Subtype of EGFR exon 19 deletion mutations

Epidermal growth factor receptor (EGFR) mutations in non-small cell lung cancer (NSCLC) are associated with favorable clinical response to EGFR tyrosine kinase inhibitors (TKIs). There are several EGFR-TKIs approved in the US, Japan, and other countries for the treatment of NSCLC with EGFR mutation. The first-generation EGFR-TKIs, gefitinib and erlotinib, bind reversibly to the Adenosine tri-phosphate-binding pockets of the receptor, whereas the second-generation TKIs, afatinib and dacomitinib additionally react covalently with the side-chain of cysteine 797 in EGFR (1). A third-generation TKI osimertinib has been shown to improve progression-free survival (PFS) (2) and overall survival (OS) (3) compared to the first-generation EGFR-TKIs in the first-line setting, and also been shown to be effective in the second-line treatment for patients with EGFR p.T790M mutation (4).

There are two common EGFR mutations; one is in-frame deletions in exon 19 (19Del) and the other is a point mutation in exon 21 (p.L858R), which account for approximately 90% of all alterations and are associated with sensitivity to EGFR-TKIs (5). The efficacy of EGFR-TKIs has established for these common mutations, however, few prospective data are available for other uncommon mutations. Uncommon EGFR mutations are highly heterogeneous including p.G719X, p.L861Q, p.S768I, and others (6), and vary widely in terms of their sensitivity to EGFR-TKIs. Afatinib has been applied most for these uncommon mutations possibly because of current availability of data in previous clinical studies, in which patients with uncommon mutations were included (6,7). Recent studies indicate that osimertinib might be active also against certain uncommon EGFR mutations (8,9). However, the optimal treatment strategy for these uncommon EGFR mutations has not been established.

Although it is fully established that NSCLCs with 19Del are sensitive to EGFR-TKIs, recent studies revealed that there are some subtypes among 19Del. The most frequently observed 19Del is the elimination of 5 amino acids (E746-A750) between the third β-strand of the EGFR tyrosine kinase domain and its key regulatory αC helix (10). However, several other 19Del mutations have also been demonstrated between amino acids 745 and 753. Many of these deletions are replacement of the deleted amino acids with a non-native residue which start at leucine 747, where proline and serine respectively are introduced, resulted in L747-A750>P and L747-P753>S variants (11). Very little is known about potential differences in sensitivity to EGFR-TKIs among individual 19Dels. The differences in TKI sensitivity among 19Del have begun to emerge from several studies. A recent report of in vitro study suggested that L747-A750>P variant was associated with poor inhibition by erlotinib and osimertinib but was strongly inhibited by afatinib, partly due to structural characteristic of the variant (12). Although there were some different results in different studies, the importance of EGFR-TKI selection specific to each mutation has been highlighted in these studies.

Grant et al. recently reported that patients of NSCLC with L747-A750>P variant of 19Del was associated with inferior PFS compared with the main E746-A750 variant when treated with osimertinib as a first-line therapy (13). They performed a multicenter, retrospective cohort study based on an international cancer registry conducted by American Association for Cancer Research that linked next-generation genome sequencing (NGS) data with clinical information of patients treated at 18 contributing institutions (14). In the study, they identified 72 distinct variants of 19Del ranging in frequency from 28.1% of E746-A750 to 0.03% of L747-A750>P, and demonstrated that main E746-A750 was associated with significantly prolonged PFS (median 21.3 months with 95% confidence interval of 17.0–31.7 months) versus L747-A750>P (median 11.7 months with 95% confidence interval of 10.8–29.4, P=0.043) in patients treated with first-line osimertinib. Although there are some limitations in their study, including its retrospective study design and limited number of patients with uncommon 19Del patients, that is the largest study to compare the clinical efficacy of osimertinib between patients with tumors harboring main E746-A750 and other uncommon 19Dels such as L747-A750>P. In fact, this registry contained more than 3,000 patients of EGFR-mutated NSCLC including 86 with E746-A750 and 36 with L747-A750>P, and relevant data including demographic information, smoking history, treatment history, and disease control and survival outcomes were extracted from the electronic medical record. Since there are significant differences in the survival outcomes in their report, it seems reasonable that L747-A750>P variant of 19Del would be classified as one of uncommon EGFR mutations.

From now on, new therapeutic options might be applied for patients with such uncommon 19Del variant as L747-A750>P because of significant inferior survival outcomes. A simple approach would be the first or second-generation TKIs. In above mentioned basic research, Truini et al. investigated in vitro TKI sensitivity of human lung adenocarcinoma cell lines that carried 19Del variants. They generated cell lines transfected with L747-A750>P constructs and demonstrated that those cells exhibited increased sensitivity to afatinib compared to erlotinib or osimertinib (12). These findings strongly suggest that afatinib would be a key for the treatment of these uncommon 19Dels.

