|Year : 2017 | Volume
| Issue : 5 | Page : 15-24
Epidermal growth factor receptor T790M mutation: A major culprit in the progression of epidermal growth factor receptor-driven non-small cell lung cancer and the role of repeat biopsy
S Aggarwal1, S Patil2, N Rohtagi3
1 Department of Medical Oncology, Sir Ganga Ram Hospital, New Delhi, India
2 Senior Consulting Medical Oncologist, HCG Bangalore Institute of Oncology, Bengaluru, Karnataka, India
3 Consultant Medical Oncology, Max Super Speciality Hospital, New Delhi, India
|Date of Web Publication||29-Dec-2017|
Dr. S Aggarwal
Department of Medical Oncology, Sir Ganga Ram Hospital, New Delhi
Source of Support: None, Conflict of Interest: None
Non-small cell lung cancer (NSCLC) accounts for the majority of primary lung cancer cases worldwide. The activating mutations of epidermal growth factor receptor (EGFR) have been demonstrated to associate with the development of NSCLC, with T790M mutation being the most common. Over the years, EGFR tyrosine kinase inhibitors (TKIs) were developed to target EGFR-related mutations. However, patients with activating EGFR mutations who are initially responsive to EGFR-TKIs eventually develop acquired resistance after a median progression-free survival of 10–16 months, followed by disease progression. Recently, the third-generation EGFR inhibitors have emerged as potential therapeutics to block the growth of EGFR T790M-positive tumors. This article reviews the emerging data regarding EGFR mutations and clinical evidence on third-generation agents against EGFR T790M mutation in the treatment of patients with advanced NSCLC. It also reviews the role of repeat biopsy in improving the success rates of treatment of EGFR T790M-derived drug-resistant NSCLC.
Keywords: Epidermal growth factor receptor T790M, non-small cell lung cancer, repeat biopsy, tyrosine kinase inhibitors
|How to cite this article:|
Aggarwal S, Patil S, Rohtagi N. Epidermal growth factor receptor T790M mutation: A major culprit in the progression of epidermal growth factor receptor-driven non-small cell lung cancer and the role of repeat biopsy. Indian J Cancer 2017;54, Suppl S1:15-24
|How to cite this URL:|
Aggarwal S, Patil S, Rohtagi N. Epidermal growth factor receptor T790M mutation: A major culprit in the progression of epidermal growth factor receptor-driven non-small cell lung cancer and the role of repeat biopsy. Indian J Cancer [serial online] 2017 [cited 2022 Jun 27];54, Suppl S1:15-24. Available from: https://www.indianjcancer.com/text.asp?2017/54/5/15/221922
| » Introduction|| |
Non-small cell lung cancer (NSCLC) represents the major form of lung cancer and it accounts for about 85% of primary lung cancers. It remains insidious until the disease is well advanced and at diagnosis, most of the patients present with locally advanced, metastatic, or distant spread of disease., Histologically, NSCLC can be broadly categorized into squamous and nonsquamous (adenocarcinoma, large cell carcinoma) cell carcinomas. With the advent of molecular profiling techniques, analysis of tumor samples revealed that few of the genes and pathways are deregulated in NSCLC patients. One such pathway is the epidermal growth factor receptor (EGFR) signaling pathway. The activating (sensitizing) mutations of EGFR occur in approximately 10%–15% of NSCLC cases in Caucasian patients and about 47% in Asian NSCLC patients. In Indian NSCLC patients, the prevalence of EGFR mutation is 23%–40%. Mutation rate has been reported to be significantly higher in females as compared to men and nonsmokers as against smokers.,,, Majority of the patients who initially have sensitizing mutations ultimately develop acquired mutation in the due course of treatment with first-line therapy. Further, regional differences have also been reported, with a higher incidence of 65% in the South Indian population as compared to 33% in North Indian population.
Treatment success in NSCLC patients is far from reality. Till the time patients are diagnosed, most of them would have already developed locally advanced or metastatic disease and cannot undergo surgical resection. Moreover, cytotoxic chemotherapy and radiation therapy are associated with relatively serious side effects, affecting patients' quality of life., The knowledge that substantial proportion of advanced NSCLC patients harbor sensitizing and subsequently acquired EGFR mutations led to evolution of target-based therapies. Over the years, first- (gefitinib, erlotinib), second- (afatinib), and third (osimertinib)-generation EGFR tyrosine kinase inhibitors (TKIs) were developed to aim for EGFR-related mutations. Despite the efficacy and superiority of the first- and second-generation EGFR-TKIs over conventional treatment, majority of the patients develop acquired resistance. Ultimately, this results into progressive disease (PD), with a median of 9–13 months' progression-free survival (PFS). One of the common acquired mutations of clinical relevance is T790M mutation. Re-biopsy results of various samples have revealed that EGFR T790M mutation was present in approximately 50%–60% of resistant cases. Therefore, EGFR T790M mutation has emerged as a major culprit in developing acquired resistance against the first- and second-generation EGFR-TKIs. Recently, the third-generation EGFR inhibitors have emerged as potential therapeutics to block the growth of EGFR T790M-positive tumors. More importantly, unlike the first- and second-generation EGFR-TKIs, the third-generation TKIs have a significantly increased potency for most prevalent EGFR T790M mutation than for wild-type EGFR.
