutation, in all other exon 20 mutations, first-generation oral TKIs seem to be ineffective with response rates between 8% and 27% and a median PFS of <3 months., The response rates of second-generation TKIs were also dismal in this subset of patients (8.7% response rate, 2.7 months PFS)., Preclinical models have shown poor response of third-generation TKIs as well in lung cancers harboring exon 20 insertion mutations.,
De novo T790M mutation
T790M mutation constitutes 50% of the acquired resistance mutations after TKI therapy. This mutation is considered to develop under selection pressure when on treatment with TKI. There is an increasing evidence to show that T790M mutation may exist in low frequency prior to EGFR-TKI treatment, but becomes the dominant clone after exposure to these agents. The rate at which de novo T790M mutations are encountered depends on the population screened and the method used for mutation detection. With direct sequencing, this mutation can be identified in 0.4%–3% of all NSCLCs and in 1%–8% of all EGFR-mutant NSCLCs. If more sensitive techniques such as mass spectrometry, mutant-enriched polymerase chain reaction (PCR), and colony hybridization assays are used, T790M mutation can be detected in 31%–79% of the patients with activating EGFR mutations.,,,,,
Germline EGFR T790M mutations have been reported in association with familial NSCLC. Among the patients with de novo T790M mutation, 50% can be attributed to germline mutation. Patients with germline EGFR mutation can present with bilateral ground-glass opacities and pulmonary nodules, and their disease tends to follow an indolent course. The highest incidence of germline T790M mutation is found among those patients who have pretreatment EGFR T790M somatic mutations. Thus, it becomes imperative to perform germline testing in all patients with de novo EGFR T790M mutation.
The above-mentioned trials clearly show the inferior outcomes associated with the presence of de novo T790M mutation. In these patients, treatment with reversible TKI may not be optimal and use of cytotoxic chemotherapy may be considered. The newer oral TKIs such as osimertinib and rociletinib may be options. In the AURA1 trial, there were seven patients with de novo T790M. Osimertinib as a first-line treatment resulted in a response in six of the seven patients. Thus, the response rate was 85.7%, and the duration of response ranged from 6.9 to 27.7 months [Table 6] and [Table 7].
|Table 6: Trials showing the outcome of patients with de novo T790M mutations in advanced NSCLC|
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|Table 7: Comparison between the various tyrosine kinase inhibitors available - dose, major side effects, dose modification, cost (Indian rupees), central nervous system penetration|
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Other causes for baseline resistance to tyrosine kinase inhibitor
Activation of alternative pathways thereby nullifying the dependence of the tumor on the EGFR pathway is another mechanism of de novo resistance to TKI. K-Ras (6.7%) and PIK3CA (4.1%) mutations are important, but rare mutations which could lead to baseline resistance.,
Uncommon mutations and how to treat them
Most of the Phase III studies of EGFR TKIs include patients with either deletion in exon 19 or L858R mutation in exon 21 of EGFR. These mutations are called the common EGFR-sensitizing mutations, which represent 85%–90% of all EGFR mutations in NSCLC., Many other uncommon mutations have also been reported which include G719X in exon 18 (G719C, G719S, and G719A), L861Q in exon 21, S768I in exon 20, and exon 20 insertions. The frequency of these uncommon mutations has been reported to range from 1% to 10%, although compound mutations can have a frequency of 30% among the EGFR-mutated patients. In a retrospective study done by our team at the Tata Memorial Hospital, Mumbai, the most frequent uncommon mutations observed were complex dual mutations (50.6%), followed by exon 20 insertions (19.3%), exon 20 T790M (12%), and exon 18 G719X (9.6%). Within the subgroup of dual mutations, the largest subset of patients consisted of exon 19 deletion in combination with exon 20 T790M mutation (20.4%) followed by exon 21 L858R mutation (18.4%) also in combination with exon 20 T790M mutation. Initially, in view of the poor response to earlier generation oral TKIs (response rate, 32.4%; median PFS, 3.9 months; median OS, 17.4 months), platinum-based chemotherapy was considered the appropriate first-line treatment. However, additional studies have found that this subgroup of patients constitute a heterogeneous group with differential sensitivity and varied responses to treatment. Among these rare mutations, G719X and L861Q have been found to have responsiveness to erlotinib and gefitinib. However, the NEJ002 trial showed that gefitinib was ineffective against both the above-mentioned mutations. Post hoc analysis from Lux-lung 2, Lux-Lung 3, and Lux-Lung 6 trials showed the activity of afatinib in patients with G719X, L861Q, and S768I mutations with median PFS of 13.8 months, 8.2 months, and 14.7 months, respectively. Thus, this subset of patients can be treated with afatinib as first-line therapy. Another subset of patients who have been found to have response to TKI therapy are the patients with complex mutations. TKI-sensitive dual and complex TKI-sensitive and insensitive mutations tend to have greater response to oral TKI therapy. In contrast, exon 20 insertions, exon 20 S768I, and exon 21 L861Q were associated with unfavorable responses to oral TKI therapy with median PFS of <6 months.
There was a Phase II trial of osimertinib in 36 patients with uncommon EGFR mutations, defined as an activating EGFR mutation other than exon 19 deletion, L858R, T790M, and insertion in exon 20. The response rate was 50% (95% CI: 32.8–67.2), and the disease control rate was 88.9% (95% CI: 78.1–99.7). Responses were noted in 7 (77.8%) patients with L861Q mutation who had a partial response, 10 (52.6%) with G719A/C/D/S/X mutation, and 3 (37.5%) with S768I mutation. The median PFS was 9.5 months (range, 1.0–20.1), and the median duration of response was 7 months (95% CI: 4.7–9.3). Thus, osimertinib is a reasonable option in patients with uncommon EGFR-sensitizing mutations.,
Several drugs in the development phase appear to have promising activity, especially in exon 20 insertions. TAK-788, an oral investigational EGFR/Her2 inhibitor, may have efficacy in patients with EGFR exon 20 insertions. In the recently presented Phase I/II study in patients with advanced untreated NSCLC with EGFR exon 20 insertions, the objective response rate was 54% (95% CI: 33.37–73.41), and the disease control rate was 89%. The median time to response was 56 days. About 10.7% of the patients discontinued TAK-788 due to adverse events and the common severe adverse events included diarrhea (26%) and hypokalemia, nausea, and stomatitis in 7% each. Early results from a Phase II trial in patients with metastatic NSCLC with mutations/insertions in EGFR or Her2 exon 20, except T790M, showed that poziotinib led to an objective response rate at 8 weeks of 58% (95% CI: 40.9–73) and a disease control rate of 90%. The median PFS was 5.6 months (95% CI: 5.06 to NA). Grade 3 and higher toxicities occurred in 60% of the patients, commonly skin rash in 27.5% and diarrhea in 12.5%. The results from the phase II ZENITH20 trial are awaited.