There are other possible treatment strategies for EGFR-mutated NSCLC. One is the combination of EGFR-TKIs and anti-angiogenetic agent. Preclinical studies have demonstrated that the vascular endothelial growth factor (VEGF) and EGFR pathways are interrelated (15). Previous clinical trials in Japan have suggested that the combination of erlotinib and an anti-VEGF antibody bevacizumab would be beneficial concerning the PFS (16,17). More recently, an anti-VEGF receptor antibody ramucirumab plus erlotinib showed a significant improvement in PFS in patients with EGFR-mutated NSCLC (18). Limited data are available for second-generation EGFR-TKIs in combination with anti-angiogenetic agents. Afatinib was examined in a randomized, phase II trial combined with bevacizumab as first-line treatment for patients with EGFR-mutated NSCLC, but the study failed to prolong PFS (19). More recently, osimertinib also failed to improve PFS in combination with bevacizumab among patients with nonsquamous NSCLC harboring EGFR mutations as first-line treatment (20). The activities of EGFR-TKIs and anti-angiogenic agents for patients with minor EGFR-mutations have not been examined, so some combinations should be examined for patients with 19Del variants such as L747-A750>P.Another strategy for EGFR-mutated NSCLC is a combination of EGFR-TKI and cytotoxic chemotherapy with the hope of synergistical effect to induce apoptosis and/or to suppress signal-regulated kinase phosphorylation (21). Combination of gefitinib and carboplatin plus pemetrexed improved PFS in patients with untreated advanced NSCLC with EGFR mutations compared with gefitinib alone with acceptable toxicities (22). In another study with similar setting, adding pemetrexed and carboplatin chemotherapy to gefitinib significantly prolonged PFS and OS (23). Furthermore, in a recent study, a combination of osimertinib and platinum-based chemotherapy demonstrated prolonged PFS compared to osimertinib monotherapy as a first-line treatment for advanced NSCLC with EGFR mutations (24). Detailed description of minor 19Del cannot be found in these studies, so combination of TKIs and platinum-based chemotherapy also should be examined for those populations in the future.

Recently, genomic concomitant alterations that may accompany EGFR mutations have been considered to affect the response to EGFR-TKIs. Though the incidence of concomitant alterations in patients with 19Dels were reported to be lesser than in patients with p.L858R (25), further research is warranted to reveal the impact of such concomitant alterations on sensitivity or resistance to EGFR-TKIs.

In conclusion, given the rapid progression of sensitive mutation detection methodologies, such as NGS and circulating cell-free DNA techniques, physicians will be more likely to encounter cases of NSCLC with uncommon mutations in clinical practice. Based on a report of Grant et al., it seems reasonable to classify subtypes of 19Del such as L747-A750>P as uncommon EGFR mutation. Suitable treatment strategies for patients with these mutations should be tailored for each subtype.

Acknowledgments

Funding: None.

Footnote

Provenance and Peer Review: This article was commissioned by the editorial office, Translational Lung Cancer Research. The article has undergone external peer review.

Peer Review File: Available at https://tlcr.amegroups.com/article/view/10.21037/tlcr-23-680/prf

Conflicts of Interest: The author has completed the ICMJE uniform disclosure form (available at https://tlcr.amegroups.com/article/view/10.21037/tlcr-23-680/coif). The author reports grants and personal fees from ONO, Bristol-Meyers Squib, and Glaxo SmithKline, and personal fees from ONO, Chugai, Behringer Ingelheim, NIHON KAYAKU and AstraZeneca. The author has no other conflicts of interest to declare.

Ethical Statement: The author is accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