Furthermore, the role of biopsy and re-biopsy in the treatment success of EGFR-TKIs cannot be ignored. Biopsy has been considered as an important pathological evaluation by various guidelines to histologically classify lung cancer, determine the extent of invasion, metastasis, margins, and the presence of gene alterations/mutations., However, recommending re-biopsy in routine clinical practice after disease progression still needs recognition. Re-biopsy is important to identify the mechanism of acquired resistance, mainly due to T790M, because third-generation EGFR-TKIs have significantly increased potency against the most prevalent T790M mutation. Early research efforts with osimertinib and rociletinib reported promising efficacy in patients with T790M-positive acquired resistance, and the utility of these agents in clinical trial settings provided a potential clear value to repeat biopsies upon progression.
The aim of this review article is to gain knowledge about therapeutic options in case of sensitizing and acquired mutations in EGFR with a special emphasis on T790M mutations. Here, we try to provide insights into the capacity of repeat biopsy in improving the success rates of treatment of EGFR T790M-derived drug-resistant NSCLC, which may help in clinical decision-making. The entire information has been aligned in an attempt to create awareness among clinicians to practice repeat biopsy to differentiate patients with T790M mutations, for which third-generation EGFR-TKI treatment is readily available.
| » Epidermal Growth Factor Receptor and Sites Of Mutation In Epidermal Growth Factor Receptor|| |
EGFR is a transmembrane receptor tyrosine kinase protein which regulates both cell proliferation and apoptosis through signal transduction pathways. It consists of an extracellular ligand binding domain, a transmembrane portion, and intracellular tyrosine kinase domain that occupy exons 18–24. When a specific ligand binds to an EGFR, phosphorylation of the tyrosine kinase domain occurs which leads to downstream signal transduction by various pathways. Subsequent events include autophosphorylation of key tyrosine residues in the tyrosine kinase domain and activation of tyrosine kinase activity, which further activate the downstream PIK3CA/AKT1/MTOR and RAS/RAF1/MAP2K1 pathways. The end result of these pathways is either cell proliferation or cell maintenance by inhibition of apoptosis [Figure 1]., Deregulation of EGFR pathway leads to increased intracellular pathway activity through tyrosine auto-phosphorylation. This in turn, directly or indirectly, leads to cell proliferation, angiogenesis, invasion, and metastasis. Overexpression of EGFR has been reported and implicated in the pathogenesis of many human malignancies.
|Figure 1: The epidermal growth factor receptor signaling pathway. Epidermal growth factor receptor is composed of an extracellular domain, a transmembrane lipophilic segment, and an intracellular region containing tyrosine kinase domains that occupy exons 18–24|
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Tyrosine kinase domain (exons 18–21) is the major site in EGFR gene where a majority of DNA mutations have been identified. [Figure 2] shows the types of mutations in different exons and also depicts their sensitivity and resistance to EGFR TKI therapy. These mutations can be divided into three major categories: (1) in-frame deletions in exon 19, (2) insertion mutations in exon 20, (3) and missense mutations in exons 18–21. There are over twenty variant types of exon 19 deletions. In patients with NSCLC, the most commonly found EGFR mutations are deletions in exon 19 (Exon19-del in 45% of patients) and a mutation in exon 21 (L858R in 40%). Both mutations result in the activation of the tyrosine kinase domain and both are sensitive to first- and second-generation TKIs, such as gefitinib, erlotinib, and afatinib. Thus, these mutations are referred to as sensitizing mutations.
|Figure 2: Response of different epidermal growth factor receptor mutations in exons 18–21 to targeted therapy Out of 26 exons in chromosome 7p11.2, exons 18–21 in the tyrosine kinase region of the epidermal growth factor receptor gene are scaled up. Their responsiveness toward targeted therapies is depicted|
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Despite initial response to sensitizing mutations, first- and second-generation EGFR-TKIs invariably develop PD. This is because acquired resistance is developed due to further mutations in tyrosine kinase domain. The most important mutation is T790M in exon 20, which is associated with around ~62% of the patients with acquired resistance to first-generation EGFR-TKIs [Figure 3]a. In this point mutation T790M, methionine substitutes for threonine at amino acid position 790 of EGFR gene.,,,
|Figure 3: (a and b) Mechanism of acquired resistance after epidermal growth factor receptor-tyrosine kinase inhibitor therapy. Reported occurrence of each mechanism varies from cohort to cohort. So, the prevalence rates have been shown in range and therefore totals do not equal 100%. MET: mesenchymal–epithelial transitions; SCLC: Small cell lung cancer. Structure of T790M|
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| » Treatment Paradigm In Advanced Non-Small Cell Lung Cancer With Sensitizing Mutation|| |
The presence of sensitizing mutations, namely, EGFR exon 19 deletion or exon 21 L858R mutation is predictive of treatment benefit from EGFR TKI therapy in advanced NSCLC patients. The National Comprehensive Cancer Network (NCCN) guidelines recommend first-generation reversible EGFR-TKIs, gefitinib and erlotinib, as first-line therapy. Afatinib, a second-generation EGFR TKI, is an irreversible inhibitor of the entire ErbB/HER family of receptors including EGFR and HER2. In addition to the recommendations of the NCCN, the Food and Drug Administration (FDA) has also approved afatinib as first-line treatment for patients with metastatic nonsquamous NSCLC who have sensitizing EGFR mutations. Before starting treatment, EGFR mutation testing is recommended in patients with nonsquamous NSCLC (adenocarcinoma and large cell carcinoma) in order to confirm the type of sensitizing mutation.