Another approach to managing patients with uncommon EGFR mutations may be to use the combination of an oral TKI with chemotherapy, because the study of gefitinib versus gefitinib with pemetrexed and carboplatin chemotherapy included patients with rare EGFR mutations.
Specific diagnostic tests for the detection of epidermal growth factor receptor mutation
Epidermal growth factor receptor testing
EGFR mutation testing has evolved from a single gene test to multiplex hotspot mutation testing. There is no consensus as to which is the best method for EGFR mutation detection. EGFR mutation testing techniques can be classified as:
- Nontargeted assays:
- Sanger sequencing
- Targeted assay (PCR based)
- Next-generation sequencing (NGS).
Sanger sequencing was the method of choice for the detection of EGFR mutations in the early clinical trials with erlotinib and gefitinib., Steps involved in this technique include extraction of DNA followed by DNAase PCR-based amplification and sequencing. However, this is a multistep process which makes it time-consuming. It requires a large sample amount for analysis, and the tumor sample needs to have more than 25% mutant DNA for optimal mutation detection. The main advantage of Sanger sequencing is identification of all known and previously unknown mutations in the studied region.
Pyrosequencing is a DNA-sequencing technology based on sequencing by synthesis principle. This technique is a real-time bioluminescence technique, in which the phosphate released during nucleotide incorporation in a growing DNA is converted to light through a series of enzymatic reactions. Pyrosequencing identifies individual bases or short stretches of nucleic acid sequences. This simple technique is robust, fast, sensitive, and cost-effective, which helps in detecting the mutation, along with characterization and quantification of the mutation.,,
Targeted assays are much more sensitive than direct sequencing and require only 5%–10% of the mutant tumor DNA. Targeted assays can identify prespecified mutations in a short period of time within a single assay, but are unable to identify novel mutations.,
Commercially available EGFR-targeted assays include:
- Cobas EGFR mutation testing
- Therascreen EGFR mutation testing
- MassARRAY system
- SNaPshot Multiplex kit
- Quantitative PCR (Taqman).
NGS or massive parallel sequencing technology enables the detection of multiple genetic alterations in both the constitutional and cancer genome. The technique analyzes numerous DNA molecules simultaneously and can detect all the clinically relevant genetic alterations such as single-nucleotide alteration, copy number changes, and genetic rearrangements in multiple genes. However, its effective implementation requires good-quality DNA, preferably from a tumor-rich sample. In samples with a low tumor content, careful analysis would be needed making the whole process tedious and thus increasing the overall cost.
Plasma-based epidermal growth factor receptor testing
Genotyping of cell-free DNA (cfDNA) present in the blood and other body fluids is another technique which has emerged as an alternative. The principle underlying this methodology is that free DNA which is released after cell death or apoptosis can help in detecting EGFR mutations in a noninvasive manner., Plasma genotyping assays are associated with excellent specificity (>95%) and moderately high sensitivity (70%–80%).,, Owing to such high specificity and its relevance, the Food and Drug Administration has approved well-validated assays (Cobas, Thermo Fisher Scientific) for the detection of EGFR mutation status in patients with advanced NSCLC when tumor genotyping is not possible. However, the approval also recommends the performance of standard genotyping in the event of a negative result in view of the moderate sensitivity.
Central nervous system penetration of tyrosine kinase inhibitors
Approximately one-third of the patients harboring EGFR TKI-sensitizing mutations develop disease progression during treatment in the form of brain metastasis. For successful treatment of brain metastasis, the oral TKI must be able to cross the blood–brain barrier. The first-generation and second-generation TKIs (gefitinib, erlotinib, and afatinib) are considered to have poor biopharmaceutical properties for penetrating the blood–brain barrier, mostly due to their interaction with P-glycoprotein and breast cancer resistance protein. In view of the poor penetration of first and second generation of TKI, whole-brain radiotherapy remains the standard for patients with symptomatic brain metastasis. However, this approach is fraught with the risk of development of neurocognitive deficits and persistence of neurological deficits.
Among the first-generation TKI, erlotinib achieves good CNS concentration. In a case series of nine patients with EGFR-mutant NSCLC who had CNS progression (brain metastasis or leptomeningeal disease) on conventional dosing of erlotinib, pulsatile high-dose erlotinib was administered (1500 mg orally weekly); 6 (66%) out of 9 patients had partial response. The median time to CNS progression was 2.7 months (0.8–14.5 months), and the treatment was well tolerated. In preclinical studies, osimertinib was found to achieve greater penetration of the mouse blood–brain barrier and also induced sustained tumor regression in EGFR-mutant mouse brain metastasis., In the subset analysis of the FLAURA trial (116 treatment-naïve patients with EGFR-mutated advanced NSCLC and CNS metastases), there was prolongation of PFS in the osimertinib arm in comparison to the gefitinib or erlotinib arm (15.2 vs. 9.6 months; HR: 0.47; 95% CI: 0.30–0.74), along with prolonged median CNS PFS (not reached vs. 13.9 months; HR: 0.48; 95% CI: 0.26–0.86) and lower rate of CNS progression. The use of osimertinib upfront as therapy for CNS metastasis has not been tested or proven in randomized trials. However, given the excellent CNS response identified in the above-mentioned trials, it can be considered as an option in this setting.
Special populations – Patients with poor performance status and elderly patients
Despite major developments in the management of NSCLC over the years, optimal treatment for patients with poor PS and elderly patients is not clear. Elderly patients and patients with poor PS (ECOG PS ≥2) have historically been excluded from all major trials, resulting in lack of data for this subset of patients. However, in the case of NSCLC with EGFR mutation, some of the trials have included elderly patients and PS 2 patients in view of relative ease of administration of TKIs with a favorable toxicity profile. IPASS, EURTAC, and OPTIMAL trials included both elderly patients over 65 years of age (23%–50% of total patients) and patients with PS 2 (7%–14% of total patients). These trials showed that oral TKIs led to a survival advantage. Gefitinib seemed to be well tolerated in the elderly; liver enzyme derangement and skin reactions were the major side effect. Conversely, erlotinib resulted in more severe toxicity resulting in dose reductions.,, Similarly, subgroup analysis of the Lux-Lung 3, 6, and 7 trials showed that afatinib resulted in Grade 3/4 toxicity in half of the elderly patients, with diarrhea and skin rash being the most common toxicities.
