|MOLECULAR TUMOR BOARD
|Year : 2022 | Volume
| Issue : 1 | Page : 122-130
EGFR exon 20 insertion in non-small cell lung cancer
Goutam Santosh Panda1, Vanita Noronha1, Omshree Shetty2, Subhash Yadav2, Rajiv Kumar2, Vijay Patil1, Pratik Chandrani1, Amit Janu3, Abhishek Mahajan1, Anuradha Chougule1, Kumar Prabhash1
1 Department of Medical Oncology, Tata Memorial Hospital, Homi Bhabha National Institute (HBNI), Mumbai, Maharashtra, India
2 Department of Pathology, Tata Memorial Hospital, Homi Bhabha National Institute (HBNI), Mumbai, Maharashtra, India
3 Department of Radiodiagnosis, Tata Memorial Hospital, Homi Bhabha National Institute (HBNI), Mumbai, Maharashtra, India
|Date of Submission||08-Feb-2022|
|Date of Decision||20-Feb-2022|
|Date of Acceptance||11-Mar-2022|
|Date of Web Publication||31-Mar-2022|
Professor, Department of Medical Oncology, Tata Memorial Hospital, Dr. E Borges Road, Parel, Mumbai - 400 012, Maharashtra
Source of Support: None, Conflict of Interest: None
|How to cite this article:|
Panda GS, Noronha V, Shetty O, Yadav S, Kumar R, Patil V, Chandrani P, Janu A, Mahajan A, Chougule A, Prabhash K. EGFR exon 20 insertion in non-small cell lung cancer. Cancer Res Stat Treat 2022;5:122-30
|How to cite this URL:|
Panda GS, Noronha V, Shetty O, Yadav S, Kumar R, Patil V, Chandrani P, Janu A, Mahajan A, Chougule A, Prabhash K. EGFR exon 20 insertion in non-small cell lung cancer. Cancer Res Stat Treat [serial online] 2022 [cited 2022 May 21];5:122-30. Available from: https://www.crstonline.com/text.asp?2022/5/1/122/341261
| Case Summary|| |
History and Examination
A 50-year-old lady with no history of smoking and no comorbidities presented in December 2020 with a 6-month history of dry cough and weight loss. At presentation, she had an Eastern Cooperative Oncology Group performance status (ECOG PS) of 2 and there was no palpable lymphadenopathy.
Investigations and Diagnosis
Computed tomography (CT) thorax revealed an area of consolidation measuring 8.5 x 4 x 4.5 cm in the anterior basal and medial basal segments of the lower lobe of the right lung, mediastinal lymphadenopathy, and bilateral lung nodules, suspicious for metastatic malignancy [Figure 1]. CT-guided biopsy from the lung mass revealed adenocarcinoma. Thus, the patient was diagnosed with lung adenocarcinoma, cT4cN3cM1a, staged according to the American Joint Committee on Cancer (AJCC) staging system, 8th edition. Immunohistochemistry for anaplastic lymphoma kinase (ALK), ROS proto-oncogene 1 (ROS1), and programmed death-ligand 1 (PD-L1) was negative. Fluorescence in situ hybridization (FISH) for ALK1 was also negative.
|Figure 1: Computed tomography scan of the patient showing consolidation involving the lower lobe of right lung|
Click here to view
The patient refused intravenous chemotherapy; therefore, she was empirically started on erlotinib in January 2021. The in-house epidermal growth factor receptor (EGFR) reverse transcription-polymerase chain reaction (RT-PCR) report, which was available in March 2021, showed an EGFR exon 20 insertion mutation (Ex20ins). The patient continued to refuse chemotherapy, and she was, therefore, continued on erlotinib after a thorough discussion of the possible treatment options, effects, and side effects. In April 2021, she had disease progression with multiple new-onset lung nodules. At progression, she had an ECOG PS of 1, there was no deterioration of her general condition, and there were no fresh complaints. Erlotinib was stopped and the patient was again advised chemotherapy. Repeat biopsy from the lung mass revealed adenocarcinoma. Next-generation sequencing (NGS) was performed on this specimen. The patient consented to receive chemotherapy. She was started on pemetrexed–carboplatin doublet, and radiologic imaging revealed stable disease after four cycles. Maintenance pemetrexed was administered. The disease progressed in the lungs in Sept 2021 after four cycles of maintenance pemetrexed. The patient's general condition was well preserved with an ECOG PS of 1 and she had not developed any new symptoms.
NGS analysis was carried out on the post-erlotinib progression biopsy specimen using the MiSeq for Illumina Focus panel for the detection of DNA alterations, including single-nucleotide variants (SNVs) and insertions/deletions in 42 genes, 139 RNA fusions, gene amplification events in 24 genes, and microsatellite instability (MSI) status at six unique loci. The DNA and RNA libraries were prepared using the Solid Tumor Plus library preparation kit and loaded on the Illumina MiSeq system for sequencing. The data were analyzed using the SOPHiA DDM, a platform for data analysis and clinical report generation. With a mean depth of coverage for SNV/DNA variants of 1339, the patient was found to harbor an insertion mutation (pHis773dup; variant description: NM_005228: c. 2317_2319dup) in exon 20 of EGFR with a variant allele frequency of 51% [Table 1]. The mutation was classified as a tier I pathogenic variant. No other mutation was identified, and the MSI status was also found to be stable in the NGS.