Moreover, both the European Society of Medical Oncology (ESMO) and the American College of Chest Physicians  also recommend gefitinib and erlotinib as first-line treatment in metastatic NSCLC with EGFR mutation. Both the agents were recommended on the basis of phase III clinical trials [Table 1], which demonstrated higher response rate, longer PFS, and better quality of life when compared with the first-line chemotherapy. As shown in [Table 1], second-generation EGFR TKI, afatinib, also shows a longer PFS in comparison with first-line chemotherapy when used as the first-line treatment for EGFR mutation-positive NSCLC. In general, EGFR-TKIs are better tolerated than chemotherapy. This was documented in the quality of life analysis of the Iressa Pan-Asia Study and OPTIMAL and LUX-LUNG 3–6 trials. Although first- and second-generation EGFR-TKIs represent the standard of care for advanced NSCLC patients whose tumor harbors sensitizing mutation, a majority of patients have PD often within a year of treatment. According to an estimate, most patients with EGFR-mutant NSCLC and treated with EGFR-TKIs develop resistance within 9–13 months [Table 2].
|Table 1: Studies of first- and second-generation tyrosine kinase inhibitors as first-line therapy in patients with epithelial growth factor receptor-positive non-small cell lung cancer|
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|Table 2: Resistance to first- and second-generation epidermal growth factor receptor tyrosine kinase inhibitors due to emergence of T790M mutation|
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| » Secondary Or Acquired Resistance Against First- And Second - Generation Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitors|| |
Despite the initial good response to reversible/ first-line EGFR-TKIs, secondary or acquired resistance to treatment eventually develops. Jackman et al. proposed a clinical definition of acquired resistance to EGFR-TKIs in patients with NSCLC [Table 3]. These criteria aimed to benefit both practicing oncologists and research undertaken in patients who had acquired resistance from the first-line EGFR-TKIs.
|Table 3: Detailed definition of acquired resistance to epidermal growth factor receptor-tyrosine kinase inhibitors proposed by Jackman et al.|
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Among the several other mechanisms of acquired resistance to first- and second-generation EGFR-TKIs, the most common one is T790M, which occurs as a result of a mutation in exon 20 of the EGFR gene [Figure 3]a. T790M mutation has been observed when biopsy was obtained at the time of relapse following gefitinib or erlotinib treatment in patients with the exon 19 deletion or the L858R EGFR mutation. T790M mutation occurs due to substitution of a bulky methionine residue for threonine at the gatekeeper residue in position 790 in the kinase domain of EGFR [Figure 3]b.
The following changes occur due to mutation at T790M: binding of reversible TKIs is reduced due to steric hindrance; potency of EGFR-TKIs is reduced due to increased phosphorylation levels; and affinity of EGFR to ATP (adenosine triphosphate) is altered, rendering ATP as the favored substrate compared with ATP-competitive EGFR-TKIs. T790M mutation in a gefitinib-sensitive cell line has been supposed to be mediated by maintenance of PI3K/Akt activation in the presence of gefitinib. Other common causes of acquired resistance are as follows: amplification of mesenchymal–epithelial transition (MET) gene (5%–11%) and transformation to small-cell undifferentiated carcinoma histology (3%–14%)., Three, less frequent, secondary EGFR mutations are D761Y, T854A, and L747S. The clinical relevance of them has to be proven. It has been observed that among patients with acquired resistance to EGFR TKI, the presence of T790M mutation was associated with a more favorable prognosis than those tumors which do not harbor the T790M mutation. Moreover, patients with acquired resistance to gefitinib, erlotinib, and afatinib and harboring T790M mutation can potentially have a rapid clinical decline and short survival.
| » Treatment Options After Progression On Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitors|| |
Several strategies have been adopted in case of disease progression after first-generation EGFR TKI therapy. These strategies include TKI continuation with or without chemotherapy; TKI continuation with local therapy; and combination therapy. Treatment options are based on the mechanism of resistance to the initial EGFR TKI treatment and whether the patient is symptomatic or asymptomatic., However, as a matter of fact, T790M is a major cause of acquired mutation related to EGFR, and hence disease progression on primary treatment with first- and second-generation EGFR-TKIs occurs in about two-thirds of the cases, hence it could be an ideal target for the exploration for newer therapies. [Figure 4] shows treatment approach in case of disease progression due to various types of mutations in EGFR domain and progression type in advanced NSCLC patients.
