Is osimertinib effective as 2nd line treatment in T790M-negative EGFR mutant NSCLC?

Introduction

Advanced non-small cell lung cancer (NSCLC) is a heterogeneous disease and during the past years, we have witnessed the evolution of a precision medicine approach guided by numerous gene mutations as prognostic and predictive biomarkers. Epidermal growth factor receptor (EGFR) gene mutations are frequently observed in a subgroup of patients with lung adenocarcinoma and well-established demographic characteristics, such as non- or light smoking history, female sex, and Asian or East Asian heritage (1). Osimertinib, a third-generation EGFR tyrosine kinase inhibitor (TKI) is the current standard of care as first-line treatment in patients with common EGFR mutations (Exon Del 19 and Exon 21 L858R mutations). In addition, it is indicated by the US Food and Drug Administration (FDA) and European Medicine Agency (EMA) for patients with EGFR T790M mutations either as first-line therapy or post-progression after treatment with first or second-generation TKIs.

Original article

In the original article that accompanies this editorial commentary, Takeda et al. have conducted a phase II trial to evaluate the efficacy of osimertinib as second-line treatment in patients with EGFR mutant NSCLC that have progressed after treatment with first or second EGFR TKIs and do not harbor an EGFR T790M mutation (2). The authors need to be congratulated on attempting to address a long-standing question regarding effectiveness of osimertinib in non-T790M resistance. Is osimertinib effective in patients with EGFR mutant disease already exposed to first- or second-generation TKIs? Of note, patients included in this study had already received platinum-based chemotherapy, although the timing of administration of chemotherapy is not clearly stated.

This phase II study included two cohorts: cohort one included patients with isolated central nervous system (CNS) progression and cohort two included patients with systemic disease progression. The authors report only the results for cohort two because cohort one was being recruited at the time when the paper was published. The primary endpoint of the study was objective response rate (ORR), defined as radiographic partial or complete response, evaluated by an independent review committee. In the phase I study assessing the efficacy and safety of osimertinib in patients with EGFR mutant NSCLC that has progressed on first or second EGFR TKIs, ORR produced by osimertinib in patients without an EGFR T790M mutation was 21% and median progression-free survival (PFS) was 2.8 months (3). Based on these published data, the assumed ORR achieved by osimertinib in this study was 25%.

The study met its primary endpoint, resulting in an ORR of 29.1%, surpassing the necessary threshold response rate for primary analysis. Indeed, the ORR yielded by osimertinib is somewhat numerically higher than the one (21%) reported in the phase I AURA study in a similar subgroup of patients (3). This may be interpreted by the diverse escalating doses of osimertinib in patients who participated in AURA I, as the authors meticulously state. Nevertheless, since the ORR and PFS produced by osimertinib in this study is higher compared to standard third line chemotherapy regimens such as docetaxel or pemetrexed (8–9%) (4), the authors suggest that osimertinib could be a potential third line option for patients that have progressed after 1^st or 2^nd generation TKIs, given that they have already been subjected to a carboplatin-based chemotherapy regimen.

First issue

So how could this phase II study by Takeda et al. be incorporated into current clinical practice? Osimertinib has now been established as standard first-line treatment for advanced EGFR-mutated NSCLC at least for patients with common EGFR mutations (Exon Del 19 and Exon 21 L858R) in the majority of countries, given the dramatic difference in PFS (18.9 vs. 10.2 months, P<0.001) and overall survival (OS) (38.6 vs. 31.8 months, P=0.046) shown in the landmark phase III FLAURA trial, compared to erlotinib or gefitinib (5,6). This is currently supported by both the National Comprehensive Cancer Network (NCCN) and European Society for Medical Oncology (ESMO) guidelines. Thus, the results of this study cannot be easily reproduced in current everyday practice where 1^st or 2^nd generation TKIs are no longer considered a standard first-line treatment. This point is also stated by the authors as a limitation in their study. One possible exception could be patients with uncommon EGFR mutations, such as S768I, L861Q, and G719X. In a combined post-hoc analysis of one phase II (LUX-Lung2) and two phase III trials (LUX-Lung3 and LUX-lung6), afatinib has shown promising results in patients harboring these mutations, yielding an ORR of 78–100% and a PFS of 8.2–14.7 months depending on the mutation (7). Of note, real-life retrospective data have also shown significant activity of osimertinib in patients with uncommon EGFR mutations, mainly G719X and L861Q (8). Nevertheless, when afatinib is administered as the first-line treatment in these patients, osimertinib could be a later line treatment option.

