Resistance to EGFR Inhibitors: Fitness, Competition, and Diversity

Despite the unprecedented rapid advances in cancer therapeutics development, drug resistance remains a clinical challenge in precision oncology. Resistance is diverse at various levels with inter- and intra-tumor heterogeneity. Targeted therapy resistance can largely be categorized into three classes, including pathway reactivation (re-engagement of original effectors, aka “on-target” resistance), pathway bypass (activation of a parallel pathway converging on the same downstream output, aka “off-target” resistance), and pathway indifference (development of a cellular state independent of the initial therapeutic target, including histology transformation and other unknown mechanism of resistance).1Konieczkowski D.J. Johannessen C.M. Garraway L.A. A convergence-based framework for cancer drug resistance.Cancer Cell. 2018; 33: 801-815Abstract Full Text Full Text PDF PubMed Scopus (138) Google Scholar As different therapeutics apply different selection and evolution pressure on cancer cells, tumor evolution occurs by means of different routes with the results of competitively survived resistant clones with diversity. The principles of Darwinian Natural Selection also apply to therapeutic resistance and cancer cell survival. The discovery of EGFR mutations in lung cancer as an actionable driver oncogene led to the development of EGFR-targeted therapies, especially small molecule tyrosine kinase inhibitors (TKIs), which have been the “poster child” for precision oncology in solid tumors.2Pao W. Chmielecki J. Rational, biologically based treatment of EGFR-mutant non-small-cell lung cancer.Nat Rev Cancer. 2010; 10: 760-774Crossref PubMed Scopus (885) Google Scholar Because of the extensive success of TKI use and the relatively large population of patients with EGFR-mutant NSCLC, the characterization of the resistance mechanisms to EGFR TKI is also a “poster child” for understanding how the resistance incidence and spectrum shift with the evolution of therapeutics development. The EGFR TKI resistance mechanism spectrum fits into the above-mentioned three classes: EGFR pathway reactivation, EGFR pathway bypass, and pathway indifference including histology transformation.3Kobayashi S. Boggon T.J. Dayaram T. et al.EGFR mutation and resistance of non-small-cell lung cancer to gefitinib.N Engl J Med. 2005; 352: 786-792Crossref PubMed Scopus (3533) Google Scholar, 4Le X. Puri S. Negrao M.V. et al.Landscape of EGFR -dependent and -independent resistance mechanisms to osimertinib and continuation therapy post-progression in EGFR-mutant NSCLC.Clin Cancer Res. 2018; 24: 6195-6203Crossref PubMed Scopus (239) Google Scholar, 5Oxnard G.R. Hu Y. Mileham K.F. et al.Assessment of resistance mechanisms and clinical implications in patients with EGFR T790M-positive lung cancer and acquired resistance to osimertinib.JAMA Oncol. 2018; 4: 1527-1534Crossref PubMed Scopus (432) Google Scholar, 6Piotrowska Z. Isozaki H. Lennerz J.K. et al.Landscape of acquired resistance to osimertinib in EGFR-mutant NSCLC and clinical validation of combined EGFR and RET inhibition with osimertinib and BLU-667 for acquired RET fusion.Cancer Discov. 2018; 8: 1529-1539Crossref PubMed Scopus (279) Google Scholar, 7Lin C.C. Shih J.Y. Yu C.J. et al.Outcomes in patients with non-small-cell lung cancer and acquired Thr790Met mutation treated with osimertinib: a genomic study.Lancet Respir Med. 2018; 6: 107-116Abstract Full Text Full Text PDF PubMed Scopus (108) Google Scholar The gatekeeper EGFR T790M mutation occurs in more than half of the EGFR-mutant NSCLC treated with first- or second-generation TKIs.3Kobayashi S. Boggon T.J. Dayaram T. et al.EGFR mutation and resistance of non-small-cell lung cancer to gefitinib.N Engl J Med. 2005; 352: 786-792Crossref PubMed Scopus (3533) Google Scholar This phenomenon led to the development of T790M overcoming third-generation TKI, such as osimertinib.8Janne P.A. Yang J.C. Kim D.W. et al.AZD9291 in EGFR inhibitor-resistant non-small-cell lung cancer.N Engl J Med. 2015; 372: 1689-1699Crossref PubMed Scopus (1680) Google Scholar When osimertinib was first used in the second-line setting treating T790M-positive NSCLCs, multiple research groups published their work on characterizing osimertinib-resistant mechanisms, and their results were quite converged.4Le X. Puri S. Negrao M.V. et al.Landscape of EGFR -dependent and -independent resistance mechanisms to osimertinib and continuation therapy post-progression in EGFR-mutant NSCLC.Clin Cancer Res. 2018; 24: 6195-6203Crossref PubMed Scopus (239) Google Scholar, 5Oxnard G.R. Hu Y. Mileham K.F. et al.Assessment of resistance mechanisms and clinical implications in patients with EGFR T790M-positive lung cancer and acquired resistance to osimertinib.JAMA Oncol. 