|Table 1: Next-generation sequencing of the patient with EGFR exon 20 insertion mutation|
Click here to view
| Excerpts from the Discussion in the Molecular Tumor Board|| |
EGFR Ex20ins mutations are the third most prevalent subtype of EGFR mutations, accounting for approximately 10%-12% of all EGFR-mutant non-small cell lung cancers (NSCLCs). They are mutually exclusive of other known driver mutations., Ex20ins in EGFR-mutant NSCLC include in-frame insertions and/or duplications of 3 to 21 base pairs typically occurring between amino acids (AA) 761 and 775.[2–4] The first- and second-generation EGFR tyrosine kinase inhibitors (TKIs) have limited activity against EGFR Ex20ins, apart from the EGFR Ex20ins A763_Y764insFQEA and H773dup, H773_V774insNPH, and N771delinsKG mutations.[5–7] The data regarding osimertinib in EGFR Ex20ins are conflicting with some preclinical studies reporting efficacy, while others have suggested a lack of efficacy. Both mobocertinib and amivantamab are approved options for second- or later-line therapy in patients with EGFR Ex20ins. As our patient had progressed on platinum-based chemotherapy and as neither of the approved therapeutic choices was available in India at the time, the Molecular Tumor Board recommended procuring amivantamab for the patient through an expanded access program.
The patient was started on single agent amivantamab in December 2021, and she tolerated it well, except for grade 2 skin rash. She developed coronavirus disease 2019 (COVID-19) infection and was advised home isolation, hence amivantamab was held for 3 weeks. Amivantamab was restarted at the same dose after recovery from COVID-19. Response assessment scan after 6 cycles showed stable disease, and she continues on amivantamab.
| Discussion|| |
EGFR Ex20ins: Molecular Insights
EGFR Ex20ins spans the AA762–823 and has two segments: the regulatory C-helix domain (AA762–766) and the loop that precedes it (AA767–774). EGFR Ex20ins often occur between AA761 and AA775 and comprise in-frame insertions and/or duplications of 3 to 21 base pairs [Figure 2]., Of >60 distinct activating EGFR Ex20ins discovered to date, most consist of one to four AA insertions situated in the loop after the C-helix [Figure 2]., The substantial variety of detected insertions contrasts sharply with both EGFR exon 19 deletion (del19) mutations, which show less diversity with a narrow range of in-frame insertions and/or deletions (indels) and HER2 Ex20ins mutations, which most typically occur as A775_G776insYVMA. Unlike EGFR del19 and L858R mutations, the most prevalent EGFR Ex20ins has no effect on the structure of the EGFR adenosine triphosphate (ATP)-binding pocket, according to early crystal structure research. Thus, although EGFR del19 and L858R mutations enhance the relative affinity for EGFR TKIs over ATP compared to wild-type EGFR, EGFR Ex20ins mutations do not., Notably, three-dimensional modeling of EGFR Ex20ins D770insNPG-solved crystal structures comparing EGFR T790M and wild-type EGFR revealed that this representative EGFR Ex20ins exhibited a structure similar to the EGFR T790M model in terms of gatekeeper residue positioning, confirming the reason for non-covalent, first-generation TKI resistance. Steric hindrance is caused by putting the C-helix and P-loop closer to the drug-binding pocket, which lowers the TKI binding. These structural differences explain the difficulties in creating effective small-molecule EGFR Ex20ins inhibitors, as well as the lack of clinical effectiveness of first- and second-generation EGFR TKIs against EGFR Ex20ins–positive tumors.,,, Notably, the EGFR Ex20ins A763_Y764insFQEA has been demonstrated to have a 10-fold greater binding affinity for first-generation EGFR TKIs than other EGFR Ex20ins mutations, corresponding to a higher ratio of TKI-to-ATP affinity and subsequent higher susceptibility to TKI-induced receptor inhibition in vitro and in vivo. Some case reports have also reported the efficacy of afatinib in patients with H773dup, H773_V774insNPH, and N771delinsKG mutations,[5–7] albeit the structural elements of these unique variations that might explain this sensitivity have not been thoroughly explored.
|Figure 2: Location of EGFR exon 20 insertion mutations and sensitivity to TKIs. EGFR = epidermal growth factor receptor, TKIs = tyrosine kinase inhibitors|
Click here to view
EGFR Ex20ins versus ERBB2 Ex20ins
Although these mutations share a similar biology and some therapies are active in both types of Ex20ins mutations, the molecular features and spectrum of mutations found in HER2 Ex20ins-positive NSCLC have less heterogeneity and follow a different pattern compared to EGFR Ex20ins-mutant NSCLC.
Testing for EGFR Ex20ins
Why to test?
Similar to the classical sensitizing EGFR L858R and del19, EGFR Ex20ins mutation is considered a molecular driver of NSCLC. EGFR ex20ins is the third most common EGFR mutation after del19 and L858R, accounting for up to 12% of all EGFR-activating mutations.[2–4] Furthermore, the frequency of EGFR Ex20ins–mutated cases ranges from 0.1% to 4% of all NSCLC cases, which is comparable to that of other targetable driver mutations like ROS1 that are commonly tested for as part of the standard workup of patients with advanced NSCLC. With the development of newer therapies, targeting this mutation might improve the outcome of these patients.
How to detect?
EGFR mutations can be detected by either PCR or NGS. The advantages of NGS over PCR include its comprehensiveness and the use of minimal amount of tumor tissue. PCR has been reported to miss approximately 50% cases of EGFR exon20ins identified by NGS. Limitations of NGS include availability of multiple platforms using different methodologies that affect types of alterations detected. Additional drawbacks of NGS include the long turnaround time, high cost, and its inaccessibility, especially in community practices.