References

1. Peters S, Zimmermann S, Adjei AA. Oral epidermal growth factor receptor tyrosine kinase inhibitors for the treatment of non-small cell lung cancer: comparative pharmacokinetics and drug-drug interactions. Cancer Treat Rev 2014;40:917-26. [Crossref] [PubMed]
2. Soria JC, Ohe Y, Vansteenkiste J, et al. Osimertinib in Untreated EGFR-Mutated Advanced Non-Small-Cell Lung Cancer. N Engl J Med 2018;378:113-25. [Crossref] [PubMed]
3. Ramalingam SS, Vansteenkiste J, Planchard D, et al. Overall Survival with Osimertinib in Untreated, EGFR-Mutated Advanced NSCLC. N Engl J Med 2020;382:41-50. [Crossref] [PubMed]
4. Mok TS, Wu YL, Ahn MJ, et al. Osimertinib or Platinum-Pemetrexed in EGFR T790M-Positive Lung Cancer. N Engl J Med 2017;376:629-40. [Crossref] [PubMed]
5. Ladanyi M, Pao W. Lung adenocarcinoma: guiding EGFR-targeted therapy and beyond. Mod Pathol 2008;21:S16-22. [Crossref] [PubMed]
6. Yang JC, Schuler M, Popat S, et al. Afatinib for the Treatment of NSCLC Harboring Uncommon EGFR Mutations: A Database of 693 Cases. J Thorac Oncol 2020;15:803-15. [Crossref] [PubMed]
7. Yang JC, Sequist LV, Geater SL, 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. [Crossref] [PubMed]
8. Cho JH, Lim SH, An HJ, et al. Osimertinib for Patients With Non-Small-Cell Lung Cancer Harboring Uncommon EGFR Mutations: A Multicenter, Open-Label, Phase II Trial (KCSG-LU15-09). J Clin Oncol 2020;38:488-95. [Crossref] [PubMed]
9. Ji J, Aredo JV, Piper-Vallillo A, et al. Osimertinib in NSCLC With Atypical EGFR-Activating Mutations: A Retrospective Multicenter Study. JTO Clin Res Rep 2023;4:100459. [Crossref] [PubMed]
10. Murray S, Dahabreh IJ, Linardou H, et al. Somatic mutations of the tyrosine kinase domain of epidermal growth factor receptor and tyrosine kinase inhibitor response to TKIs in non-small cell lung cancer: an analytical database. J Thorac Oncol 2008;3:832-9. [Crossref] [PubMed]
11. Sharma SV, Bell DW, Settleman J, et al. Epidermal growth factor receptor mutations in lung cancer. Nat Rev Cancer 2007;7:169-81. [Crossref] [PubMed]
12. Truini A, Starrett JH, Stewart T, et al. The EGFR Exon 19 Mutant L747-A750>P Exhibits Distinct Sensitivity to Tyrosine Kinase Inhibitors in Lung Adenocarcinoma. Clin Cancer Res 2019;25:6382-91. [Crossref] [PubMed]
13. Grant MJ, Aredo JV, Starrett JH, et al. Efficacy of Osimertinib in Patients with Lung Cancer Positive for Uncommon EGFR Exon 19 Deletion Mutations. Clin Cancer Res 2023;29:2123-30. [Crossref] [PubMed]
14. AACR Project GENIE: Powering Precision Medicine through an International Consortium. Cancer Discov 2017;7:818-31. [Crossref] [PubMed]
15. Byers LA, Heymach JV. Dual targeting of the vascular endothelial growth factor and epidermal growth factor receptor pathways: rationale and clinical applications for non-small-cell lung cancer. Clin Lung Cancer 2007;8:S79-85. [Crossref] [PubMed]
16. Seto T, Kato T, Nishio M, et al. Erlotinib alone or with bevacizumab as first-line therapy in patients with advanced non-squamous non-small-cell lung cancer harbouring EGFR mutations (JO25567): an open-label, randomised, multicentre, phase 2 study. Lancet Oncol 2014;15:1236-44. [Crossref] [PubMed]
17. Saito H, Fukuhara T, Furuya N, et al. Erlotinib plus bevacizumab versus erlotinib alone in patients with EGFR-positive advanced non-squamous non-small-cell lung cancer (NEJ026): interim analysis of an open-label, randomised, multicentre, phase 3 trial. Lancet Oncol 2019;20:625-35. [Crossref] [PubMed]
18. Nakagawa K, Garon EB, Seto T, et al. Ramucirumab plus erlotinib in patients with untreated, EGFR-mutated, advanced non-small-cell lung cancer (RELAY): a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet Oncol 2019;20:1655-69. [Crossref] [PubMed]
19. Ninomiya T, Ishikawa N, Kozuki T, et al. A randomized phase II study of afatinib alone or combined with bevacizumab for treating chemo-naïve patients with non-small cell lung cancer harboring EGFR mutations. Lung Cancer 2023;184:107349. [Crossref] [PubMed]
20. Kenmotsu H, Wakuda K, Mori K, et al. Randomized Phase 2 Study of Osimertinib Plus Bevacizumab Versus Osimertinib for Untreated Patients With Nonsquamous NSCLC Harboring EGFR Mutations: WJOG9717L Study. J Thorac Oncol 2022;17:1098-108. [Crossref] [PubMed]
21. Yang Z, Tam KY. Combination Strategies Using EGFR-TKi in NSCLC Therapy: Learning from the Gap between Pre-Clinical Results and Clinical Outcomes. Int J Biol Sci 2018;14:204-16. [Crossref] [PubMed]
22. Hosomi Y, Morita S, Sugawara S, et al. Gefitinib Alone Versus Gefitinib Plus Chemotherapy for Non-Small-Cell Lung Cancer With Mutated Epidermal Growth Factor Receptor: NEJ009 Study. J Clin Oncol 2020;38:115-23. [Crossref] [PubMed]
23. Noronha V, Patil VM, Joshi A, et al. Gefitinib Versus Gefitinib Plus Pemetrexed and Carboplatin Chemotherapy in EGFR-Mutated Lung Cancer. J Clin Oncol 2020;38:124-36. [Crossref] [PubMed]
24. Jänne P, Planchard D, Cheng Y, et al. Osimertinib With/Without Platinum-Based Chemotherapy as First-line Treatment in Patients with EGFRm Advanced NSCLC (FLAURA2). 2023 World Conference on Lung Cancer; Singapore: International Association for Study of Lung Cancer; 2023.
25. Hong S, Gao F, Fu S, et al. Concomitant Genetic Alterations With Response to Treatment and Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitors in Patients With EGFR-Mutant Advanced Non-Small Cell Lung Cancer. JAMA Oncol 2018;4:739-42. [Crossref] [PubMed]