Second issue

A second issue that arises from this study is that when selecting a possible therapeutic option for a patient with EGFR-mutated NSCLC, we should meticulously explore what are the arrows in the quiver. Indeed, the most important mechanism of acquired drug resistance against 1^st generation TKIs is a secondary T790M mutation. Other rare secondary EGFR mutations, such as L747S, D761Y, and T854A, have also been reported to be responsible for gefitinib or erlotinib resistance. Several case reports have demonstrated a possible efficacy of osimertinib in these cases (9,10). Activation of alternative bypass or downstream pathways is a crucial mechanism of resistance against 1^st generation TKIs, the most frequent being HER2 overexpression or HER2 mutations (11). T-DM1, trastuzumab-deruxtecan, and anti-HER2 TKI pyrotinib have all shown activity against HER2 mutant NSCLC (12,13). MET amplification can be targeted with osimertinib and savolitinib. In addition, 1–2% of patients who progress on 1^st generation TKIs have acquired mutations at KRAS, BRAF and PI3KCA genes which can be targeted with corresponding targeted drugs, such as sotorasib, dabrafenib/trametinib and PI3K inhibitors (11). Approximately 3–14% of patients show morphological transformation to small cell or squamous carcinoma, that can be treated with platinum-based chemotherapy (14). As precision medicine is evolving and basket trials are designed, a wide variety of novel targeted drugs are increasingly becoming available depending on the contextual molecular alterations that are found during disease progression and produce higher response and disease control rates. On the other hand, recent phase II studies conducted in EGFR mutated patients, such as ILLUMINATE and Impower151 have only shown modest activity of immunotherapy combinations (15,16), therefore attenuating the role of immunotherapy as a later line treatment in EGFR-mutated NSCLC.

Third issue

Next, another important issue that arises is intratumor heterogeneity. The authors in this study should be congratulated on being able to secure tissue samples for EGFR T790M mutation verification. However, a small tissue sample at progression might not be fully representative of the whole tumor and several T790M mutations might not have been detected. Indeed, the authors also state this point as a limitation in their study. Liquid biopsy is a minimally invasive blood-based approach that has the potential for real-time monitoring of molecular alterations. In the AURA study, plasma samples derived from patients who participated in the study captured additional EGFR T790M mutations in 31% of patients whose tissue samples were negative for the presence of the mutation (17). In future trials, matched tissue and plasma-based samples should be required for enrollment for better detection of corresponding molecular alterations.

Fourth issue

Last, although the molecular basis of the effectiveness of osimertinib was not investigated in this study, the question of whether there is a role of osimertinib in non-T790M resistance remains largely unanswered. Is osimertinib effectiveness observed in this study attributed to therapeutic activity against other resistance mechanisms such as MET amplification, HER2 overexpression, other mutations such as KRAS, BRAF, and PIK3CA or is it simply due to missed T790M mutations (e.g., no detection due to lack of paired liquid biopsies)? This remains an important question that may need preclinical studies or additional early phase clinical trials to be addressed.

Summary

In conclusion, based on this phase II study, osimertinib could be a potential option as a later line treatment in patients that have progressed after 1^st or 2^nd generation TKIs and do not harbor a T790M mutation. However, several limitations hamper the wide incorporation of these results into clinical practice. A design of a trial that prospectively compares osimertinib to standard chemotherapy 3^rd line regimens in this subgroup of patients is infeasible, especially after the results of the FLAURA study, which has established osimertinib as standard first-line treatment (5,6). However, a subgroup of patients with rare EGFR mutations treated with the 2^nd generation TKI afatinib may benefit from this approach. Given the high efficacy of osimertinib in CNS disease, the upcoming results of the study by Takeda et al. in this cohort of patients might be interesting and are eagerly awaited. On the other hand, several mechanisms of resistance are emerging, and corresponding targeted drugs with high response rates are becoming increasingly available. Next generation sequencing is the cornerstone of the detection of novel molecular alterations at progression, but matched liquid biopsies may optimize results for improved selection of therapy in EGFR-mutated patients.