Whom and when to test?
The clinicodemographic profile of patients with EGFR Ex20ins is similar to that of patients with the more common del19 and L858R mutations, that is, more likely to occur in women, nonsmokers, with adenocarcinoma histology, and associated with an increased predisposition to develop brain metastases., If not tested for at baseline, EGFR Ex20ins should be tested for at relapse.
A retrospective study from our institute looking at uncommon EGFR mutations demonstrated that approximately 20% of patients with EGFR mutations harbored EGFR Ex20ins and these patients had a median progression free survival (PFS) of 6 months (95% confidence interval [CI], 2.4–9.6), and median overall survival (OS) of 15.8 months (95% CI, 6.2–25.3). Another study by our team reported dismal outcomes with a median OS of only 5 months (95% CI, 0.17–9.8) in patients with EGFR Ex20ins.
The various studies evaluating therapies for advanced NSCLC with EGFR ex20ins are summarized in [Table 2].
|Table 2: Summary of trials investigating various therapies for advanced NSCLC with EGFR exon 20 insertion mutation|
Click here to view
Epidermal growth factor receptor tyrosine kinase inhibitors
First-generation TKIs (erlotinib, gefitinib)
These reversible, ATP-competitive EGFR TKIs are active against the classical sensitizing del19 and L858R mutations, resulting in an objective response rate (ORR) up to 72% and a median PFS of 8–10 months in patients with advanced NSCLC harboring these mutations.[25–27] Apart from A763_Y764insFQEA mutation, the outcome with first-generation EGFR TKIs has been dismal with an ORR of 8% in one study and 27% in another study, with a median PFS of <3 months.,
Second-generation TKIs (afatinib, dacomitinib, neratinib)
Unlike the first-generation TKIs, the second-generation EGFR TKIs irreversibly bind to a specific site with a cysteine residue (C797S) and also have activity against at least one more EGFR family member. Afatinib is approved in patients with NSCLC with rare EGFR mutations (G719X, S786I, L861Q) based on the clinical activity of the drug, as noted in the post hoc analysis of the LUX-Lung 2, LUX-Lung 3, and LUX-Lung 6 trials. Afatinib, however, had minimal activity in a cohort of 23 patients with EGFR Ex20ins (ORR, 8.7%; PFS, 2.7 months [95% CI, 1.8–4.2] months). The efficacy of afatinib in patients with H773_V774insNPH, and N771delinsKG mutations has been suggested in few case reports.[5–7]
Preclinical data have reported the efficacy of dacomitinib, neratinib, and afatinib in certain types of EGFR Ex20ins mutations. In particular, insertion mutations that introduce a glycine residue at position 770 are particularly susceptible to the EGFR/HER2-targeting drug, dacomitinib. Additionally, the only patient who had a partial response to dacomitinib in a Phase I trial had the D770delinsGY mutation.
Third-generation EGFR TKIs (osimertinib, rociletinib)
Data regarding the efficacy of osimertinib in EGFR Ex20ins mutations have been conflicting with some studies showing benefit, and others reporting a lack of activity., Hirano et al. have noted a better half-maximal inhibitory concentration (IC50) for osimertinib compared to other EGFR TKIs; yet the IC50 for osimertinib in EGFR Ex20ins was 10–100 times higher than those for del19, L858R, and T790M. Hence, it was presumed that a higher dose of osimertinib may lead to better efficacy in EGFR Ex20ins. A recent Phase II single-arm study on patients with EGFR Ex20ins who had received at least one prior line of therapy reported that the double dose of osimertinib, that is, 160 mg orally daily, resulted in an encouraging median PFS of 9.7 (95% CI, 4.07–not evaluable) months and a disease control rate of 85%. An earlier Phase II study testing the efficacy of osimertinib 80 mg orally once daily in patients with EGFR Ex20ins who had failed standard chemotherapy reported a disappointing median PFS of 3.5 (95% CI, 1.6–not reached) months.
Poziotinib is an irreversible EGFR TKI that is structurally similar to afatinib, with some unique features such as higher freedom of rotation around the amine and ether groups and more halogenation of the terminal benzene ring. Poziotinib has more favorable in vitro activity and IC50 than both osimertinib and afatinib (potency approximately 100 and 40 times higher compared to osimertinib and afatinib, respectively) in EGFR Ex20ins–mutant cell lines. [Table 2] depicts the relevant research studies including those in genetically engineered mouse models, patient-derived xenografts (PDX), Phase I studies, and the multicenter Phase II ZENITH 20 study. The results of the ZENITH 20 trial conducted on patients with EGFR Ex20ins who had progressed on at least one line of therapy and received poziotinib 16 mg orally once daily showed an ORR of 14.8% and a median PFS of 4.2 months. Responses were predominantly noted in cases with insertions between residues M766 and D770 of exon 20 (18.2%). The adverse effects of this drug, such as skin and gastrointestinal toxicity, necessitated dose reductions in 65% of the patients. This highlights the challenge in achieving an adequate therapeutic index with poziotinib, similar to the other second-generation EGFR TKIs, afatinib and dacomitinib, due to the EGFR–wild-type adverse effects. The ongoing ZENITH trial is exploring alternative dosing strategies for poziotinib, for example, 8 mg twice a day (NCT03318939), to improve the tolerability and safety.