The TOPICAL study was performed in advanced NSCLC patients who were unfit for chemotherapy due to poor PS (PS >2) and/or multiple comorbidities; patients with brain metastases were not permitted. Only 7% of patients had activating EGFR mutations. Six hundred and seventy patients were randomized to either erlotinib (E) arm or to placebo (P). The use of erlotinib resulted in a PFS of 2.8 months compared to 2.6 months in the placebo arm (unadjusted HR: 0.83; 95% CI: 0.71–0.97, P= 0·019; adjusted HR: 0.80; 95% CI: 0.68–0.93; P= 0.0054) and similar OS in both the groups, 3.7 (E) months versus 3.6 (P) months; HR, 0.94; 95% CI, 0.81–1.10; P= 0.46. Patients who received erlotinib and developed rash in the first cycle (within the first 28 days of therapy) had a better OS (HR: 0.76; 95% CI: 0.63–0.92; P= 0.0058), compared to placebo. Similarly, the TIMELY study, a single-arm phase II trial of afatinib in patients with advanced NSCLC unfit for chemotherapy, showed a median PFS of 7.9 months (95% CI: 4.6–10.2 months) with a median OS of 15.5 months (95% CI: 10.9–25.1 months). However, the rate of toxicity was high with 59% of patients experiencing at least one Grade 3 or 4 toxicity.
AURA3 and FLAURA studies included patients with advanced age (35–88 years and 25–85 years, respectively). The survival benefit provided with osimertinib was maintained across different age groups with comparable toxicities.,
Optimal therapy for a patient with epidermal growth factor receptor mutation in first-line palliative setting
In EGFR mutation-positive advanced NSCLC, the use of TKIs has been well established with the results of the randomized clinical trials comparing various TKIs (gefitinib, erlotinib, afatinib, dacomitinib, and osimertinib) against chemotherapy. However, with emergence of drug resistance to oral TKI within approximately 1–1.5 years of therapy, we need alternatives to prolong survival. Combining therapies with nonoverlapping mechanisms may help us in tackling the issue of intratumor heterogeneity and de novo resistant clones. The earlier generation oral TKIs including gefitinib, erlotinib, and afatinib have been shown to be equiefficacious., The newer TKIs, dacomitinib  and osimertinib, and the combination strategy of oral TKI with chemotherapy , lead to prolongation of PFS and OS when compared to the first-generation oral TKIs. There is no head-to-head comparison between these two approaches (osimertinib or dacomitinib vs. the combination of gefitinib with chemotherapy). However, given the low toxicity and convenience of taking only an oral medication, osimertinib may be the preferred first-line option in countries where it is available and where the patients can afford the medication or are reimbursable. With two randomized Phase III trials showing improvement of PFS and OS with the use of combination of oral TKI with chemotherapy (carboplatin + pemetrexed), this represents a valid alternative first-line therapy for EGFR-mutant NSCLC., In low–middle-income countries and places where osimertinib is not available or not affordable for the majority of patients, the preferred option in the first line should be a combination of oral TKI with chemotherapy in fit patients.
In case of patients with PS >2, the use of oral TKI alone may be considered as these patients may not tolerate the toxicity associated with chemotherapy. In case of uncommon mutations such as G719X, S768I, and L861Q, afatinib, osimertinib, or the combination of oral TKI with chemotherapy may be considered. In patients with de novo T790M mutation or exon 20 insertions, osimertinib or chemotherapy may be the preferred treatment of choice.
| Conclusion|| |
Management of NSCLC has come a long way, which is clearly seen in the improvement in the OS with the use of different agents. Tumors harboring sensitizing EGFR mutation have particularly improved responses with the use of anti-EGFR TKIs. However, most patients eventually develop resistance within about 1 year of treatment initiation. Two main strategies have been used to prolong this 1-year PFS timeline. First, the use of second- and third-generation TKIs, which has provided encouraging results, albeit with the inherent risk of development of resistance to these newer agents. Second, combination of TKIs with chemotherapy or anti-VEGF agents (bevacizumab or ramucirumab) which has resulted in mixed responses. Future studies must be aimed at tackling these problems. Other mechanisms of resistance apart from T790M, like c-met, PI3CA, and Her2 amplification, must also be targeted in future.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
| References|| |
Siegel RL, Miller KD, Jemal A. Cancer statistics, 2019. CA Cancer J Clin 2019;69:7-34.
Schiller JH, Harrington D, Belani CP, Langer C, Sandler A, Krook J, et al.
Comparison of four chemotherapy regimens for advanced non-small-cell lung cancer. N Engl J Med 2002;346:92-8.
Druker BJ, Talpaz M, Resta DJ, Peng B, Buchdunger E, Ford JM, et al.
Efficacy and safety of a specific inhibitor of the BCR-ABL tyrosine kinase in chronic myeloid leukemia. N Engl J Med 2001;344:1031-7.
da Cunha Santos G, Shepherd FA, Tsao MS. EGFR mutations and lung cancer. Annu Rev Pathol Mech Dis 2011;6:49-69.
Rusch V, Baselga J, Cordon-Cardo C, Orazem J, Zaman M, Hoda S, et al.
Differential expression of the epidermal growth factor receptor and its ligands in primary non-small cell lung cancers and adjacent benign lung. Cancer Res 1993;53:2379-85.
Kris MG, Natale RB, Herbst RS, Lynch TJ Jr., Prager D, Belani CP, et al.
Efficacy of gefitinib, an inhibitor of the epidermal growth factor receptor tyrosine kinase, in symptomatic patients with non-small cell lung cancer: A randomized trial. JAMA 2003;290:2149-58.
Fukuoka M, Yano S, Giaccone G, Tamura T, Nakagawa K, Douillard JY, et al.
Multi-institutional randomized phase II trial of gefitinib for previously treated patients with advanced non-small-cell lung cancer (The IDEAL 1 trial) [corrected]. J Clin Oncol 2003;21:2237-46.
Lynch TJ, Bell DW, Sordella R, Gurubhagavatula S, Okimoto RA, Brannigan BW, et al.
Activating mutations in the epidermal growth factor receptor underlying responsiveness of non-small-cell lung cancer to gefitinib. N Engl J Med 2004;350:2129-39.
Paez JG, Jänne PA, Lee JC, Tracy S, Greulich H, Gabriel S, et al.
EGFR mutations in lung cancer: Correlation with clinical response to gefitinib therapy. Science 2004;304:1497-500.
Gazdar A. Activating and resistance mutations of EGFR in non-small-cell lung cancer: role in clinical response to EGFR tyrosine kinase inhibitors. Oncogene 2009;28(Suppl 1):S24-31.
Cortes-Funes H, Gomez C, Rosell R, Valero P, Garcia-Giron C, Velasco A, et al.
Epidermal growth factor receptor activating mutations in Spanish gefitinib-treated non-small-cell lung cancer patients. Ann Oncol 2005;16:1081-6.
Dong J, Hu Z, Wu C, Guo H, Zhou B, Lv J, et al.
Association analyses identify multiple new lung cancer susceptibility loci and their interactions with smoking in the Chinese population. Nat Genet 2012;44:895-9.
Reinersman JM, Johnson ML, Riely GJ, Chitale DA, Nicastri AD, Soff GA, et al.
Frequency of EGFR and KRAS mutations in lung adenocarcinomas in African Americans. J Thorac Oncol 2011;6:28-31.
