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

Abstract

Osimertinib was initially approved for T790M-positive non-small cell lung cancer (NSCLC) and, more recently, for first-line treatment of -mutant NSCLC. However, resistance mechanisms to osimertinib have been incompletely described. 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. 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, = 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, = 0.02). 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.

Plasma next generation sequencing and droplet digital PCR‐based detection of epidermal growth factor receptor (EGFR) mutations in patients with advanced lung cancer treated with subsequent‐line osimertinib

“…In our patient cohort, we detected the previously reported, and likely resistance‐associated changes, BRAF V600E and PIK3CA using plasma NGS. We have not detected other secondary EGFR mutations such as C797 and L792 or C‐MET amplification which were reported to be present in 26% and 14% of cases respectively likely due to the sample size. There were four cases of acquired TP53 mutations at the time of osimertinib resistance, with patient 3 reaching a very high allelic frequency of 24% (Table ).…”

Lung cancer models reveal SARS-CoV-2-induced EMT contributes to COVID-19 pathophysiology

“…EGFR-mutated NSCLCs are routinely and effectively treated with EGFR TKIs, but resistance inevitably develops via characteristic mechanisms including secondary EGFR resistance mutations (i.e. T790M) and, notably, EMT 68 . Thus, we evaluated expression of ACE2 in EGFR-mutated NSCLC cells (HCC4006 and HCC827) treated with the EGFR TKI erlotinib until resistance occurred 69 .…”

Genetic alterations in epidermal growth factor receptor‑tyrosine kinase inhibitor‑na�ve non‑small cell lung carcinoma

“…Gene amplification of ERBB2, MET, MDM2 or CDK4 alone leads to poor prognosis for NSCLC regardless of EGFR gene mutation (25)(26)(27). Furthermore, Le et al (11) and Blakely et al (14) reported that cell cycle gene alteration, such as CDK4 or CDK6, shortens PFS following osimertinib therapy. Patients with EGFR mutant NSCLC accompanied by TP53 mutation, ERBB2 amplification, or MET amplification before first-or second-generation EGFR-TKI treatment exhibited a shorter time to progression and also showed resistance to third-generation EGFR-TKIs (12,13,28).…”

“…Several other mechanisms of resistance against all generation EGFR-TKIs have been identified including tertiary gene mutations other than EGFR C797S mutation (9)(10)(11), activation of bypass signaling by gene amplification (e.g., ERBB2 (12) and MET (13,14), driver gene mutations (e.g., RAS, RAF and PIK3CA) (3,15), gene alteration in cell cycle genes (14), and transformation to mesenchyme, small cell carcinoma (SCC), or squamous cell carcinoma (SqCC) (2,16,17). These described EGFR-TKI resistance mechanisms may also be expressed during the pre-TKI NSCLC state (6,15) and can be a challenge for cancer treatment of NSCLC patients with EGFR mutations.…”