Tumor Analyses Reveal Squamous Transformation and Off-Target Alterations As Early Resistance Mechanisms to First-line Osimertinib in -Mutant Lung Cancer.

Purpose: Patterns of resistance to first-line osimertinib are not well-established and have primarily been evaluated using plasma assays, which cannot detect histologic transformation and have differential sensitivity for copy number changes and chromosomal rearrangements.

Experimental Design: To characterize mechanisms of resistance to osimertinib, patients with metastatic -mutant lung cancers who received osimertinib at Memorial Sloan Kettering Cancer Center and had next-generation sequencing performed on tumor tissue before osimertinib initiation and after progression were identified.

Results: Among 62 patients who met eligibility criteria, histologic transformation, primarily squamous transformation, was identified in 15% of first-line osimertinib cases and 14% of later-line cases. Nineteen percent (5/27) of patients treated with first-line osimertinib had off-target genetic resistance (2 amplification, 1 mutation, 1 fusion, and 1 fusion) whereas 4% (1/27) had an acquired mutation ( G724S). Patients with squamous transformation exhibited considerable genomic complexity; acquired mutation, chromosome 3q amplification, and amplification were all seen. Patients with transformation had shorter time on osimertinib and shorter survival compared with patients with on-target resistance. Initial sensitizing mutation, time on osimertinib treatment, and line of therapy also influenced resistance mechanism that emerged. The compound mutation S768 + V769L and the mutation H1094Y were identified and validated as resistance mechanisms with potential treatment options.

Conclusions: Histologic transformation and other off-target molecular alterations are frequent early emerging resistance mechanisms to osimertinib and are associated with poor clinical outcomes..