Shi Y, Au JS, Thongprasert S, Srinivasan S, Tsai CM, Khoa MT, et al.
A prospective, molecular epidemiology study of EGFR mutations in Asian patients with advanced non-small-cell lung cancer of adenocarcinoma histology (PIONEER). J Thorac Oncol 2014;9:154-62.
Noronha V, Prabhash K, Thavamani A, Chougule A, Purandare N, Joshi A, et al.
EGFR mutations in Indian lung cancer patients: Clinical correlation and outcome to EGFR targeted therapy. PLoS One 2013;8:e61561.
Sahoo R, Harini VV, Babu VC, Patil Okaly GV, Rao S, Nargund A, et al.
Screening for EGFR mutations in lung cancer, a report from India. Lung Cancer 2011;73:316-9.
Herbst RS, Prager D, Hermann R, Fehrenbacher L, Johnson BE, Sandler A, et al.
TRIBUTE: A phase III trial of erlotinib hydrochloride (OSI-774) combined with carboplatin and paclitaxel chemotherapy in advanced non-small-cell lung cancer. J Clin Oncol 2005;23:5892-9.
Eberhard DA, Johnson BE, Amler LC, Goddard AD, Heldens SL, Herbst RS, et al.
Mutations in the epidermal growth factor receptor and in KRAS are predictive and prognostic indicators in patients with non-small-cell lung cancer treated with chemotherapy alone and in combination with erlotinib. J Clin Oncol 2005;23:5900-9.
Mok TS, Wu YL, Thongprasert S, Yang CH, Chu DT, Saijo N, et al.
Gefitinib or carboplatin-paclitaxel in pulmonary adenocarcinoma. N Engl J Med 2009;361:947-57.
Fukuoka M, Wu YL, Thongprasert S, Sunpaweravong P, Leong SS, Sriuranpong V, et al.
Biomarker analyses and final overall survival results from a phase III, randomized, open-label, first-line study of gefitinib versus carboplatin/paclitaxel in clinically selected patients with advanced non-small-cell lung cancer in Asia (IPASS). J Clin Oncol 2011;29:2866-74.
Patil VM, Noronha V, Joshi A, Choughule AB, Bhattacharjee A, Kumar R, et al.
Phase III study of gefitinib or pemetrexed with carboplatin in EGFR-mutated advanced lung adenocarcinoma. ESMO Open 2017;2:e000168.
Patil V, Noronha V, Joshi A, Chougule A, Bhattacharjee A, Goel A, et al
. Quality-adjusted time without symptoms or toxicity (Q-TWiST) analysis of a Phase III randomized trial to compare the benefit of gefitinib versus pemetrexed/carboplatin for epidermal growth factor receptor-mutated non-small cell lung cancer. Cancer Res Stat Treat 2019;2:21-7. [Full text]
Maemondo M, Inoue A, Kobayashi K, Sugawara S, Oizumi S, Isobe H, et al.
Gefitinib or chemotherapy for non-small-cell lung cancer with mutated EGFR. N Engl J Med 2010;362:2380-8.
Inoue A, Kobayashi K, Maemondo M, Sugawara S, Oizumi S, Isobe H, et al.
Updated overall survival results from a randomized phase III trial comparing gefitinib with carboplatin-paclitaxel for chemo-naïve non-small cell lung cancer with sensitive EGFR gene mutations (NEJ002). Ann Oncol 2013;24:54-9.
Han JY, Park K, Kim SW, Lee DH, Kim HY, Kim HT, et al.
First-SIGNAL:First-line single-agent iressa versus gemcitabine and cisplatin trial in never-smokers with adenocarcinoma of the lung. J Clin Oncol 2012;30:1122-8.
Yoshioka H, Mitsudomi T, Morita S, Yatabe Y, Negoro S, Okamoto I, et al
. Final overall survival results of WJTOG 3405, a randomized phase 3 trial comparing gefitinib (G) with cisplatin plus docetaxel (CD) as the first-line treatment for patients with non-small cell lung cancer (NSCLC) harboring mutations of the epidermal growth factor receptor (EGFR). J Clin Oncol 2014;32 Suppl 15:8117.
Mitsudomi T, Morita S, Yatabe Y, Negoro S, Okamoto I, Tsurutani J, et al.
Gefitinib versus cisplatin plus docetaxel in patients with non-small-cell lung cancer harbouring mutations of the epidermal growth factor receptor (WJTOG3405): An open label, randomised phase 3 trial. Lancet Oncol 2010;11:121-8.
Shepherd FA, Rodrigues Pereira J, Ciuleanu T, Tan EH, Hirsh V, Thongprasert S, et al.
Erlotinib in previously treated non-small-cell lung cancer. N Engl J Med 2005;353:123-32.
Rosell R, Carcereny E, Gervais R, Vergnenegre A, Massuti B, Felip E, et al.
Erlotinib versus standard chemotherapy as first-line treatment for European patients with advanced EGFR mutation-positive non-small-cell lung cancer (EURTAC): A multicentre, open-label, randomised phase 3 trial. Lancet Oncol 2012;13:239-46.
Zhou C, Wu YL, Chen G, Feng J, Liu XQ, Wang C, et al.
Erlotinib versus chemotherapy as first-line treatment for patients with advanced EGFR mutation-positive non-small-cell lung cancer (OPTIMAL, CTONG-0802): A multicentre, open-label, randomised, phase 3 study. Lancet Oncol 2011;12:735-42.
Wu YL, Zhou C, Liam CK, Wu G, Liu X, Zhong Z, et al.
First-line erlotinib versus gemcitabine/cisplatin in patients with advanced EGFR mutation-positive non-small-cell lung cancer: Analyses from the phase III, randomized, open-label, ENSURE study. Ann Oncol 2015;26:1883-9.
Hu S, Xie G, Zhang DX, Davis C, Long W, Hu Y, et al.
Synthesis and biological evaluation of crown ether fused quinazoline analogues as potent EGFR inhibitors. Bioorg Med Chem Lett 2012;22:6301-5.
Shi Y, Wang L, Han B, Li W, Yu P, Liu Y, et al
. First-line icotinib versus cisplatine/pemetrexed plus pemetrexed maintenance therapy in lung adenocarcinoma patients with sensitizing EGFR mutation (CONVINCE). J Clin Oncol 2016;34 Suppl 15:9041.
Takeda M, Nakagawa K. First- and second-generation EGFR-TKIs are all replaced to osimertinib in chemo-naive EGFR mutation-positive non-small cell lung cancer? Int J Mol Sci 2019;20. pii: E146.
Yang JC, Schuler MH, Yamamoto N, O'Byrne KJ, Hirsh V, Mok T, et al
. LUX-Lung 3: A randomized, open-label, phase III study of afatinib versus pemetrexed and cisplatin as first-line treatment for patients with advanced adenocarcinoma of the lung harboring EGFR-activating mutations. J Clin Oncol 2012;30 Suppl 18:LBA7500.