Mobocertinib, previously known as TAK-788, is an irreversible EGFR TKI that binds to C797, which was specifically designed to target EGFR ex20ins, without significantly affecting the wild-type EGFR. Clinical data have shown the efficacy of mobocertinib in previously treated patients with EGFR Ex20ins mutation; the median PFS (investigator assessed) was 7.3 months and the ORR ranged from 32% to 42%., The adverse events with mobocertinib were akin to those from other EGFR TKIs, such as diarrhea, paronychia, and skin rash. Mobocertinib was granted accelerated approval from the Food and Drug Administration (FDA) on September 15, 2021, for patients with advanced or metastatic NSCLC with EGFR Ex20ins post-progression on or after platinum-based chemotherapy.
Other novel EGFR TKIs
- CLN-081 (TAS6417): This drug, like other irreversible EGFR TKIs, covalently binds to the EGFR protein at C797. Various preclinical studies have demonstrated the selectivity and potency of CLN-081 in patients with EGFR Ex20ins., The interim results of a Phase I/IIa trial, which enrolled patients harboring EGFR Ex20ins, showed promising results with CLN-081, with 40% achieving partial responses and 56% achieving stable disease.
- BDTX-189: This drug is currently being tested in a Phase I/II trial (NCT04209465) in patients with advanced solid tumors with EGFR/ERBB2 exon 20 mutations with no standard therapy available or who are unsuitable or unable to tolerate standard therapy.
Because of the paucity of effective targeted agents, chemotherapy remains the recommended first-line systemic treatment in patients with EGFR Ex20ins mutations and clinical outcomes are comparable to those attained in EGFR–wild-type NSCLC. Pemetrexed-based regimens had led to better survival, both PFS and OS, compared to non-pemetrexed–based chemotherapy.,
Recently published real-world data from Bazhenova et al. reported that patients with EGFR Ex20ins mutations derive little benefit from EGFR TKIs with a median real-world PFS (rwPFS) of 2.9 (95% CI, 2.14–3.91) months, compared to a median rwPFS of 6.6 months from platinum-based chemotherapy. The study also reported that platinum-based chemotherapy was the most common first-line systemic therapy and among the EGFR TKIs, the first-generation EGFR TKIs were more commonly used than the second- and third-generation TKIs.
A nation-wide study of NSCLC patients with EGFR Ex20ins in China has shown that the addition of bevacizumab to second-line chemotherapy in patients with EGFR Ex20ins mutation led to a statistically significant improvement in the median PFS ([6.0 months; 95% CI, 4–8] vs. [2.4 months; 95% CI, 1.8–3]; P = 0.013). However, the addition of bevacizumab in the first-line setting did not lead to a better PFS.
The role of immunotherapy particularly, as a part of first-line chemo-immunotherapy in patients with EGFR Ex20ins mutation is little understood. In some countries, the IMpower150 regimen (carboplatin, paclitaxel, bevacizumab, and atezolizumab) is approved for the treatment of metastatic non-squamous NSCLC, based on the randomized Phase III trial that showed improved OS in non-squamous NSCLC, regardless of PD-L1 expression level or the presence of EGFR or ALK alterations. Bazhenova et al. recently reported that in a real-world cohort of patients with EGFR Ex20ins mutation treated in the first-line setting, there was no statistically significant benefit from the use of platinum-based chemo-immunotherapy (median rwPFS, 4.8 months; median real-world OS (rwOS), 11 months) compared to platinum-based chemotherapy alone (median rwPFS, 6.6 months; median rwOS, 17.4 months). Another recently published retrospective study reported that the median time on chemo-immunotherapy was similar between patients with EGFR Ex20ins mutations and those without known driver alterations in EGFR, ALK, RET, and BRAF V600E (median 7 vs. 5 months; hazard ratio [HR], 1.1; 95% CI, 0.52–2.41; P = 0.8). The low response to immunotherapy noted in patients with EGFR Ex20ins mutation is similar to that noted in other molecularly driven NSCLC subtypes.,
Monoclonal antibody–based therapies
Amivantamab is a bispecific antibody that targets both EGFR and c-MET. Because it is only approved for use in the second- and later-line of therapy, it does not necessarily affect the first-line treatment for patients with EGFR Ex20ins mutations. However, it is an excellent choice for patients who have progressed on platinum-based chemotherapy. Amivantamab gained approval in May 2021 based on the results of the CHRYSALIS trial, which enrolled 81 patients with EGFR Ex20ins who had progressed on platinum-based chemotherapy. Amivantamab was administered at the recommended phase 2 dose (RP2D) of 1050 mg (1400 mg for patients who weighed 80 kg or more) and led to an ORR of 40% and a median PFS of 8.3 (95% CI, 6.5–10.9) months., Approximately 86% patients developed rashes, albeit many were mild. Approximately two-thirds of the patients developed infusion-related reactions. These appeared to be the most prevalent on the first day of the first cycle of therapy.
A multicenter, global, Phase III randomized study (PAPILLON, NCT04538664) of amivantamab plus chemotherapy versus chemotherapy only in the first-line setting for patients with advanced NSCLC harboring EGFR Ex20ins mutations is now underway; our center, Tata Memorial Hospital, Mumbai, India, is participating in this study.
