Synapse - Tumor analyses reveal squamous transformation and off-target alterations as early resistance mechanisms to first-line osimertinib in EGFR-mutant lung cancer

Tumor analyses reveal squamous transformation and off-target alterations as early resistance mechanisms to first-line osimertinib in EGFR-mutant lung cancer Journal Article

Authors:	Schoenfeld, A. J.; Chan, J. M.; Kubota, D.; Sato, H.; Rizvi, H.; Daneshbod, Y.; Chang, J. C.; Paik, P. K.; Offin, M.; Arcila, M. E.; Davare, M. A.; Shinde, U.; Pe'er, D.; Rekhtman, N.; Kris, M. G.; Somwar, R.; Riely, G. J.; Ladanyi, M.; Yu, H. A.
Article Title:	Tumor analyses reveal squamous transformation and off-target alterations as early resistance mechanisms to first-line osimertinib in EGFR-mutant lung cancer
Abstract:	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 EGFR-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 MET amplification, 1 KRAS mutation, 1 RET fusion, and 1 BRAF fusion) whereas 4% (1/27) had an acquired EGFR mutation (EGFR G724S). Patients with squamous transformation exhibited considerable genomic complexity; acquired PIK3CA mutation, chromosome 3q amplification, and FGF amplification were all seen. Patients with transformation had shorter time on osimertinib and shorter survival compared with patients with on-target resistance. Initial EGFR sensitizing mutation, time on osimertinib treatment, and line of therapy also influenced resistance mechanism that emerged. The compound mutation EGFR S768 thorn V769L and the mutation MET 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.
Keywords:	adenocarcinoma; mutations; impact; patient; acquired-resistance; carcinomas; afatinib; tki therapy; s768i
Journal Title:	Clinical Cancer Research
Volume:	26
Issue:	11
ISSN:	1078-0432
Publisher:	American Association for Cancer Research
Date Published:	2020-06-01
Start Page:	2654
End Page:	2663
Language:	English
ACCESSION:	WOS:000537852100025
DOI:	10.1158/1078-0432.CCR-19-3563
PROVIDER:	wos
PUBMED:	31911548
PMCID:	PMC7448565
Notes:	Article -- Source: Wos