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Table of Contents
REVIEW ARTICLE
Year : 2019  |  Volume : 2  |  Issue : 1  |  Page : 36-53

Epidermal growth factor receptor-mutated non-small-cell lung cancer: A primer on contemporary management


Department of Medical Oncology, Tata Memorial Hospital, Mumbai, Maharashtra, India

Date of Web Publication9-Sep-2019

Correspondence Address:
Vanita Noronha
Department of Medical Oncology, Tata Memorial Hospital, Mumbai - 400 012, Maharashtra
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/CRST.CRST_51_19

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  Abstract 


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 2019 Nov 13];2:36-53. Available from: http://www.crstonline.com/text.asp?2019/2/1/36/266465




  Introduction Top


With an estimated 1.5 million deaths each year, lung cancer is the most common cause of cancer-related death worldwide.[1] 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.[2] 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.[3] The success of imatinib in chronic myeloid leukemia has demonstrated the effectiveness of therapy which targets the critical genetic driver.[4] 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.[5]

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.[6] 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.[7],[8] 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.[9],[10]

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.[5] The most common mutations are in-frame deletions (Class I) in exon 19 and point mutations in exon 21 (L858R).[11] 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.[10],[12],[13],[14] 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%.[15] The incidence rate in Indian patients is approximately 20%–23%.[16],[17]


  Anti-Epidermal Growth Factor Receptor Agents Top


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.[3]

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.[18] 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).[19] 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.[9]

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.

Gefitinib

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.[20],[21] 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.[22],[23] 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

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.[29] 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.
Table 2: Trials comparing erlotinib with chemotherapy in advanced NSCLC

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Icotinib

Icotinib is an oral selective EGFR TKI made in China.[33] 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.[34]

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.[35] 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.

Afatinib

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).[36]

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.[39]

Dacomitinib

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.[41] 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.[42] 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.[43]

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.[44] 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.[45] 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

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).[46] 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.[47] 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.[48] 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%).[49] 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.[50]

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.[51],[52]

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.[53]

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.[54]


  Combination Strategies With Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitor Top


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.[18],[55],[56] 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.[57] 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).[58] 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.[59] 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).[60] 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.[63],[64] 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.[65],[66] 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).[67] 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).[68] 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.[70] 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.[71]

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).[72],[73],[74],[75],[76],[77] 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.[13],[78],[79],[80]

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.[81] 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%).[82] The incidence of this mutation ranges from 4% to 10% of all observed EGFR mutations in NSCLC.[81],[83],[84],[85] 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%.[86]

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.[81] 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.[87],[88] The response rates of second-generation TKIs were also dismal in this subset of patients (8.7% response rate, 2.7 months PFS).[89],[90] Preclinical models have shown poor response of third-generation TKIs as well in lung cancers harboring exon 20 insertion mutations.[90],[91]

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.[92],[93],[94],[95],[96],[97]

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.[97] 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.[98]

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.[100] 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].[46]
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.[101],[102]

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.[20],[30] 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.[103] 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.[104] 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.[105] 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.[106] 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.[89] 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.[104]

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.[107],[108]

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.[109] 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%.[110] 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.[60]

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:

  1. Nontargeted assays:


    1. Sanger sequencing
    2. Pyrosequencing.


  2. Targeted assay (PCR based)
  3. Next-generation sequencing (NGS).


Sanger sequencing

Sanger sequencing was the method of choice for the detection of EGFR mutations in the early clinical trials with erlotinib and gefitinib.[111],[112] 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.[113] The main advantage of Sanger sequencing is identification of all known and previously unknown mutations in the studied region.

Pyrosequencing

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.[112],[114],[115]

Targeted assays

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.[116],[117]

Commercially available EGFR-targeted assays include:

  1. Cobas EGFR mutation testing
  2. Therascreen EGFR mutation testing
  3. MassARRAY system
  4. SNaPshot Multiplex kit
  5. Quantitative PCR (Taqman).


Next-generation sequencing

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.[118]

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.[119],[120] Plasma genotyping assays are associated with excellent specificity (>95%) and moderately high sensitivity (70%–80%).[121],[122],[123] 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.[124] 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.[125] 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.[126] 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.[48],[127] 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.[49] 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.[21],[30],[31] 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.[128]

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.[129] 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.[130]

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.[46],[49]

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.[131],[132] The newer TKIs, dacomitinib [41] and osimertinib,[49] and the combination strategy of oral TKI with chemotherapy [59],[60] 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.[59],[60] 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.[86] In patients with de novo T790M mutation or exon 20 insertions, osimertinib or chemotherapy may be the preferred treatment of choice.


  Conclusion Top


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

Nil.

Conflicts of interest

There are no conflicts of interest.



 
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