|Figure 4: Treatment algorithm for Stage IIIB–IV lung carcinoma with epidermal growth factor receptor-activating mutation. EGFR: Epidermal growth factor receptor; PS: Performance status (adapted from ESMO 2016)|
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Treatment with next-generation epidermal growth factor receptor tyrosine kinase inhibitors: To target T790M mutation
Recently, with the introduction of third-generation EGFR TKI, osimertinib, in the US (Nov 2015) and European markets (Feb 2016), the treatment has become possible in T790M mutant-positive advanced NSCLC patients who acquired resistance with the due course of first- and second-generation EGFR-TKI treatment. The approval was granted in the US and European markets on the basis of clinical trials enlisted in [Table 4]. Indeed, the NCCN provides guidelines regarding progression after EGFR TKI and has considered osimertinib into their most current recommendations. It is an irreversible mutant-selective EGFR TKI of commonly mutated forms of EGFR (exon 19 deletion, L858R/T790M, and wild-type EGFR). It is the only approved EGFR TKI currently indicated for patients with metastatic EGFR T790M mutation-positive NSCLC. Osimertinib was studied in two multicenter, single-arm, open-label trials in patients with disease progression after previous treatment with an EGFR TKI [Table 4]. The pooled analysis of these studies showed that objective response rate (ORR) was 57% and 61% in study 1 and study 2, respectively. The majority (96%) of patients with confirmed objective responses had ongoing responses ranging from 1.1 to 5.6 months after a median duration of follow-up of 4.2 months for study 1 and 4.0 months for study 2. The most common adverse events associated with osimertinib 80 mg/day were diarrhea and rash. However, the incidence was dissimilar and improved compared to gefitinib, erlotinib, and afatinib. Another third-generation EGFR TKI, olmutinib (HM61713/BI 1482694), is approved in South Korea recently. It is also a mutant-selective irreversible kinase inhibitor which showed activities against cell lines and xenograft tumors harboring EGFR exon 19 deletion or L858R/T790M. In a phase I/II trial which tested 800 mg/day dose of olmutinib on 76 patients harboring T790M mutation, ORR was 62% and the disease control rate (DCR) was 91%. Diarrhea, rash, nausea, and pruritus are the most common drug-related adverse events associated with this drug. Eluxa1, the global phase II trial evaluating the efficacy and safety of BI 1482694, is ongoing. Other third-generation EGFR-TKIs such as ASP8273, EGF816, PFE-X775, dacomitinib, aflutinib, and avitinib are still under different phases of clinical development. Rociletinib, another third-generation EGFR TKI, which had initially garnered a great attention has been abandoned since the initially reported ORR of 59% has been reduced to 45%. To get the maximum efficacy of third-generation EGFR-TKIs, a companion diagnostic test, COBAS, was also approved by the FDA (Nov 2015) to distinguish EGFR T790M mutant-positive NSCLC patients from the rest of the population.
Osimertinib displayed significant exposure in the brain activity against EGFRm NSCLC brain metastasis compared with the other EGFR-TKIs in preclinical studies. Subsequently, benefit was tested clinically in AURA3, with longer median duration of PFS among patients receiving osimertinib than among those receiving platinum therapy plus pemetrexed (8.5 months vs. 4.2 months; hazard ratio, 0.32; 95% confidence interval, 0.21–0.49). Moreover, central nervous system analysis in the pooled analysis of Phase II AURA extension and AURA2 revealed ORR, complete response, and DCR of 53%, 12%, and 92%, respectively. A Phase I study (BLOOM) of osimertinib (160 mg, QD) was conducted in patients with EGFRm advanced NSCLC who had progressed on prior EGFR-TKI therapy and had leptomeningeal disease. The interim findings of the study showed that of the 12 patients completed a 12-week (IC) Intracranial image assessment, 7 had radiological improvement, 2 had stable disease, and 3 were not evaluable (NE). Similarly, 12 patients reached 12-week neurological assessment: of seven symptomatic patients, three improved, one had no change, and two were NE. Osimertinib (160 mg QD) demonstrates positive preliminary safety and efficacy. Further, the BLOOM study calls for the evaluation of osimertinib in this setting.
Other treatment options
The NCCN clinical practice guidelines (2015) elaborate an algorithm for the patients where EGFR mutation is discovered during erlotinib/afatinib with or without first-line chemotherapy. It recommends erlotinib/afatinib to be continued in case of asymptomatic/symptomatic progression, brain metastasis, or systemic progression. However, additional therapy such as whole-brain radiotherapy (WBRT) or local therapy may be added.
Although continuing targeted therapy beyond progression is a common practice in other molecularly defined tumors, the decision to continue EGFR-TKI after acquired resistance in NSCLC should be made on an individual basis considering the nature of the progression, the tolerability of the current treatment regimen, and the patient's preferences. Treatment with only chemotherapy in patients failing on EGFR-TKI has witnessed significant longer OS and PFS than best supportive care. However, addition of EGFR-TKI is still a matter of debate. While results of FASTACT II and LUX-Lung 5 trials showed improvement in PFS and ORR when first-generation EGFR-TKIs were administered in combination to chemotherapy,, IMPRESS trial showed no clinical benefit.
Local therapy (surgery, radiation therapy, radiofrequency ablation) could be an effective option in case of local progression. In the instances where patient exhibits symptomatic brain metastases after first-line EGFR-TKI therapy, the NCCN recommends local treatment plus continuation of EGFR-TKI therapy for isolated lesion or WBRT along with EGFR-TKI therapy for multiple lesions. In case of symptomatic extracranial lesions, local therapy should be added to the EGFR-TKI for an isolated lesion [Figure 5]a.,,
|Figure 5: (a and b) Treatment paradigm for EGFR mutation-positive NSCLC. *Options include surgical resection and stereotactic radiosurgery. EGFR: Epidermal growth factor receptor; MET: Mesenchymal–epithelial transition; NSCLC: Non-small cell lung cancer; SCLC: Small cell lung cancer; TKI: Tyrosine kinase inhibitor; WBRT: Whole-brain radiotherapy. A proposed paradigm for use of plasma genotyping for epidermal growth factor receptor T790M. Plasma genotyping for T790M is a screening test before biopsy. Biopsy would only be needed for patients with no T790M detected in plasma. FDA: US Food and Drug Administration; FFPE: Formalin fixed, paraffin embedded; TKI: Tyrosine kinase inhibitor.|
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Combination therapy aiming to target primary oncogene and ultimately compensatory signaling pathways is also suggested. Efforts have been made to hamper tumor regression by targeting MET and EGFR together in tumors with MET amplification. Combination of EGFR-TKI, afatinib, with EGFR monoclonal antibody, cetuximab, has shown ORR in 40% patients with acquired resistance to erlotinib or gefitinib in Phase I/II trial.