Yang JC, Wu YL, Schuler M, Sebastian M, Popat S, Yamamoto N, et al.
Afatinib versus cisplatin-based chemotherapy for EGFR mutation-positive lung adenocarcinoma (LUX-lung 3 and LUX-lung 6): Analysis of overall survival data from two randomised, phase 3 trials. Lancet Oncol 2015;16:141-51.
Wu YL, Zhou C, Hu CP, Feng J, Lu S, Huang Y, et al.
Afatinib versus cisplatin plus gemcitabine for first-line treatment of Asian patients with advanced non-small-cell lung cancer harbouring EGFR mutations (LUX-lung 6): An open-label, randomised phase 3 trial. Lancet Oncol 2014;15:213-22.
Park K, Tan EH, O'Byrne K, Zhang L, Boyer M, Mok T, et al.
Afatinib versus gefitinib as first-line treatment of patients with EGFR mutation-positive non-small-cell lung cancer (LUX-lung 7): A phase 2B, open-label, randomised controlled trial. Lancet Oncol 2016;17:577-89.
Paz-Ares L, Tan EH, O'Byrne K, Zhang L, Hirsh V, Boyer M, et al.
Afatinib versus gefitinib in patients with EGFR mutation-positive advanced non-small-cell lung cancer: Overall survival data from the phase IIb LUX-lung 7 trial. Ann Oncol 2017;28:270-7.
Wu YL, Cheng Y, Zhou X, Lee KH, Nakagawa K, Niho S, et al.
Dacomitinib versus gefitinib as first-line treatment for patients with EGFR-mutation-positive non-small-cell lung cancer (ARCHER 1050): A randomised, open-label, phase 3 trial. Lancet Oncol 2017;18:1454-66.
Mok TS, Cheng Y, Zhou X, Lee KH, Nakagawa K, Niho S, et al.
Improvement in overall survival in a randomized study that compared dacomitinib with gefitinib in patients with advanced non-small-cell lung cancer and EGFR-activating mutations. J Clin Oncol 2018;36:2244-50.
Addeo A. Dacomitinib in NSCLC: A positive trial with little clinical impact. Lancet Oncol 2018;19:e4.
Wu SG, Shih JY. Management of acquired resistance to EGFR TKI-targeted therapy in advanced non-small cell lung cancer. Mol Cancer 2018;17:38.
Wu SG, Liu YN, Tsai MF, Chang YL, Yu CJ, Yang PC, et al.
The mechanism of acquired resistance to irreversible EGFR tyrosine kinase inhibitor-afatinib in lung adenocarcinoma patients. Oncotarget 2016;7:12404-13.
Yang JC, Ahn MJ, Kim DW, Ramalingam SS, Sequist LV, Su WC, et al.
Osimertinib in pretreated T790M-positive advanced non-small-cell lung cancer: AURA study phase II extension component. J Clin Oncol 2017;35:1288-96.
Mok TS, Wu Y-L, Ahn M-J, Garassino MC, Kim HR, Ramalingam SS, et al.
Osimertinib or platinum-pemetrexed in EGFR T790M-positive lung cancer. N Engl J Med 2017;376:629-40.
Ballard P, Yates JW, Yang Z, Kim DW, Yang JC, Cantarini M, et al.
Preclinical comparison of osimertinib with other EGFR-TKIs in EGFR-mutant NSCLC brain metastases models, and early evidence of clinical brain metastases activity. Clin Cancer Res 2016;22:5130-40.
Soria JC, Ohe Y, Vansteenkiste J, Reungwetwattana T, Chewaskulyong B, Lee KH, et al
. Osimertinib in untreated EGFR-mutated advanced non-small-cell lung cancer. N Engl J Med 2018;378:113-25.
Thress KS, Paweletz CP, Felip E, Cho BC, Stetson D, Dougherty B, et al.
Acquired EGFR C797S mutation mediates resistance to AZD9291 in non-small cell lung cancer harboring EGFR T790M. Nat Med 2015;21:560-2.
Yu HA, Tian SK, Drilon AE, Borsu L, Riely GJ, Arcila ME, et al.
Acquired resistance of EGFR-mutant lung cancer to a T790M-specific EGFR inhibitor: Emergence of a third mutation (C797S) in the EGFR tyrosine kinase domain. JAMA Oncol 2015;1:982-4.
Goldberg ME, Montesion M, Young L, Suh J, Greenbowe J, Kennedy M, et al.
Multiple configurations of EGFR exon 20 resistance mutations after first – And third-generation EGFR TKI treatment affect treatment options in NSCLC. PLoS One 2018;13:e0208097.
Wang S, Song Y, Liu D. EAI045: The fourth-generation EGFR inhibitor overcoming T790M and C797S resistance. Cancer Lett 2017;385:51-4.
Giaccone G, Herbst RS, Manegold C, Scagliotti G, Rosell R, Miller V, et al.
Gefitinib in combination with gemcitabine and cisplatin in advanced non-small-cell lung cancer: A phase III trial – INTACT 1. J Clin Oncol 2004;22:777-84.
Herbst RS, Giaccone G, Schiller JH, Natale RB, Miller V, Manegold C, et al.
Gefitinib in combination with paclitaxel and carboplatin in advanced non-small-cell lung cancer: A phase III trial – INTACT 2. J Clin Oncol 2004;22:785-94.
Wu YL, Lee JS, Thongprasert S, Yu CJ, Zhang L, Ladrera G, et al.
Intercalated combination of chemotherapy and erlotinib for patients with advanced stage non-small-cell lung cancer (FASTACT-2): A randomised, double-blind trial. Lancet Oncol 2013;14:777-86.
Cheng Y, Murakami H, Yang PC, He J, Nakagawa K, Kang JH, et al.
Randomized phase II trial of gefitinib with and without pemetrexed as first-line therapy in patients with advanced nonsquamous non-small-cell lung cancer with activating epidermal growth factor receptor mutations. J Clin Oncol 2016;34:3258-66.
Nakamura A, Inoue A, Morita S, Hosomi Y, Kato T, Fukuhara T, et al
. Phase III study comparing gefitinib monotherapy (G) to combination therapy with gefitinib, carboplatin, and pemetrexed (GCP) for untreated patients (pts) with advanced non-small cell lung cancer (NSCLC) with EGFR mutations (NEJ009). J Clin Oncol 2018;36(15_suppl):9005.
Noronha V, Patil VM, Joshi A, Menon N, Chougule A, Mahajan A, et al
. Gefitinib Versus Gefitinib Plus Pemetrexed and Carboplatin Chemotherapy in EGFR-Mutated Lung Cancer. J Clin Oncol 2019;JCO.19.01154.
Gatzemeier U, Pluzanska A, Szczesna A, Kaukel E, Roubec J, De Rosa F, et al.
