Landscape of EGFR-Dependent and -Independent Resistance Mechanisms to Osimertinib and Continuation Therapy Beyond Progression in EGFR-Mutant NSCLC

Abstract

Purpose: Osimertinib was initially approved for T790M-positive non-small cell lung cancer (NSCLC) and, more recently, for first-line treatment of EGFR-mutant NSCLC. However, resistance mechanisms to osimertinib have been incompletely described.

Experimental design: Using cohorts from The University of Texas MD Anderson Lung Cancer Moonshot GEMINI and Moffitt Cancer Center lung cancer databases, we collected clinical data for patients treated with osimertinib. Molecular profiling analysis was performed at the time of progression in a subset of the patients.

Results: In the 118 patients treated with osimertinib, 42 had molecular profiling at progression. T790M was preserved in 21 (50%) patients and lost in 21 (50%). EGFR C797 and L792 (26%) mutations were the most common resistance mechanism and were observed exclusively in T790M-preserved cases. MET amplification was the second most common alteration (14%). Recurrent alterations were observed in 22 genes/pathways, including PIK3CA, FGFR, and RET. Preclinical studies confirmed MET, PIK3CA, and epithelial-to-mesenchymal transition as potential resistance drivers. Alterations of cell-cycle genes were associated with shorter median progression-free survival (PFS, 4.4 vs. 8.8 months, P = 0.01). In 76 patients with progression, osimertinib was continued in 47 cases with a median second PFS (PFS2) of 12.6 months; 21 patients received local consolidation radiation with a median PFS of 15.5 months. Continuation of osimertinib beyond progression was associated with a longer overall survival compared with discontinuation (11.2 vs. 6.1 months, P = 0.02).

Conclusions: Osimertinib resistance is associated with diverse, predominantly EGFR-independent genomic alterations. Continuation of osimertinib after progression, alone or in conjunction with radiotherapy, may provide prolonged clinical benefit in selected patients.See related commentary by Devarakonda and Govindan, p. 6112.

Figure 1.

Kaplan-Meier estimates of survivals for osimertinib-treated patients and subgroups (A) Progression-free survival 1 (PFS1) 8.8 months (CI 95% 6.7–10.7); (B) overall survival since diagnosis (OS DX) was 71.9 months (95% CI, 51.4–92.1) (C) OS1 continued vs. discontinued osimertinib 11.2 months vs. 6.1 months, (HR 0.45, 95% CI 0.2 – 0.9), log-rank p=0.02); (D) PFS1 in patients with preserved and altered cell cycle gene alterations, 8.8 months vs 4.4 months (HR 2.8, 95% CI 1.2 – 6.4, log-rank p=0.01).

Figure 2.

Recurrent genomic alterations associated with osimertinib resistance (A) co-occurring mutations for 42 cases having genetic profiling at progression to osimertinib. Blue box: mutations; red box: amplification; purple box: mutation and/or amplification. GM: germline T790M. (B) EGFR tertiary mutations in T790M-preserved cases (C) EGFR tertiary mutations in T790M-loss cases.

Figure 3.

EGFR-independent potential mechanisms of resistance (A) HCC827 parental cells and cells with acquired resistance to EGFR inhibitors were tested for protein levels of E-cadherin, vimentin and c-Met (B) HCC827 parental cells and cells with acquired resistance to EGFR inhibitors were evaluated for MET copy number changes. H1993 cells were used as positive control (C) MET small molecule inhibitor (EMD 1214063) IC50 in HCC827 parental cells and cells with acquired resistance to EGFR inhibitors (D) Osimertinib IC50 to HCC4006 cells with overexpression of BRAF, FGFR1b, PDGFRa and PIK3CA E545K (E) H1975 parental cells and cells with acquired resistance to osimertinib (OR2 and OR13) were tested for protein levels of E-cadherin and vimentin (F) Norepinephrine (1uM) increases HCC827 cells proliferation in the presence of osimertinib, and propranolol (1uM) overcomes such resistance.