| » Repeat Biopsy: a Mandate to Conquer T790m Epidermal Growth Factor Receptor Mutation|| |
Biopsying tumors at the time of acquired resistance to first-line treatment helps devise the next best therapy for a patient. Until very recently, before the emergence of T790M mutation-specific therapy, trend for repeat biopsy was not very well established. This was because other known acquired mutations were seen less frequently compared to T790M EGFR mutation (~50%) [Figure 3]a and hence failed to lead broad adoption of repeat biopsy.
The recent US FDA approval of T790M-specific third-generation EGFR-TKIs, osimertinib (olmutinib in the pipeline), has now presented a very compelling rationale for repeat biopsy to ensure evidence of T790M-acquired mutation. For that reason, cobas® (Roche; Basel, Switzerland) EGFR mutation test has also been approved as a companion diagnostic.
Recent reports in Japanese patients have also emphasized the feasibility of re-biopsy in current clinical practice to decide the future mode of treatment. Repeat biopsy of patients, progressed upon EGFR-TKIs, showed that 36% of patients had T790M mutation and only 3% samples were small-cell transformation. Another mutational analysis identified 38% of the patients with T790M mutation out of 48 NSCLC patients. In a multicenter, observational, retrospective study in EGFR mutation-positive NSCLC patients, approximately 50% of the patients were found to have T790M mutations and 2.2% had small-cell histology transformation upon re-biopsy. In this study, it was observed that the first-generation TKIs, erlotinib and gefitinib, induced more T790M mutations than the second-generation afatinib. In another prospective study, re-biopsies for the mutational analysis of NSCLCs resistant to previous chemotherapy were feasible in all patients (n = 75) and are adequate in approximately four-fifths of patients with the positive results for T790M mutation in five patients. [Table 3] enlists percentage T790M mutations emerged as a result of first- and second-generation EGFR-TKI treatment, observed in various case reports and clinical studies.
Therefore, repeat biopsy should now become a new paradigm [Figure 5]b of clinical practice in advanced NSCLC patients who progress on first- and second-generation EGFR-TKIs. However, accessibility to tumor site and skill and experience with re-biopsy are equally important to bring the benefits.
| » Scenario of Repeat Biopsy in Current Clinical Practice|| |
According to the ESMO guidelines 2016, treatment strategy should have the following sequence of events: After patients are confirmed to have NSCLC based on pathologic diagnosis, a clinical evaluation needs to be done. The clinical stage is initially determined from disease history (i.e., cough, dyspnea, chest pain, and weight loss) and physical examination together with the limited battery of tests. Stage confirmation should be done according to the American Joint Committee on Cancer/Union for International Cancer Control system. In case of Stage IIIB-IV lung carcinoma with EGFR-activating mutation, treatment algorithm as shown in [Figure 4] should be followed. Repeat biopsy or liquid biopsy needs to be done to decide the future course of action in case of disease/systemic progression, and osimertinib is the only presently available option if repeat biopsy confirms T790M mutation.,
Currently, only few re-biopsies are performed in relapses or disease progression of advanced NSCLC. They are not very customary in the clinical practice of lung cancer. However, it is not possible to properly target treatments in cases of disease progression without knowing the nature of mutation. Liquid biopsy provides a potent alternative to tissue biopsy in the diagnosis of NSCLC. Various studies to validate polymerase chain reaction (PCR)-based methods to identify EGFR mutants in NSCLC are published., In a recent AURA3 trial, concordance of clinical benefit of osimertinib between plasma T790M-positive patients and tissue T790M-positive patients was observed, based on which the authors recommend routine biopsy testing for patients with a plasma T790M-negative test where feasible. Similar concordance (78.0% for TKI-sensitizing mutations and 65.9% for T790M) for mutation detection by droplet digital PCR (ddPCR) in plasma compared with tumor tissue or malignant fluid specimens was also demonstrated in NSCLC patients, indicating noninvasive genotyping by ddPCR with cell-free DNA extracted from plasma as a promising approach for detection of gene mutations during targeted treatment. In a survey conducted by the NCCN for clinicians about testing for mutations and the use of targeted treatments of NSCLC, 82% of respondents noted that they test for mutations prior to first-line therapy. Clinicians were also asked how they treat patients with driver mutations (EGFR, ALK) who developed resistance to first-line targeted therapy. Most of the clinicians (45%) were still prescribing erlotinib while pemetrexed (35%), and docetaxel (29%) and afatinib (22%) were their second choice. Most importantly, in this survey, more than 70% of respondents indicated that they generally do not conduct a repeat biopsy at disease progression.
| » Conclusion|| |
Disease progression in advanced NSCLC patients during first- and second-generation EGFR-TKI therapy presents a significant challenge to the clinicians. With the advancement in molecular techniques, T790M mutation has been attributed to approximately half of such patients who develop acquired resistance to EGFR-TKIs. Recently, with the approval of T790M-specific osimertinib, it has become possible to offer a highly effective, generally well-tolerated option to the patients, positive to T790M mutation. Hence, a molecular analysis through re-biopsy of patient's tumor becomes extremely important at disease progression in order to serve appropriate treatment option. Results of re-biopsy stratify patients who may benefit from third-generation TKI, osimertinib. However, insufficient specimen and absence of tumor component in the sample are among few of the limitations that should be taken care while collecting sample for repeat biopsy. Finally, improved understanding on the underneath genomics of acquired resistance and the development of targeted therapy hand in hand is a step forward to come closer to personalized medicine for ideal outcomes in NSCLC patients.