Phase III study of erlotinib in combination with cisplatin and gemcitabine in advanced non-small-cell lung cancer: The tarceva lung cancer investigation trial. J Clin Oncol 2007;25:1545-52.
Yang J, Cheng Y, Murakami H, Yang PC, He J, Nakagawa K, et al
. 1381PD Gefitinib with or without pemetrexed in nonsquamous (NS) non-small cell lung cancer (NSCLC) with EGFR mutation (mut): Final overall survival (OS) results from a randomized phase II study. Ann Oncol 2018;29 Suppl 8:mdy292.004.
Reck M, von Pawel J, Zatloukal P, Ramlau R, Gorbounova V, Hirsh V, et al
. Phase III trial of cisplatin plus gemcitabine with either placebo or bevacizumab as first-line therapy for nonsquamous non-small-cell lung cancer: AVAil. J Clin Oncol 2009;27:1227-34.
Sandler A, Gray R, Perry MC, Brahmer J, Schiller JH, Dowlati A, et al.
Paclitaxel-carboplatin alone or with bevacizumab for non-small-cell lung cancer. N Engl J Med 2006;355:2542-50.
Herbst R, Stern H, Amler L, Otterson G, Lin M, O'Connor P, et al
. Abstract #LB-131: Biomarker evaluation in the Phase III, placebo (P)-controlled, randomized BeTa trial of bevacizumab (B) and erlotinib (E) for patients (pts) with advanced non-small cell lung cancer (NSCLC) after failure of standard 1st
-line chemotherapy: Correlation with treatment outcomes. Cancer Res 2009;69 Suppl 9:LB-131.
Herbst RS, Ansari R, Bustin F, Flynn P, Hart L, Otterson GA, et al.
Efficacy of bevacizumab plus erlotinib versus erlotinib alone in advanced non-small-cell lung cancer after failure of standard first-line chemotherapy (BeTa): A double-blind, placebo-controlled, phase 3 trial. Lancet 2011;377:1846-54.
Seto T, Kato T, Nishio M, Goto K, Atagi S, Hosomi Y, et al.
Erlotinib alone or with bevacizumab as first-line therapy in patients with advanced non-squamous non-small-cell lung cancer harbouring EGFR mutations (JO25567): An open-label, randomised, multicentre, phase 2 study. Lancet Oncol 2014;15:1236-44.
Saito H, Fukuhara T, Furuya N, Watanabe K, Sugawara S, Iwasawa S, et al
. Erlotinib plus bevacizumab versus erlotinib alone in patients with EGFR-positive advanced non-squamous non-small-cell lung cancer (NEJ026): Interim analysis of an open-label, randomised, multicentre, phase 3 trial. Lancet Oncol 2019;20:625-35.
Yamamoto N, Seto T, Nishio M, Goto K, Okamoto I, Yamanaka T, et al
. Erlotinib plus bevacizumab (EB) versus erlotinib alone (E) as first-line treatment for advanced EGFR mutation-positive non-squamous non-small-cell lung cancer (NSCLC): Survival follow-up results of JO25567. J Clin Oncol 2018;36 Suppl 15:9007.
Garon EB, Ciuleanu TE, Arrieta O, Prabhash K, Syrigos KN, Goksel T, et al.
Ramucirumab plus docetaxel versus placebo plus docetaxel for second-line treatment of stage IV non-small-cell lung cancer after disease progression on platinum-based therapy (REVEL): A multicentre, double-blind, randomised phase 3 trial. Lancet 2014;384:665-73.
Nakagawa K, Garon EB, Seto T, Nishio M, Ponce Aix S, Chiu CH, et al
. RELAY: A multinational, double-blind, randomized Phase 3 study of erlotinib (ERL) in combination with ramucirumab (RAM) or placebo (PL) in previously untreated patients with epidermal growth factor receptor mutation-positive (EGFRm) metastatic non-small cell lung cancer (NSCLC). J Clin Oncol 2019;37 Suppl 15:9000.
Lee CK, Man J, Lord S, Cooper W, Links M, Gebski V, et al.
Clinical and molecular characteristics associated with survival among patients treated with checkpoint inhibitors for advanced non-small cell lung carcinoma: A systematic review and meta-analysis. JAMA Oncol 2018;4:210-6.
Brahmer J, Reckamp KL, Baas P, Crinò L, Eberhardt WE, Poddubskaya E, et al.
Nivolumab versus docetaxel in advanced squamous-cell non-small-cell lung cancer. N Engl J Med 2015;373:123-35.
Borghaei H, Paz-Ares L, Horn L, Spigel DR, Steins M, Ready NE, et al.
Nivolumab versus docetaxel in advanced nonsquamous non-small-cell lung cancer. N Engl J Med 2015;373:1627-39.
Herbst RS, Baas P, Kim DW, Felip E, Pérez-Gracia JL, Han JY, et al.
Pembrolizumab versus docetaxel for previously treated, PD-L1-positive, advanced non-small-cell lung cancer (KEYNOTE-010): A randomised controlled trial. Lancet 2016;387:1540-50.
Rittmeyer A, Barlesi F, Waterkamp D, Park K, Ciardiello F, von Pawel J, et al.
Atezolizumab versus docetaxel in patients with previously treated non-small-cell lung cancer (OAK): A phase 3, open-label, multicentre randomised controlled trial. Lancet 2017;389:255-65.
Fehrenbacher L, Spira A, Ballinger M, Kowanetz M, Vansteenkiste J, Mazieres J, et al.
Atezolizumab versus docetaxel for patients with previously treated non-small-cell lung cancer (POPLAR): A multicentre, open-label, phase 2 randomised controlled trial. Lancet 2016;387:1837-46.
Yu S, Liu D, Shen B, Shi M, Feng J. Immunotherapy strategy of EGFR mutant lung cancer. Am J Cancer Res 2018;8:2106-15.
Haratani K, Hayashi H, Tanaka T, Kaneda H, Togashi Y, Sakai K, et al.
Tumor immune microenvironment and nivolumab efficacy in EGFR mutation-positive non-small-cell lung cancer based on T790M status after disease progression during EGFR-TKI treatment. Ann Oncol 2017;28:1532-9.
Gainor JF, Shaw AT, Sequist LV, Fu X, Azzoli CG, Piotrowska Z, et al.
EGFR mutations and ALK rearrangements are associated with low response rates to PD-1 pathway blockade in non-small cell lung cancer: A retrospective analysis. Clin Cancer Res 2016;22:4585-93.
Yasuda H, Park E, Yun CH, Sng NJ, Lucena-Araujo AR, Yeo WL, et al.
Structural, biochemical, and clinical characterization of epidermal growth factor receptor (EGFR) exon 20 insertion mutations in lung cancer. Sci Transl Med 2013;5:216ra177.
Vyse S, Huang PH. Targeting EGFR exon 20 insertion mutations in non-small cell lung cancer. Signal Transduct Target Ther 2019;4:5.