2018; 4: 1527-1534Crossref PubMed Scopus (432) Google Scholar, 6Piotrowska Z. Isozaki H. Lennerz J.K. et al.Landscape of acquired resistance to osimertinib in EGFR-mutant NSCLC and clinical validation of combined EGFR and RET inhibition with osimertinib and BLU-667 for acquired RET fusion.Cancer Discov. 2018; 8: 1529-1539Crossref PubMed Scopus (279) Google Scholar, 7Lin C.C. Shih J.Y. Yu C.J. et al.Outcomes in patients with non-small-cell lung cancer and acquired Thr790Met mutation treated with osimertinib: a genomic study.Lancet Respir Med. 2018; 6: 107-116Abstract Full Text Full Text PDF PubMed Scopus (108) Google Scholar All indicated that osimertinib effectively decreased T790M clones but induced triple mutations, such as L858R/T790M/C797S, as the EGFR pathway reactivation-resistant mechanism. Interestingly, the incidence of the triple mutation was much lower than the 50% to 60% of T790M incidence. In the category of pathway bypass mechanisms, MET amplification remained roughly the same in terms of incidence, but acquired fusions, such as RET or ALK fusion, were found to be new mechanisms mediating resistance to osimertinib.6Piotrowska Z. Isozaki H. Lennerz J.K. et al.Landscape of acquired resistance to osimertinib in EGFR-mutant NSCLC and clinical validation of combined EGFR and RET inhibition with osimertinib and BLU-667 for acquired RET fusion.Cancer Discov. 2018; 8: 1529-1539Crossref PubMed Scopus (279) Google Scholar With the decrease of EGFR pathway reactivation incidence, the pathway indifferent incidence has increased, although the understanding of this category was somewhat limited by undersampling owing to biopsy requirement and limitation on pathological interpretation.9Schoenfeld A.J. Yu H.A. The evolving landscape of resistance to osimertinib.J Thorac Oncol. 2020; 15: 18-21Abstract Full Text Full Text PDF PubMed Scopus (34) Google Scholar Nonetheless, this body of work have guided subsequent clinical development in the last few years, especially for each of the genetically driven resistance mechanisms. There is still a lot to be learned regarding resistance mechanisms in EGFR-mutant NSCLC, especially when osimertinib is used in the first-line setting and especially in the category of pathway indifference resistance cancers. In this issue of the Journal of Thoracic Oncology, Choudhury et al.10Choudhury N.J. Marra A. Sui J.S.Y. et al.Molecular biomarkers of disease outcomes and mechanisms of acquired resistance to first-line osimertinib in advanced EGFR-mutant lung cancers.J Thorac Oncol. 2023; 18: 463-475Abstract Full Text Full Text PDF Scopus (1) Google Scholar set out to characterize mechanisms of acquired resistance to first-line osimertinib in advanced EGFR-mutant lung cancers. They reported a single-center retrospective analysis on patients with EGFR-mutant NSCLC who received osimertinib as first-line therapy, regarding clinical characteristics and genetic association with clinical outcome. In the 95 patients with postprogression biopsies, known resistance mechanisms were identified in approximately half of the cases, confirming that acquired “on-target” EGFR reactivation by means of acquired EGFR mutations, such as C797S or G724S, and “off-target” bypass pathway activation, such as MET amplification, or RET or BRAF fusions, were still observed, similar to prior reports.9Schoenfeld A.J. Yu H.A. The evolving landscape of resistance to osimertinib.J Thorac Oncol. 2020; 15: 18-21Abstract Full Text Full Text PDF PubMed Scopus (34) Google Scholar In this cohort, approximately 15% of the patients had histology transformation as the resistance mechanism and there were remaining patients (47.5%) with unknown resistance mechanisms. Interestingly and to a degree surprising, in the clinical outcome analysis, the histology transformation was not associated with inferior outcomes. In the comparison of the postresistance survival durations, the three categories of the known resistance mechanism group and the remaining patients without classified resistant mechanism had similar survival duration (p = 0.07). On further analysis, the authors found that tailored therapy at resistance was the key factor for a better outcome and small cell targeting therapy was classified as tailored therapy. This result is important for clinical practice and strongly argues that a repeat biopsy and molecular profiling is a crucial part of clinical decision-making for patients with osimertinib resistance NSCLC, which is consistent with current National Comprehensive Cancer Network guidelines. Beyond clinically indicated next-generation sequencing molecular profiling and clinical outcome analyses, the authors aimed to take a step forward to understand tumor evolution with osimertinib as the selection pressure. There was a trend of increase in APOBEC signature after tumor cells had osimertinib treatment (28% in post-osimertinib versus 10% pre-osimertinib). Furthermore, tumor mutational burden (TMB) was significantly higher in post-progression tumors with median TMB at post-osimertinib 5.3 mutations per megabase versus pre-osimertinib 4.4 mutations per megabase. Those results indicated that with targeted therapy as the selection pressure, clonal evolution of the competitive surviving tumor cells revealed chromosomal instability and associated large-scale genomic events. Both the increase of APOBEC signature and TMB could be the results of the evolutionary survival strategy. As the authors pointed out “Inhibition of APOBEC enzymatic activity is, therefore, a possible avenue for addressing drug resistance” to prevent or delay resistance.11Selenica P. Marra A. Choudhury N.J. et al.APOBEC mutagenesis, kataegis, chromothripsis in EGFR-mutant osimertinib-resistant lung adenocarcinomas.Ann Oncol. 