The authors acknowledge AstraZeneca Pharma India Ltd and Jeevan Scientific for medical writing and editing support.
Financial support and sponsorship
Financial support to authors - Nil.
The supplement issue in which this article has been published has been sponsored by AstraZeneca Pharma India Ltd.
Conflicts of interest
There are no conflicts of interest.
| » References|| |
Midha A, Dearden S, McCormack R. EGFR mutation incidence in non-small cell lung cancer of adenocarcinoma histology: A systematic review and global map by ethnicity (mutMapII). Am J Cancer Res 2015;5:2892-911.
Travis WD, Brambilla E, Nicholson AG, Yatabe Y, Austin JHM, Beasley MB,et al
. The 2015 world health organization classification of lung tumors: Impact of genetic, clinical and radiologic advances since the 2004 classification. J Thorac Oncol 2015;10:1243-60.
Kota R, Gundeti S, Gullipalli M, Linga VG, Maddali LS, Digumarti R,et al
. Prevalence and outcome of epidermal growth factor receptor mutations in non-squamous non-small cell lung cancer patients. Lung India 2015;32:561-5.
] [Full text]
Wang S, Cang S, Liu D. Third-generation inhibitors targeting EGFR T790M mutation in advanced non-small cell lung cancer. J Hematol Oncol 2016;9:34.
Bhatt AD, Pai R, Rebekah G, Nehru GA, Dhananjayan S, Samuel A,et al
. Clinicopathologic features of non-small cell lung cancer in India and correlation with epidermal growth factor receptor mutational status. Indian J Cancer 2013;50:94-101. [Full text]
Choughule A, Noronha V, Joshi A, Desai S, Jambhekar N, Utture S,et al
. Epidermal growth factor receptor mutation subtypes and geographical distribution among Indian non-small cell lung cancer patients. Indian J Cancer 2013;50:107-11. [Full text]
Doval DC, Azam S, Batra U, Choudhury KD, Talwar V, Gupta SK,et al
. Epidermal growth factor receptor mutation in lung adenocarcinoma in India: A single center study. J Carcinog 2013;12:12.
] [Full text]
Aggarwal S, Patil S, Minhans S, Pungliya M. A study of EGFR mutation in nonsmoker NSCLC: Striking disparity between north and South India patients. Am Soc Clin Oncol 2012;30:15_suppl, e18041.
Klastersky J, Awada A. Milestones in the use of chemotherapy for the management of non-small cell lung cancer (NSCLC). Crit Rev Oncol Hematol 2012;81:49-57.
Wang J, Wang B, Chu H, Yao Y. Intrinsic resistance to EGFR tyrosine kinase inhibitors in advanced non-small cell lung cancer with activating EGFR mutations. Onco Targets Ther 2016;9:3711-26.
Cortot AB, Jänne PA. Molecular mechanisms of resistance in epidermal growth factor receptor-mutant lung adenocarcinomas. Eur Respir Rev 2014;23:356-66.
Ettinger DS, Wood DE, Akerley W, Bazhenova LA, Borghaei H, Camidge DR,et al
. Non-small cell lung cancer, version 6.2015. J Natl Compr Canc Netw 2015;13:515-24.
Prabhakar CN. Epidermal growth factor receptor in non-small cell lung cancer. Transl Lung Cancer Res 2015;4:110-8.
Cheng L, Alexander RE, Maclennan GT, Cummings OW, Montironi R, Lopez-Beltran A,et al
. Molecular pathology of lung cancer: Key to personalized medicine. Mod Pathol 2012;25:347-69.
Bethune G, Bethune D, Ridgway N, Xu Z. Epidermal growth factor receptor (EGFR) in lung cancer: An overview and update. J Thorac Dis 2010;2:48-51.
Ma C, Wei S, Song Y. T790M and acquired resistance of EGFR TKI: A literature review of clinical reports. J Thorac Dis 2011;3:10-8.
Yu HA, Sima CS, Huang J, Solomon SB, Rimner A, Paik P,et al
. Local therapy with continued EGFR tyrosine kinase inhibitor therapy as a treatment strategy in EGFR-mutant advanced lung cancers that have developed acquired resistance to EGFR tyrosine kinase inhibitors. J Thorac Oncol 2013;8:346-51.
Peters S, Adjei AA, Gridelli C, Reck M, Kerr K, Felip E,et al
. Metastatic non-small cell lung cancer (NSCLC): ESMO clinical practice guidelines for diagnosis, treatment and follow-up. Ann Oncol 2012;23 Suppl 7:vii56-64.
Socinski MA, Evans T, Gettinger S, Hensing TA, VanDam Sequist L, Ireland B,et al
. Treatment of stage IV non-small cell lung cancer: Diagnosis and management of lung cancer, 3rd
ed: American college of chest physicians evidence-based clinical practice guidelines. Chest 2013;143:e341S-68S.