Arcila ME, Nafa K, Chaft JE, Rekhtman N, Lau C, Reva BA, et al.
EGFR exon 20 insertion mutations in lung adenocarcinomas: Prevalence, molecular heterogeneity, and clinicopathologic characteristics. Mol Cancer Ther 2013;12:220-9.
Yasuda H, Kobayashi S, Costa DB. EGFR exon 20 insertion mutations in non-small-cell lung cancer: Preclinical data and clinical implications. Lancet Oncol 2012;13:e23-31.
Oxnard GR, Lo PC, Nishino M, Dahlberg SE, Lindeman NI, Butaney M, et al.
Natural history and molecular characteristics of lung cancers harboring EGFR exon 20 insertions. J Thorac Oncol 2013;8:179-84.
Noronha V, Choughule A, Patil VM, Joshi A, Kumar R, Susan Joy Philip D, et al.
Epidermal growth factor receptor exon 20 mutation in lung cancer: Types, incidence, clinical features and impact on treatment. Onco Targets Ther 2017;10:2903-8.
Naidoo J, Sima CS, Rodriguez K, Busby N, Nafa K, Ladanyi M, et al.
Epidermal growth factor receptor exon 20 insertions in advanced lung adenocarcinomas: Clinical outcomes and response to erlotinib. Cancer 2015;121:3212-20.
Beau-Faller M, Prim N, Ruppert AM, Nanni-Metéllus I, Lacave R, Lacroix L, et al.
Rare EGFR exon 18 and exon 20 mutations in non-small-cell lung cancer on 10 117 patients: A multicentre observational study by the French ERMETIC-IFCT network. Ann Oncol 2014;25:126-31.
Yang JC, Sequist LV, Geater SL, Tsai CM, Mok TS, Schuler M, et al.
Clinical activity of afatinib in patients with advanced non-small-cell lung cancer harbouring uncommon EGFR mutations: A combined post-hoc
analysis of LUX-lung 2, LUX-lung 3, and LUX-lung 6. Lancet Oncol 2015;16:830-8.
Yang M, Xu X, Cai J, Ning J, Wery JP, Li QX, et al.
NSCLC harboring EGFR exon-20 insertions after the regulatory C-helix of kinase domain responds poorly to known EGFR inhibitors. Int J Cancer 2016;139:171-6.
Floc'h N, Martin MJ, Riess JW, Orme JP, Staniszewska AD, Ménard L, et al.
Antitumor activity of osimertinib, an irreversible mutant-selective EGFR tyrosine kinase inhibitor, in NSCLC harboring EGFR exon 20 insertions. Mol Cancer Ther 2018;17:885-96.
Inukai M, Toyooka S, Ito S, Asano H, Ichihara S, Soh J, et al.
Presence of epidermal growth factor receptor gene T790M mutation as a minor clone in non-small cell lung cancer. Cancer Res 2006;66:7854-8.
Maheswaran S, Sequist LV, Nagrath S, Ulkus L, Brannigan B, Collura CV, et al.
Detection of mutations in EGFR in circulating lung-cancer cells. N Engl J Med 2008;359:366-77.
Rosell R, Molina MA, Costa C, Simonetti S, Gimenez-Capitan A, Bertran-Alamillo J, et al.
Pretreatment EGFR T790M mutation and BRCA1 mRNA expression in erlotinib-treated advanced non-small-cell lung cancer patients with EGFR mutations. Clin Cancer Res 2011;17:1160-8.
Su KY, Chen HY, Li KC, Kuo ML, Yang JC, Chan WK, et al.
Pretreatment epidermal growth factor receptor (EGFR) T790M mutation predicts shorter EGFR tyrosine kinase inhibitor response duration in patients with non-small-cell lung cancer. J Clin Oncol 2012;30:433-40.
Yu HA, Arcila ME, Hellmann MD, Kris MG, Ladanyi M, Riely GJ. Poor response to erlotinib in patients with tumors containing baseline EGFR T790M mutations found by routine clinical molecular testing. Ann Oncol 2014;25:423-8.
Watanabe M, Kawaguchi T, Isa S, Ando M, Tamiya A, Kubo A, et al.
Ultra-sensitive detection of the pretreatment EGFR T790M mutation in non-small cell lung cancer patients with an EGFR-activating mutation using droplet digital PCR. Clin Cancer Res 2015;21:3552-60.
Yu HA, Arcila ME, Harlan Fleischut M, Stadler Z, Ladanyi M, Berger MF, et al.
Germline EGFR T790M mutation found in multiple members of a familial cohort. J Thorac Oncol 2014;9:554-8.
Costa C, Molina MA, Drozdowskyj A, Giménez-Capitán A, Bertran-Alamillo J, Karachaliou N, et al.
The impact of EGFR T790M mutations and BIM mRNA expression on outcome in patients with EGFR-mutant NSCLC treated with erlotinib or chemotherapy in the randomized phase III EURTAC trial. Clin Cancer Res 2014;20:2001-10.
Prabhash K. Treatment of advanced nonsmall cell lung cancer:First line, maintenance and second line – Indian consensus statement update. South Asian J Cancer 2019;8:1-7.
] [Full text]
Linardou H, Dahabreh IJ, Kanaloupiti D, Siannis F, Bafaloukos D, Kosmidis P, et al.
Assessment of somatic k-RAS mutations as a mechanism associated with resistance to EGFR-targeted agents: A systematic review and meta-analysis of studies in advanced non-small-cell lung cancer and metastatic colorectal cancer. Lancet Oncol 2008;9:962-72.
Ludovini V, Bianconi F, Pistola L, Chiari R, Minotti V, Colella R, et al.
Phosphoinositide-3-kinase catalytic alpha and KRAS mutations are important predictors of resistance to therapy with epidermal growth factor receptor tyrosine kinase inhibitors in patients with advanced non-small cell lung cancer. J Thorac Oncol 2011;6:707-15.
Syahruddin E, Wulandari L, Sri Muktiati N, Rima A, Soeroso N, Ermayanti S, et al.
Uncommon EGFR mutations in cytological specimens of 1,874 newly diagnosed Indonesian lung cancer patients. Lung Cancer (Auckl) 2018;9:25-34.
Kate S, Chougule A, Joshi A, Noronha V, Patil V, Dusane R, et al.
Outcome of uncommon EGFR mutation positive newly diagnosed advanced non-small cell lung cancer patients: A single center retrospective analysis. Lung Cancer (Auckl) 2019;10:1-10.
Arrieta O, Cardona AF, Corrales L, Campos-Parra AD, Sánchez-Reyes R, Amieva-Rivera E, et al.
The impact of common and rare EGFR mutations in response to EGFR tyrosine kinase inhibitors and platinum-based chemotherapy in patients with non-small cell lung cancer. Lung Cancer 2015;87:169-75.