Amivantamab, necitumumab, and cetuximab are now being studied in conjunction with numerous second- and third-generation EGFR TKIs. When compared to afatinib alone, the addition of cetuximab to afatinib did not lead to improved PFS, but was associated with more skin-related toxicities in patients with canonical EGFR mutations. Of note, three out of four patients with advanced NSCLC with EGFR Ex20ins and progression on platinum-based chemotherapy ± EGFR TKI attained partial responses from the combination of afatinib and cetuximab. The interim results of a single-arm Phase II study of afatinib plus cetuximab in patients with NSCLC with EGFR Ex20ins showed a median PFS of 5.5 months, a disease control rate of 59% at 18 weeks, and manageable toxicity. The combination of amivantamab and the third-generation EGFR TKI, lazertinib, is being studied in the CHRYSALIS-2 study in patients who have EGFR ex20ins mutated–NSCLC and have progressed on platinum-based chemotherapy. A Phase I study of necitumumab plus osimertinib in patients with EGFR TKI–resistant NSCLC found that two out of four patients with EGFR Ex20ins responded to the regimen, with a median PFS of 5.3 months.
Other systemic therapies
Luminespib, a heat shock protein (HSP) 90 inhibitor, has shown activity against EGFR Ex20ins in preclinical trials. A Phase II study reported that luminespib is well tolerated and may be active in patients with advanced NSCLC with EGFR Ex20ins. The reported median PFS and OS from luminespib were 2.9 (95% CI, 1.4–5.6) months and 13 (95% CI, 4.9–19.5) months, respectively.
Tarloxotinib is a pro-drug and is a hypoxia-activated pan-HER kinase inhibitor. The results of the Phase II clinical trial of tarloxotinib in patients with EGFR mutant, T790M-negative NSCLC who had progressed on first-line EGFR inhibitors was disheartening; although a third of the patients (7 of 21) attained stable disease, there were no confirmed partial responses, resulting in premature termination of the trial. An in vivo study employing mouse xenografts of two NSCLC cell lines with endogenous EGFR Ex20ins mutations, CUTO14 (A767_V769dupASV) and CUTO17 (N771_H773dupNPH), demonstrated good tumor regression with tarloxotinib therapy, while there was no response to afatinib.
Estrada-Bernal et al. have suggested that the anticancer activity of tarloxotinib can have a broad therapeutic index when compared to the on-target wild-type EGFR toxicity in neighboring normal tissues. An ongoing Phase II study of tarloxotinib showed that no patient with EGFR Ex20ins achieved a partial response, 55% had stable disease, and 45% had progressive disease when treated with tarloxotinib.
Central nervous system metastases
The central nervous system (CNS) action of each of these drugs is a crucial factor when evaluating the effectiveness of new targeted treatments for EGFR Ex20ins NSCLC. Most of the drugs discussed above have no particular CNS activity, although limited data from the mobocertinib clinical study reveal a lower ORR in patients with CNS metastases than those without, implying that this molecule has minimal CNS activity., Though osimertinib at high doses (160 mg orally daily) has been shown to have less activity against EGFR Ex20ins mutant NSCLC than other treatments in development, prior clinical studies in patients with classical EGFR-activating and T790M mutations have confirmed its significant CNS activity.
Preliminary evidence from a small number of patients treated with amivantamab suggests that individuals with and without brain metastases had similar results; nonetheless, its large molecular size might prevent substantial CNS activity. This is the reasoning behind clinical trials exploring the combination of monoclonal antibodies with a third-generation EGFR TKI, for example, lazertinib, which has CNS activity [Table 2].
| Conclusion|| |
NGS should be done for all patients with advanced or metastatic NSCLC. Though there is no recommended targeted therapy in the first-line setting in patients with EGFR Ex20ins, tremendous advances in research have now provided us with several targeted therapies for relapsed disease. Amivantamab in the second line provides durable responses with tolerable safety in these patients; mobercertinib is another approved treatment option.
Declaration of patient consent
The authors certify that they have obtained all appropriate patient consent forms. In the form the patient has given her consent for her images and other clinical information to be reported in the journal. The patient understands that her name and initials will not be published and due efforts will be made to conceal her identity, but anonymity cannot be guaranteed.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
| References|| |
Amin MB, Greene FL, Edge SB, Compton CC, Gershenwald JE, Brookland RK, et al
. The Eighth Edition AJCC Cancer Staging Manual: Continuing to build a bridge from a population-based to a more “personalized” approach to cancer staging. CA Cancer J Clin 2017;67:93–9.
Riess JW, Gandara DR, Frampton GM, Madison R, Peled N, Bufill JA, et al
. Diverse EGFR Exon 20 insertions and co-occurring molecular alterations identified by comprehensive genomic profiling of NSCLC. J Thorac Oncol 2018;13:1560–8.
Arcila ME, Nafa K, Chaft JE, Rekhtman N, Lau C, Reva BA, et al
. EGFR exon 20 insertion mutations in lung adenocarcinomas: Prevalence, molecular heterogeneity, and clinicopathologic characteristics. Mol Cancer Ther 2013;12:220–9.
Yasuda H, Park E, Yun CH, Sng NJ, Lucena-Araujo AR, Yeo WL, et al
. Structural, biochemical, and clinical characterization of epidermal growth factor receptor (EGFR) exon 20 insertion mutations in lung cancer. Sci Transl Med 2013;5:216ra177.
Zöchbauer-Müller S, Kaserer B, Prosch H, Cseh A, Solca F, Bauer MJ, et al
. Case report: Afatinib treatment in a patient with NSCLC harboring a rare EGFR Exon 20 mutation. Front Oncol 2021;10:593852.
Urbán L, Dóczi R, Vodicska B, Tihanyi D, Horváth M, Kormos D, et al
. Major clinical response to afatinib monotherapy in lung adenocarcinoma harboring EGFR Exon 20 insertion mutation. Clin Lung Cancer 2021;22:e112–5.