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.
Douillard JY, Ostoros G, Cobo M, Ciuleanu T, McCormack R, Webster A,et al
. First-line Gefitinib in Caucasian EGFR mutation-positive NSCLC patients: A phase-IV, open-label, single-arm study. Br J Cancer 2014;110:55-62.
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.
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.
Sequist LV, Yang JC, Yamamoto N, O'Byrne K, Hirsh V, Mok T,et al
. Phase III study of afatinib or cisplatin plus pemetrexed in patients with metastatic lung adenocarcinoma with EGFR mutations. J Clin Oncol 2013;31:3327-34.
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.
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.
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.
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.
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.
Van Assche K, Ferdinande L, Lievens Y, Vandecasteele K, Surmont V. EGFR mutation positive stage IV non-small cell lung cancer: Treatment beyond progression. Front Oncol 2014;4:350.
Califano R, Romanidou O, Mountzios G, Landi L, Cappuzzo F, Blackhall F,et al
. Management of NSCLC disease progression after first-line EGFR tyrosine kinase inhibitors: What are the issues and potential therapies? Drugs 2016;76:831-40.
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.
Ko R, Kenmotsu H, Serizawa M, Koh Y, Wakuda K, Ono A,et al
. Frequency of EGFR T790M mutation and multimutational profiles of rebiopsy samples from non-small cell lung cancer developing acquired resistance to EGFR tyrosine kinase inhibitors in Japanese patients. BMC Cancer 2016;16:864.
Sequist LV, Waltman BA, Dias-Santagata D, Digumarthy S, Turke AB, Fidias P,et al
. Genotypic and histological evolution of lung cancers acquiring resistance to EGFR inhibitors. Sci Transl Med 2011;3:75ra26.
Oxnard GR, Arcila ME, Sima CS, Riely GJ, Chmielecki J, Kris MG,et al
. Acquired resistance to EGFR tyrosine kinase inhibitors in EGFR-mutant lung cancer: Distinct natural history of patients with tumors harboring the T790M mutation. Clin Cancer Res 2011;17:1616-22.
Onitsuka T, Uramoto H, Nose N, Takenoyama M, Hanagiri T, Sugio K,et al
. Acquired resistance to gefitinib: The contribution of mechanisms other than the T790M, MET, and HGF status. Lung Cancer 2010;68:198-203.
Turke AB, Zejnullahu K, Wu YL, Song Y, Dias-Santagata D, Lifshits E,et al
. Preexistence and clonal selection of MET amplification in EGFR mutant NSCLC. Cancer Cell 2010;17:77-88.
Chen HJ, Mok TS, Chen ZH, Guo AL, Zhang XC, Su J,et al
. Clinicopathologic and molecular features of epidermal growth factor receptor T790M mutation and c-MET amplification in tyrosine kinase inhibitor-resistant Chinese non-small cell lung cancer. Pathol Oncol Res 2009;15:651-8.
Costa DB, Nguyen KS, Cho BC, Sequist LV, Jackman DM, Riely GJ,et al
. Effects of erlotinib in EGFR mutated non-small cell lung cancers with resistance to gefitinib. Clin Cancer Res 2008;14:7060-7.
Jiang SX, Yamashita K, Yamamoto M, Piao CJ, Umezawa A, Saegusa M,et al
. EGFR genetic heterogeneity of nonsmall cell lung cancers contributing to acquired Gefitinib resistance. Int J Cancer 2008;123:2480-6.
Bean J, Brennan C, Shih JY, Riely G, Viale A, Wang L,et al
. MET amplification occurs with or without T790M mutations in EGFR mutant lung tumors with acquired resistance to gefitinib or erlotinib. Proc Natl Acad Sci U S A 2007;104:20932-7.
Kosaka T, Yatabe Y, Endoh H, Yoshida K, Hida T, Tsuboi M,et al
. Analysis of epidermal growth factor receptor gene mutation in patients with non-small cell lung cancer and acquired resistance to gefitinib. Clin Cancer Res 2006;12:5764-9.
Balak MN, Gong Y, Riely GJ, Somwar R, Li AR, Zakowski MF,et al
. Novel D761Y and common secondary T790M mutations in epidermal growth factor receptor-mutant lung adenocarcinomas with acquired resistance to kinase inhibitors. Clin Cancer Res 2006;12:6494-501.
Pao W, Miller VA, Politi KA, Riely GJ, Somwar R, Zakowski MF,et al
. Acquired resistance of lung adenocarcinomas to gefitinib or erlotinib is associated with a second mutation in the EGFR kinase domain. PLoS Med 2005;2:e73.
Jackman D, Pao W, Riely GJ, Engelman JA, Kris MG, Jänne PA,et al
. Clinical definition of acquired resistance to epidermal growth factor receptor tyrosine kinase inhibitors in non-small cell lung cancer. J Clin Oncol 2010;28:357-60.
Yu HA, Arcila ME, Rekhtman N, Sima CS, Zakowski MF, Pao W,et al
. Analysis of tumor specimens at the time of acquired resistance to EGFR-TKI therapy in 155 patients with EGFR-mutant lung cancers. Clin Cancer Res 2013;19:2240-7.