Watanabe S, Minegishi Y, Yoshizawa H, Maemondo M, Inoue A, Sugawara S, et al.
Effectiveness of gefitinib against non-small-cell lung cancer with the uncommon EGFR mutations G719X and L861Q. J Thorac Oncol 2014;9:189-94.
Ahn MJ, Cho JH, Sun JM, Lee SH, Ahn JS, Park K, et al
. An open-label, multicenter, phase II single arm trial of osimertinib in non-small cell lung cancer patients with uncommon EGFR mutation (KCSG-LU15-09). J Clin Oncol 2018;36(15_suppl):9050.
Pandey A, Singh A, Singh S, Kumar A. Osimertinib in G719A mutated non-small cell lung cancer with leptomeningeal metastases. Cancer Res Stat Treat 2019;2:121-3. [Full text]
Janne PA, Neal JW, Camidge DR, Spira AI, Piotrowska Z, Horn L, et al
. Antitumor activity of TAK-788 in NSCLC with EGFR exon 20 insertions. J Clin Oncol 2019;37(15_suppl):9007.
Heymach J, Negrao M, Robichaux J, Carter B, Patel A, Altan M, et al
. OA02.06 A Phase II Trial of Poziotinib in EGFR and HER2 exon 20 Mutant Non-Small Cell Lung Cancer (NSCLC). J Thorac Oncol 2018;13:S323-4.
Angulo B, Conde E, Suárez-Gauthier A, Plaza C, Martínez R, Redondo P, et al.
A comparison of EGFR mutation testing methods in lung carcinoma: Direct sequencing, real-time PCR and immunohistochemistry. PLoS One 2012;7:e43842.
Lopez-Rios F, Angulo B, Gomez B, Mair D, Martinez R, Conde E, et al.
Comparison of molecular testing methods for the detection of EGFR mutations in formalin-fixed paraffin-embedded tissue specimens of non-small cell lung cancer. J Clin Pathol 2013;66:381-5.
Pao W, Ladanyi M. Epidermal growth factor receptor mutation testing in lung cancer: Searching for the ideal method. Clin Cancer Res 2007;13:4954-5.
Ahmadian A, Ehn M, Hober S. Pyrosequencing: History, biochemistry and future. Clin Chim Acta 2006;363:83-94.
Langaee T, Ronaghi M. Genetic variation analyses by pyrosequencing. Mutat Res 2005;573:96-102.
Sheikine Y, Rangachari D, McDonald DC, Huberman MS, Folch ES, VanderLaan PA, et al.
EGFR testing in advanced non-small-cell lung cancer, A mini-review. Clin Lung Cancer 2016;17:483-92.
Miyamae Y, Shimizu K, Mitani Y, Araki T, Kawai Y, Baba M, et al.
Mutation detection of epidermal growth factor receptor and KRAS genes using the smart amplification process version 2 from formalin-fixed, paraffin-embedded lung cancer tissue. J Mol Diagn 2010;12:257-64.
Cernomaz AT, Macovei II, Pavel I, Grigoriu C, Marinca M, Baty F, et al.
Comparison of next generation sequencing, SNaPshot assay and real-time polymerase chain reaction for lung adenocarcinoma EGFR mutation assessment. BMC Pulm Med 2016;16:88.
Wan JC, Massie C, Garcia-Corbacho J, Mouliere F, Brenton JD, Caldas C, et al.
Liquid biopsies come of age: Towards implementation of circulating tumour DNA. Nat Rev Cancer 2017;17:223-38.
Oxnard GR, Paweletz CP, Sholl LM. Genomic analysis of plasma cell-free DNA in patients with cancer. JAMA Oncol 2017;3:740-1.
Douillard JY, Ostoros G, Cobo M, Ciuleanu T, Cole R, McWalter G, et al.
Gefitinib treatment in EGFR mutated Caucasian NSCLC: Circulating-free tumor DNA as a surrogate for determination of EGFR status. J Thorac Oncol 2014;9:1345-53.
Sacher AG, Komatsubara KM, Oxnard GR. Application of plasma genotyping technologies in non-small cell lung cancer: A practical review. J Thorac Oncol 2017;12:1344-56.
Marchetti A, Palma JF, Felicioni L, De Pas TM, Chiari R, Del Grammastro M, et al.
Early prediction of response to tyrosine kinase inhibitors by quantification of EGFR mutations in plasma of NSCLC patients. J Thorac Oncol 2015;10:1437-43.
de Vries NA, Buckle T, Zhao J, Beijnen JH, Schellens JH, van Tellingen O. Restricted brain penetration of the tyrosine kinase inhibitor erlotinib due to the drug transporters P-gp and BCRP. Invest New Drugs 2012;30:443-9.
Togashi Y, Masago K, Masuda S, Mizuno T, Fukudo M, Ikemi Y, et al.
Cerebrospinal fluid concentration of gefitinib and erlotinib in patients with non-small cell lung cancer. Cancer Chemother Pharmacol 2012;70:399-405.
Grommes C, Oxnard GR, Kris MG, Miller VA, Pao W, Holodny AI, et al.
“Pulsatile” high-dose weekly erlotinib for CNS metastases from EGFR mutant non-small cell lung cancer. Neuro Oncol 2011;13:1364-9.
Reungwetwattana T, Nakagawa K, Cho BC, Cobo M, Cho EK, Bertolini A, et al
. CNS response to osimertinib versus standard epidermal growth factor receptor tyrosine kinase inhibitors in patients with untreated EGFR-mutated advanced non-small-cell lung cancer. J Clin Oncol 2018;36:3290-7.
Wu YL, Sequist LV, Tan EH, Geater SL, Orlov S, Zhang L, et al.
Afatinib as first-line treatment of older patients with EGFR mutation-positive non-small-cell lung cancer: Subgroup analyses of the LUX-lung 3, LUX-lung 6, and LUX-lung 7 trials. Clin Lung Cancer 2018;19:e465-79.
Lee SM, Khan I, Upadhyay S, Lewanski C, Falk S, Skailes G, et al.
First-line erlotinib in patients with advanced non-small-cell lung cancer unsuitable for chemotherapy (TOPICAL): A double-blind, placebo-controlled, phase 3 trial. Lancet Oncol 2012;13:1161-70.
Yang JJ, Zhou Q, Yan HH, Zhang XC, Chen HJ, Tu HY, et al.
A phase III randomised controlled trial of erlotinib vs. gefitinib in advanced non-small cell lung cancer with EGFR mutations. Br J Cancer 2017;116:568-74.
Yang Z, Hackshaw A, Feng Q, Fu X, Zhang Y, Mao C, et al.
Comparison of gefitinib, erlotinib and afatinib in non-small cell lung cancer: A meta-analysis. Int J Cancer 2017;140:2805-19.
[Table 1], [Table 2], [Table 3], [Table 4], [Table 5], [Table 6], [Table 7]