2022; 33: 1284-1295Abstract Full Text Full Text PDF PubMed Scopus (5) Google Scholar There were other interesting observations reported in this work. First, the authors revealed that osimertinib was not a good option for treating atypical EGFR mutation in NSCLC. Although a small and heterogeneous group (n = 29), there was a clear inferiority in the outcomes of the atypical EGFR mutation group (real-world progression-free survival: 5.8 mo) when compared with classical EGFR mutations (real-world progression-free survival: 15.2–16.4 mo). These data are consistent with results from a recent report, revealing atypical EGFR mutations derived less benefit from osimertinib (n = 11, time-to-treatment failure = 4.1 mo), whereas afatinib can render much better treatment benefit (n = 25, time-to-treatment failure = 21.7 mo).12Robichaux J.P. Le X. Vijayan R.S.K. et al.Structure-based classification predicts drug response in EGFR-mutant NSCLC.Nature. 2021; 597: 732-737Crossref PubMed Scopus (108) Google Scholar Therefore, these data and previous studies caution the oncologists that second-generation EGFR TKIs, not third-generation EGFR TKIs, might be the more efficacious treatment for atypical EGFR-mutant NSCLC. The other genetically defined group of patients with inferior outcomes were the ones with TP53 mutation, especially the subgroup with concurrent RB1 alterations. Similar to the observation that atypical EGFR mutation lung cancers do not respond to osimertinib and classical EGFR mutations, this observation regarding TP53 plus or minus RB1 alteration has also been reported before.13Le X. Molife C. Leusch M.S. et al.TP53 co-mutation status association with clinical outcomes in patients with EGFR-mutant non-small cell lung cancer.Cancers (Basel). 2022; 14: 6127Crossref Scopus (2) Google Scholar,14Vokes N.I. Chambers E. Nguyen T. et al.Concurrent TP53 mutations facilitate resistance evolution in EGFR-mutant lung adenocarcinoma.J Thorac Oncol. 2022; 17: 779-792Abstract Full Text Full Text PDF PubMed Scopus (21) Google Scholar Nevertheless, the observation here still added to the body of evidence and supported that additional treatment strategies might be needed for this high-risk subgroup of patients. With novel therapeutics entering clinical evaluation, future strategies to directly or indirectly target TP53/MDM2 pathways might be able to improve outcomes for this EGFR/TP53 co-mutation patient population. Although resistance to EGFR TKIs remains a clinical challenge, new therapeutic strategies are being developed rapidly, thanks to our understanding of resistance mechanisms. Currently, multiple fourth-generation EGFR TKIs are in clinical investigations to overcome C797S or other EGFR pathway reactivation-mediated resistance. The combination of osimertinib and a MET inhibitor has also been found to have promising results in overcoming MET amplification-mediated resistance. The subgroups of patients with less clinical benefit from osimertinib, such as the atypical EGFR mutations or the tumors with concurrent TP53 plus or minus RB1 alterations, start to have clinical trials dedicated for them to identify better treatment regimens. Furthermore, the antibody-drug conjugates are entering clinics benefiting patients with either known or unknown resistance mechanisms to osimertinib. Future translational and clinical research focusing on the pathway indifferent resistance mechanisms, especially the tumor without apparent transformation, is urgently needed. With continued effort in understanding resistance mechanisms and developing novel strategies to tackle resistance, we aim to continue to extend the lives of patients with EGFR-mutant lung cancer. Xiuning Le: Conceptualization, Writing, Approval. Dr. Le is supported by Damon Runyon Cancer Research Foundation and V Foundation for Cancer Research. Molecular Biomarkers of Disease Outcomes and Mechanisms of Acquired Resistance to First-Line Osimertinib in Advanced EGFR-Mutant Lung CancersJournal of Thoracic OncologyVol. 18Issue 4PreviewPreferred first-line treatment for patients with metastatic EGFR-mutant lung cancer is osimertinib, yet it is not known whether patient outcomes may be improved by identifying and intervening on molecular markers associated with therapeutic resistance. Full-Text PDF