Morgillo F, Della Corte CM, Fasano M, Ciardiello F. Mechanisms of resistance to EGFR-targeted drugs: Lung cancer. ESMO Open 2016;1:e000060.
Socinski MA, Villaruz LC, Ross J. Understanding mechanisms of resistance in the epithelial growth factor receptor in non-small cell lung cancer and the role of biopsy at progression. Oncologist 2017;22:3-11.
Novello S, Barlesi F, Califano R, Cufer T, Ekman S, Levra MG,et al
. Metastatic non-small cell lung cancer: ESMO clinical practice guidelines for diagnosis, treatment and follow-up. Ann Oncol 2016;27:v1-27.
Sequist LV, Soria JC, Goldman JW, Wakelee HA, Gadgeel SM, Varga A,et al
. Rociletinib in EGFR-mutated non-small cell lung cancer. N
Engl J Med 2015;372:1700-9.
Ettinger DS, Wood DE, Akerley W, Bazhenova LA, Borghaei H, Camidge DR,et al
. NCCN guidelines insights: Non-small cell lung cancer, version 4.2016. J Natl Compr Canc Netw 2016;14:255-64.
Kim ES. Olmutinib:First global approval. Drugs 2016;76:1153-7.
Liao BC, Lin CC, Lee JH, Yang JC. Update on recent preclinical and clinical studies of T790M mutant-specific irreversible epidermal growth factor receptor tyrosine kinase inhibitors. J Biomed Sci 2016;23:86.
Park K, Lee JS, Han JY, Lee KH, Kim JH, Cho EK,et al
. 1300: Efficacy and safety of BI 1482694 (HM61713), an EGFR mutant-specific inhibitor, in T790M-positive NSCLC at the recommended phase II dose. J Thorac Oncol 2016;11:S113.
Mok TS, Wu YL, Ahn MJ, Garassino MC, Kim HR, Ramalingam SS,et al
. Osimertinib or platinum-pemetrexed in EGFR T790M-positive lung cancer. N
Engl J Med 2017;376:629-40.
Goss G, Tsai C, Shepherd F, Ahn M. MA16.11 CNS Response to Osimertinib in patients with T790M-positive advanced NSCLC: Pooled data from two phase II trials. J Thorac 2017;12:1S.
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.
Schuler M, Planchard D, Yang J, De Marinis F, Bennouna J, Kim J,et al
. Continuation of afatinib (A) beyond progression: results of a randomized, open-label, phase III trial of A plus paclitaxel (P) versus investigator's choice chemotherapy (CT) in patients (pts) with metastatic non-small-cell lung cancer (NSCLC) progressed on erlotinib/gefitinib (E/G) and A: LUX-Lung 5 (LL5). Pneumologie. 2015;69:S01.
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.
Mok T, Wu Y, Nakagawa K, Kim S, Yang J, Ahn M, et al
. Lba2_prgefitinib/chemotherapy vs chemotherapy in epidermal growth factor receptor (egfr) mutation-positive non-small-cell lung cancer (nsclc) after progression on first-line gefitinib: the phase iii, randomised impress study. Annals of Oncology. 2014;25(suppl_4).
Oxnard GR, Thress KS, Alden RS, Lawrance R, Paweletz CP, Cantarini M,et al
. Association between plasma genotyping and outcomes of treatment with osimertinib (AZD9291) in advanced non-small cell lung cancer. J Clin Oncol 2016;34:3375-82.
Xu L, Kikuchi E, Xu C, Ebi H, Ercan D, Cheng KA,et al
. Combined EGFR/MET or EGFR/HSP90 inhibition is effective in the treatment of lung cancers codriven by mutant EGFR containing T790M and MET. Cancer Res 2012;72:3302-11.
Kawamura T, Kenmotsu H, Taira T, Omori S, Nakashima K, Wakuda K,et al
. Rebiopsy for patients with non-small cell lung cancer after epidermal growth factor receptor-tyrosine kinase inhibitor failure. Cancer Sci 2016;107:1001-5.
Nosaki K, Satouchi M, Kurata T, Yoshida T, Okamoto I, Katakami N,et al
. Re-biopsy status among non-small cell lung cancer patients in Japan: A retrospective study. Lung Cancer 2016;101:1-8.
Sueoka-Aragane N, Katakami N, Satouchi M, Yokota S, Aoe K, Iwanaga K,et al
. Monitoring EGFR T790M with plasma DNA from lung cancer patients in a prospective observational study. Cancer Sci 2016;107:162-7.
Sacher AG, Paweletz C, Dahlberg SE, Alden RS, O'Connell A, Feeney N,et al
. Prospective validation of rapid plasma genotyping for the detection of EGFR and KRAS mutations in advanced lung cancer. JAMA Oncol 2016;2:1014-22.
Wu Y, Jenkins S, Ramalingam S, Han J. MA08.03 Osimertinib vs. Platinum-pemetrexed for T790M-mutation positive advanced NSCLC (AURA3): Plasma ctDNA analysis. J Thorac Oncol 2017;12:1S.
Azuma K, Takahama T, Sakai K, Takeda M. MA08.10 Detection of the T790M mutation of EGFR in plasma of advanced NSCLC patients with acquired resistance to EGFR-TKI (WJOG8014LTR). J Thorac 2017;12:1S.
[Figure 1], [Figure 2], [Figure 3], [Figure 4], [Figure 5]
[Table 1], [Table 2], [Table 3], [Table 4]
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