Lin L, Wu X, Yan S, Zhu Y, Yan Z, Lv D, et al
. Response to afatinib in a patient with NSCLC harboring novel EGFR Exon 20 insertion mutations. Onco Targets Ther 2020;13:9753–7.
Floc'h N, Martin MJ, Riess JW, Orme JP, Staniszewska AD, Ménard L, et al
. Antitumor activity of osimertinib, an irreversible mutant-selective EGFR tyrosine kinase inhibitor, in NSCLC harboring EGFR Exon 20 insertions. Mol Cancer Ther 2018;17:885–96.
Hirano T, Yasuda H, Tani T, Hamamoto J, Oashi A, Ishioka K, et al
. In vitro
modeling to determine mutation specificity of EGFR tyrosine kinase inhibitors against clinically relevant EGFR mutants in non-small-cell lung cancer. Oncotarget 2015;6:38789–803.
Cross DA, Ashton SE, Ghiorghiu S, Eberlein C, Nebhan CA, Spitzler PJ, et al
. AZD9291, an irreversible EGFR TKI, overcomes T790M-mediated resistance to EGFR inhibitors in lung cancer. Cancer Discov 2014;4:1046–61.
Fang W, Huang Y, Hong S, Zhang Z, Wang M, Gan J, et al
. EGFR exon 20 insertion mutations and response to osimertinib in non-small-cell lung cancer. BMC Cancer 2019;19:595.
Arcila ME, Chaft JE, Nafa K, Roy-Chowdhuri S, Lau C, Zaidinski M, et al
. Prevalence, clinicopathologic associations, and molecular spectrum of ERBB2 (HER2) tyrosine kinase mutations in lung adenocarcinomas Clin Cancer Res 2012;18:4910–8.
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. [Full text]
Robichaux JP, Elamin YY, Tan Z, Carter BW, Zhang S, Liu S, et al
. Mechanisms and clinical activity of an EGFR and HER2 exon 20-selective kinase inhibitor in non-small cell lung cancer. Nat Med 2018;24:638–46.
Oxnard GR, Lo PC, Nishino M, Dahlberg SE, Lindeman NI, Butaney M, et al
. Natural history and molecular characteristics of lung cancers harboring EGFR exon 20 insertions. J Thorac Oncol 2013;8:179–84.
Yang JC, Sequist LV, Geater SL, Tsai CM, Mok TS, Schuler M, et al
. Clinical activity of afatinib in patients with advanced non-small-cell lung cancer harbouring uncommon EGFR mutations: A combined post-hoc analysis of LUX-Lung 2, LUX-Lung 3, and LUX-Lung 6. Lancet Oncol 2015;16:830–8.
Bondili SK, Nandhana R, Noronha V, Pawar S, Menon N, Shetty O, et al
. HER2 alterations in non-small-cell lung cancer--Druggable or undruggable? Cancer Res Stat Treat 2021;4:374-84. [Full text]
Burnett H, Emich H, Carroll C, Stapleton N, Mahadevia P, Li T. Epidemiological and clinical burden of EGFR Exon 20 insertion in advanced non-small cell lung cancer: A systematic literature review. PLoS One 2021;16:e0247620.
Mehta A, Saifi M, Batra U, Suryavanshi M, Gupta K. Incidence of ROS1-rearranged non-small-cell lung carcinoma in India and efficacy of crizotinib in lung adenocarcinoma patients. Lung Cancer 2020;11:19–25.
Bauml JM, Viteri S, Minchom A, Bazhenova L, Ou S, Schaffer M, et al
. FP07.12 underdiagnosis of EGFR Exon 20 insertion mutation variants: Estimates from NGS-based real-world datasets. J Thorac Oncol 2021;16:S208–9.
Cardona AF, Rojas L, Zatarain-Barrón ZL, Freitas HC, Granados ST, Castillo O, et al
. EGFR exon 20 insertion in lung adenocarcinomas among Hispanics (geno1.2-CLICaP). Lung Cancer 2018;125:265–72.
Yang G, Li J, Xu H, Yang Y, Yang L, Xu F, et al
. EGFR exon 20 insertion mutations in Chinese advanced non-small cell lung cancer patients: Molecular heterogeneity and treatment outcome from nationwide real-world study. Lung Cancer 2020;145:186–94.
Kate S, Chougule A, Joshi A, Noronha V, Patil V, Dusane R, et al
. Outcome of uncommon EGFR mutation positive newly diagnosed advanced non-small cell lung cancer patients: A single center retrospective analysis. Lung Cancer 2019;10:1–10.
Noronha V, Choughule A, Patil VM, Joshi A, Kumar R, Susan Joy Philip D, et al
. Epidermal growth factor receptor exon 20 mutation in lung cancer: Types, incidence, clinical features and impact on treatment. Onco Targets Ther 2017;10:2903–8.
Hirsch FR, Varella-Garcia M, Bunn PA Jr, Franklin WA, Dziadziuszko R, Thatcher N, et al
. Molecular predictors of outcome with gefitinib in a phase III placebo-controlled study in advanced non-small-cell lung cancer. J Clin Oncol 2006;24:5034–42.
Noronha V, Patil VM, Joshi A, Menon N, Chougule A, Mahajan A, et al
. Gefitinib versus gefitinib plus pemetrexed and carboplatin chemotherapy in EGFR-mutated lung cancer. J Clin Oncol 2020;38:124–36.
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.
