Molecular Biomarkers of Disease Outcomes and Mechanisms of Acquired Resistance to First-Line Osimertinib in Advanced EGFR-Mutant Lung Cancers

Abstract

Introduction: Preferred 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.

Methods: All patients with metastatic EGFR-mutant lung cancer treated with first-line osimertinib at the Memorial Sloan Kettering Cancer Center (n = 327) were identified. Available pretreatment and postprogression tumor samples underwent targeted gene panel sequencing and mutational signature analysis using SigMA algorithm. Progression-free survival (PFS) and overall survival were estimated using the Kaplan-Meier method.

Results: Using multivariate analysis, baseline atypical EGFR (median PFS = 5.8 mo, p < 0.001) and concurrent TP53/RB1 alterations (median PFS = 10.5 mo, p = 0.015) were associated with shorter PFS on first-line osimertinib. Of 95 patients with postprogression biopsies, acquired resistance mechanisms were identified in 52% (off-target, n = 24; histologic transformation, n = 14; on-target, n = 12), with MET amplification (n = 9), small cell lung transformation (n = 7), and acquired EGFR amplification (n = 7), the most frequently identified mechanisms. Although there was no difference in postprogression survival on the basis of identified resistance (p = 0.07), patients with subsequent second-line therapy tailored to postprogression biopsy results had improved postprogression survival (hazard ratio = 0.09, p = 0.006). The paired postprogression tumors had higher tumor mutational burden (p = 0.008) and further dominant APOBEC mutational signatures (p = 0.07) compared with the pretreatment samples.

Conclusions: Patients with EGFR-mutant lung cancer treated with first-line osimertinib have improved survival with treatment adaptation on the basis of identified mechanisms of resistance at time of progression using tissue-based genomic analysis. Further survival gains may be achieved using risk-based treatment adaptation of pretreatment genomic alterations.

Keywords: EGFR; Mechanisms of resistance; Osimertinib; Targeted therapies; Tumor evolution.

Figure 1:. Efficacy of osimertinib and baseline factors impact real-world PFS on osimertinib.

A) Real-world progression-free survival (rwPFS) B) Overall survival (OS) for all patients (n = 327) treated with first-line osimertinib, with median times and 95% CIs noted. C) rwPFS stratified by baseline EGFR alterations (n = 29 atypical, n = 185 exon 19 deletion, and n = 113 L858R). D) rwPFS stratified by baseline concurrent genomic alterations for patients with available data (n = 92 neither TP53/RB1 alterations, n = 141 TP53 co-mutations, n = 50 TP53/RB1 co-mutations). CI, confidence intervals, del, deletion; med, median; mo, months.

Figure 2:. Mechanisms of acquired resistance to first-line osimertinib.

A) Identified mechanisms of resistance for 95 patients with post-progression tumor biopsy that underwent NGS with MSK-IMPACT B) Oncoprint of oncogenic, acquired alterations in post-progression samples with frequency C) Swimmers plot detailing clinical course of patients with histological transformation. Amp, amplification; SCLC, small cell lung cancer; LCNEC, large cell neuroendocrine cancer; FGA, fraction of genome altered; NGS, next-generation sequencing; WGD, whole genome doubling; HRD, homologous recombination deficiency.

Figure 3.. Mechanisms of resistance and post-progression survival.

Post-progression survival for patients stratified by mechanism of identified resistance.

Figure 4.. Methods for investigating unknown resistance.

A) Results of RNAseq testing among 95 patients with a post-progression tumor biopsy sample. B) Single patient with serial biopsies analyzed using Archer, ROS1 IHC staining and MSK-IMPACT. Figure illustrating clonality of each variant, total copy number of ERBB2/MET, and the presence of ROS1 fusion. Clonality is presented by RAF. T1=tumor biopsy 1; T2=tumor biopsy 2; T3=tumor biopsy 3; PD, progressive disease; RT, radiation. C) Sankey plot demonstrating evolution of mutational signatures derived from MSK-IMPACT before and after osimertinib treatment. D) Patterns of mutational signatures and TMB in patients with known and unknown mechanisms of resistance. IHC, immunohistochemistry; RAF, relative allele frequency; RNAseq, RNA sequencing; TMB, tumor mutational burden.