Acknowledgments

Funding: None.

Footnote

Provenance and Peer Review: This article was commissioned by the editorial office, AME Clinical Trials Review. The article has undergone external peer review.

Peer Review File: Available at https://actr.amegroups.com/article/view/10.21037/actr-23-44/prf

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://actr.amegroups.com/article/view/10.21037/actr-23-44/coif). The authors have no conflicts of interest to declare.

Ethical Statement: The authors are 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.

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References

1. Bethune G, Bethune D, Ridgway N, et al. Epidermal growth factor receptor (EGFR) in lung cancer: an overview and update. J Thorac Dis 2010;2:48-51. [PubMed]
2. Takeda M, Shimokawa M, Nakamura A, et al. A phase II study (WJOG12819L) to assess the efficacy of osimertinib in patients with EGFR mutation-positive NSCLC in whom systemic disease (T790M-negative) progressed after treatment with first- or second-generation EGFR TKIs and platinum-based chemotherapy. Lung Cancer 2023;177:44-50. [Crossref] [PubMed]
3. Jänne PA, Yang JC, Kim DW, et al. AZD9291 in EGFR inhibitor-resistant non-small-cell lung cancer. N Engl J Med 2015;372:1689-99. [Crossref] [PubMed]
4. Hanna N, Shepherd FA, Fossella FV, et al. Randomized phase III trial of pemetrexed versus docetaxel in patients with non-small-cell lung cancer previously treated with chemotherapy. J Clin Oncol 2004;22:1589-97. [Crossref] [PubMed]
5. 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]
6. 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]
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. Bar J, Peled N, Schokrpur S, et al. Uncommon EGFR mutations on osimertinib, real-life data (UNICORN study): Updated results, brain efficacy, and resistance mechanisms. J Clin Oncol 2022;40:9109. [Crossref]
9. Chiba M, Togashi Y, Bannno E, et al. Efficacy of irreversible EGFR-TKIs for the uncommon secondary resistant EGFR mutations L747S, D761Y, and T854A. BMC Cancer 2017;17:281. [Crossref] [PubMed]
10. Grolleau E, Haddad V, Boissière L, et al. Clinical Efficacy of Osimertinib in a Patient Presenting a Double EGFR L747S and G719C Mutation. J Thorac Oncol 2019;14:e151-3. [Crossref] [PubMed]
11. Sun R, Hou Z, Zhang Y, et al. Drug resistance mechanisms and progress in the treatment of EGFR-mutated lung adenocarcinoma. Oncol Lett 2022;24:408. [Crossref] [PubMed]
12. Li BT, Smit EF, Goto Y, et al. Trastuzumab Deruxtecan in HER2-Mutant Non-Small-Cell Lung Cancer. N Engl J Med 2022;386:241-51. [Crossref] [PubMed]
13. Li BT, Shen R, Buonocore D, et al. Ado-Trastuzumab Emtansine for Patients With HER2-Mutant Lung Cancers: Results From a Phase II Basket Trial. J Clin Oncol 2018;36:2532-7. [Crossref] [PubMed]
14. Marcoux N, Gettinger SN, O'Kane G, et al. EGFR-Mutant Adenocarcinomas That Transform to Small-Cell Lung Cancer and Other Neuroendocrine Carcinomas: Clinical Outcomes. J Clin Oncol 2019;37:278-85. [Crossref] [PubMed]
15. Lee C, Liao BC, Subramaniam S, et al. OA09.04 ILLUMINATE: Efficacy and Safety of Durvalumab-Tremelimumab and Chemotherapy in EGFR Mutant NSCLC Following Progression on EGFR Inhibitors. J Thorac Oncol 2023;18:S63. [Crossref]
16. Zhou C, Dong X, Chen G, et al. OA09.06 IMpower151: Phase III Study of Atezolizumab + Bevacizumab + Chemotherapy in 1L Metastatic Nonsquamous NSCLC. J Thorac Oncol 2023;18:S65. [Crossref]
17. Oxnard GR, Thress KS, Alden RS, 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. [Crossref] [PubMed]