Naidoo J, Sima CS, Rodriguez K, Busby N, Nafa K, Ladanyi M, et al
. Epidermal growth factor receptor exon 20 insertions in advanced lung adenocarcinomas: Clinical outcomes and response to erlotinib. Cancer 2015;121:3212–20.
Beau-Faller M, Prim N, Ruppert AM, Nanni-Metéllus I, Lacave R, Lacroix L, et al
. Rare EGFR exon 18 and exon 20 mutations in non-small-cell lung cancer on 10 117 patients: A multicentre observational study by the French ERMETIC-IFCT network. Ann Oncol 2014;25:126–31.
Yu HA, Riely GJ. Second-generation epidermal growth factor receptor tyrosine kinase inhibitors in lung cancers. J Natl Compr Canc Netw 2013;11:161–9.
Kosaka T, Tanizaki J, Paranal RM, Endoh H, Lydon C, Capelletti M, et al
. Response heterogeneity of EGFR and HER2 Exon 20 insertions to covalent EGFR and HER2 inhibitors. Cancer Res 2017;77:2712–21.
Jänne PA, Boss DS, Camidge DR, Britten CD, Engelman JA, Garon EB, et al
. Phase I dose-escalation study of the pan-HER inhibitor, PF299804, in patients with advanced malignant solid tumors. Clin Cancer Res 2011;17:1131–9.
Yang M, Xu X, Cai J, Ning J, Wery JP, Li QX. NSCLC harboring EGFR exon-20 insertions after the regulatory C-helix of kinase domain responds poorly to known EGFR inhibitors. Int J Cancer 2016;139:171–6.
Piotrowska Z, Wang Y, Sequist LV, Ramalingam SS. ECOG-ACRIN 5162: A phase II study of osimertinib 160 mg in NSCLC with EGFR exon 20 insertions. J Clin Oncol 2020;38:9513.
Kim TM, Ock CY, Kim M, Kim SH, Keam B, Kim YJ, et al
. 1529P-Phase II study of osimertinib in NSCLC patients with EGFR exon 20 insertion mutation: A multicenter trial of the Korean Cancer Study Group (LU17-19). Ann Oncol 2019;30:v628.
Le X, Goldman JW, Clarke JM, Tchekmedyian N, Piotrowska Z, Chu D, et al
. Poziotinib shows activity and durability of responses in subgroups of previously treated EGFR exon 20 NSCLC patients. J Clin Oncol 2020;38:9514.
Riely GJ, Neal JW, Camidge DR, Spira AI, Piotrowska Z, Costa DB, et al
. Activity and safety of mobocertinib (TAK-788) in previously treated non-small cell lung cancer with EGFR Exon 20 insertion mutations from a phase I/II trial. Cancer Discov 2021;11:1688–99.
Zhou C, Ramalingam S, Li B, Fang J, Kim TM, Kim S, et al
. OA04.03 Mobocertinib in NSCLC with EGFR Exon 20 insertions: Results from EXCLAIM and pooled platinum-pretreated patient populations. J Thorac Oncol 2021;16:S108.
Hasako S, Terasaka M, Abe N, Uno T, Ohsawa H, Hashimoto A, et al
. TAS6417, A Novel EGFR inhibitor targeting Exon 20 insertion mutations. Mol Cancer Ther 2018;17:1648–58.
Udagawa H, Hasako S, Ohashi A, Fujioka R, Hakozaki Y, Shibuya M, et al
. TAS6417/CLN-081 Is a pan-mutation-selective EGFR tyrosine kinase inhibitor with a broad spectrum of preclinical activity against clinically relevant EGFR mutations. Mol Cancer Res 2019;17:2233–43.
Piotrowska Z, Yu HA, Yang JC, Koczywas M, Smit EF, Tan DS, et al
. Safety and activity of CLN-081 (TAS6417) in NSCLC with EGFR Exon 20 insertion mutations (Ins20). J Clin Oncol 2021;39:9077.
A Study of BDTX-189, an Orally Available Allosteric ErbB Inhibitor, in Patients With Advanced Solid Tumors.-Full Text View-ClinicalTrials.Gov. Available from: https://clinicaltrials.gov/ct2/show/NCT04209465
. [Last accessed on 2022 Mar 11].
Xu CW, Wang WX, Wang D, Wang QM, Pu XX, Zhu YC, et al
. Pemetrexed-based chemotherapy for non-small-cell lung cancer patients with EGFR exon 20 insertion mutation: A multicenter study. Transl Lung Cancer Res 2020;9:1853–61.
Wu JY, Yu CJ, Shih JY. Effectiveness of treatments for advanced non-small-cell lung cancer with Exon 20 insertion epidermal growth factor receptor mutations. Clin Lung Cancer 2019;20:e620–30.
Bazhenova L, Minchom A, Viteri S, Bauml JM, Ou SI, Gadgeel SM, et al
. Comparative clinical outcomes for patients with advanced NSCLC harboring EGFR exon 20 insertion mutations and common EGFR mutations. Lung Cancer 2021;162:154–61.
Socinski MA, Jotte RM, Cappuzzo F, Orlandi F, Stroyakovskiy D, Nogami N, et al
. Atezolizumab for first-line treatment of metastatic nonsquamous NSCLC. N Engl J Med 2018;378:2288–301.
Choudhury NJ, Schoenfeld AJ, Flynn J, Falcon CJ, Rizvi H, Rudin CM, et al
. Response to standard therapies and comprehensive genomic analysis for patients with lung adenocarcinoma with EGFR Exon 20 insertions. Clin Cancer Res 2021;27:2920–7.
