Assessment of Resistance Mechanisms and Clinical Implications in Patients With EGFR T790M-Positive Lung Cancer and Acquired Resistance to Osimertinib
Geoffrey R Oxnard, Yuebi Hu, Kathryn F Mileham, Hatim Husain, Daniel B Costa, Philip Tracy, Nora Feeney, Lynette M Sholl, Suzanne E Dahlberg, Amanda J Redig, David J Kwiatkowski, Michael S Rabin, Cloud P Paweletz, Kenneth S Thress, Pasi A Jänne, Geoffrey R Oxnard, Yuebi Hu, Kathryn F Mileham, Hatim Husain, Daniel B Costa, Philip Tracy, Nora Feeney, Lynette M Sholl, Suzanne E Dahlberg, Amanda J Redig, David J Kwiatkowski, Michael S Rabin, Cloud P Paweletz, Kenneth S Thress, Pasi A Jänne
Abstract
Importance: Osimertinib mesylate is used globally to treat EGFR-mutant non-small cell lung cancer (NSCLC) with tyrosine kinase inhibitor resistance mediated by the EGFR T790M mutation. Acquired resistance to osimertinib is a growing clinical challenge that is poorly understood.
Objective: To understand the molecular mechanisms of acquired resistance to osimertinib and their clinical behavior.
Design, setting, and participants: Patients with advanced NSCLC who received osimertinib for T790M-positive acquired resistance to prior EGFR tyrosine kinase inhibitor were identified from a multi-institutional cohort (n = 143) and a confirmatory trial cohort (NCT01802632) (n = 110). Next-generation sequencing of tumor biopsies after osimertinib resistance was performed. Genotyping of plasma cell-free DNA was studied as an orthogonal approach, including serial plasma samples when available. The study and analysis were finalized on November 9, 2017.
Main outcomes and measures: Mechanisms of resistance and their association with time to treatment discontinuation on osimertinib.
Results: Of the 143 patients evaluated, 41 (28 [68%] women) had tumor next-generation sequencing after acquired resistance to osimertinib. Among 13 patients (32%) with maintained T790M at the time of resistance, EGFR C797S was seen in 9 patients (22%). Among 28 individuals (68%) with loss of T790M, a range of competing resistance mechanisms was detected, including novel mechanisms such as acquired KRAS mutations and targetable gene fusions. Time to treatment discontinuation was shorter in patients with T790M loss (6.1 vs 15.2 months), suggesting emergence of pre-existing resistant clones; this finding was confirmed in a validation cohort of 110 patients with plasma cell-free DNA genotyping performed after osimertinib resistance. In studies of serial plasma levels of mutant EGFR, loss of T790M at resistance was associated with a smaller decrease in levels of the EGFR driver mutation after 1 to 3 weeks of therapy (100% vs 83% decrease; P = .01).
Conclusions and relevance: Acquired resistance to osimertinib mediated by loss of the T790M mutation is associated with early resistance and a range of competing resistance mechanisms. These data provide clinical evidence of the heterogeneity of resistance in advanced NSCLC and a need for clinical trial strategies that can overcome multiple concomitant resistance mechanisms or strategies for preventing such resistance.
Conflict of interest statement
Conflict of Interest Disclosures: Dr Oxnard receives consulting fees from AstraZeneca, Ariad/Takeda, DropWorks, Inivata, and Novartis and honoraria from BioRad, Guardant, and Sysmex. Dr Mileham receives consulting fees or honoraria or is a paid advisory board member for AstraZeneca and Boehringer Ingelheim, is a speaker for Merck, and receives research funding from Celgene. Dr Husain receives research funding from Pfizer and speakers fees from Bristol-Myers Squibb, Merck, and AstraZeneca, and is a paid advisory board member for AstraZeneca, Abbvie, and Foundation Medicine. Dr Costa has received consulting fees or honoraria from Pfizer, AstraZeneca, and Takeda Pharmaceuticals. Dr Sholl receives consulting fees from Research to Practice. Dr Dahlberg receives consulting fees from AstraZeneca. Dr Paweletz receives consulting fees from DropWorks and honoraria from BioRad and AstraZeneca. Dr Thress is an employee of AstraZeneca. Dr Jänne receives consulting fees from AstraZeneca, Boehringer Ingelheim, Pfizer, Merrimack Pharmaceuticals, Roche/Genentech, Chugai Pharmaceuticals, Acea Biosciences, Ignyta, LOXO Oncology, ARIAD Pharmaceuticals, Eli Lilly Pharmaceuticals, and Araxes Pharmaceuticals; owns stocks in Gatekeeper Pharmaceuticals; receives research funding from Astellas Pharmaceuticals, AstraZenenca, Daiichi Sankyo, PUMA, Eli Lilly Pharmaceuticals; and receives postmarketing royalties from DFCI-owned intellectual property on EGFR mutations licensed to Lab Corp. Drs Oxnard, Paweletz, and Jänne receive royalties from DFCI-owned intellectual property on plasma genotyping licensed to MolecularMD. No other disclosures are reported.
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Source: PubMed