Hastings K, Yu HA, Wei W, Sanchez-Vega F, DeVeaux M, Choi J, et al
. EGFR mutation subtypes and response to immune checkpoint blockade treatment in non-small-cell lung cancer. Ann Oncol 2019;30:1311–20.
Lan B, Ma C, Zhang C, Chai S, Wang P, Ding L, et al
. Association between PD-L1 expression and driver gene status in non-small-cell lung cancer: A meta-analysis. Oncotarget 2018;9:7684–99.
Yun J, Lee SH, Kim SY, Jeong SY, Kim JH, Pyo KH, et al
. Antitumor activity of amivantamab (JNJ-61186372), an EGFR-MET bispecific antibody, in diverse models of EGFR Exon 20 insertion-driven NSCLC. Cancer Discov 2020;10:1194–209.
Park K, Haura EB, Leighl NB, Mitchell P, Shu CA, Girard N, et al
. Amivantamab in EGFR Exon 20 insertion-mutated non-small-cell lung cancer progressing on platinum chemotherapy: Initial results from the CHRYSALIS phase I study. J Clin Oncol 2021;39:3391–402.
Sabari JK, Shu CA, Park K, Leighl N, Mitchell P, Kim S, et al
. OA04.04 Amivantamab in post-platinum EGFR Exon 20 insertion mutant non-small cell lung cancer. J Thorac Oncol 2021;16:S108–9.
Goldberg SB, Redman MW, Lilenbaum R, Politi K, Stinchcombe TE, Horn L, et al
. Randomized trial of afatinib plus cetuximab versus afatinib alone for first-line treatment of EGFR-mutant non-small-cell lung cancer: Final results from SWOG S1403. J Clin Oncol 2020;38:4076–85.
van Veggel B, de Langen AJ, Hashemi SM, Monkhorst K, Heideman DA, Thunnissen E, et al
. Afatinib and cetuximab in four patients with EGFR Exon 20 insertion-positive advanced NSCLC. J Thorac Oncol 2018;13:1222–6.
van Veggel B, van der Wekken AJ, Paats M, Hashemi SM, Hendriks L, Sikorska K, et al
. Interim results of a phase II single arm trial combining afatinib with cetuximab in patients with EGFRex20ins positive NSCLC. J Clin Oncol 2021;39:9112.
Shu CA, Goto K, Cho BC, Griesinger F, Yang JC-H, Felip E, et al
. CHRYSALIS-2: A phase 1/1b study of lazertinib as monotherapy and in combination with amivantamab in patients with EGFR-mutant NSCLC. J Clin Oncol 2021;39 (15 Suppl):TPS9132.
Riess JW, Groshen SG, Reckamp KL, Wakelee HA, Oxnard GR, Padda SK, et al
. Osimertinib (Osi) plus necitumumab (Neci) in EGFR-mutant NSCLC: An ETCTN California cancer consortium phase I study. J Clin Oncol 2019;37:9057.
Jorge SE, Lucena-Araujo AR, Yasuda H, Piotrowska Z, Oxnard GR, Rangachari D, et al
. EGFR Exon 20 insertion mutations display sensitivity to Hsp90 inhibition in preclinical models and lung adenocarcinomas. Clin Cancer Res 2018;24:6548–55.
Piotrowska Z, Costa DB, Oxnard GR, Huberman M, Gainor JF, Lennes IT, et al
. Activity of the Hsp90 inhibitor luminespib among non-small-cell lung cancers harboring EGFR exon 20 insertions. Ann Oncol 2018;29:2092–7.
Liu SV, Aggarwal C, Brzezniak C, Doebele RC, Gerber DE, Gitlitz B, et al
. Phase 2 study of tarloxotinib bromide (TRLX) in patients (pts) with EGFR-Mutant, T790M-Negative NSCLC progressing on an EGFR TKI. J Clin Oncol 2016;34:TPS9100.
Estrada-Bernal A, Doak AE, Le AT, Zhu H, Chen N, Silva S, et al
. Abstract A157: Antitumor activity of tarloxotinib, a hypoxia-activated EGFR TKI, in patient-derived lung cancer cell lines harboring EGFR exon 20 insertions. Mol Cancer Ther 2018;17:A157.
Estrada-Bernal A, Le AT, Doak AE, Tirunagaru VG, Silva S, Bull MR, et al
. Tarloxotinib Is a hypoxia-activated Pan-HER kinase inhibitor active against a broad range of HER-family oncogenes. Clin Cancer Res 2021;27:1463–75.
Liu SV, Villaruz LC, Lee VH, Zhu VW, Baik CS, Sacher A, et al
. LBA61 First analysis of RAIN-701: Study of tarloxotinib in patients with non-small cell lung cancer (NSCLC) EGFR Exon 20 insertion, HER2-activating mutations & other solid tumours with NRG1/ERBB gene fusions. Ann Oncol 2020;31:S1189.
Janne PA, Neal JW, Camidge DR, Spira AI, Piotrowska Z, Horn L, et al
. Antitumor activity of TAK-788 in NSCLC with EGFR exon 20 insertions. J Clin Oncol 2019;37:9007.
Piper-Vallillo A, Rotow JK, Aredo JV, Shaverdashvili K, Luo J, Carlisle JW, et al
. High-dose osimertinib for CNS progression in EGFR+non-small cell lung cancer (NSCLC): A multi-institutional experience. J Clin Oncol 2020;38:9586.
[Figure 1], [Figure 2]
[Table 1], [Table 2]