Efficacy of osimertinib in patients with lung cancer positive for uncommon EGFR exon 19 deletion mutations. Clinical cancer research : an official journal of the American Association for Cancer Research Grant, M. J., Aredo, J. V., Starrett, J. H., Stockhammer, P., van Alderwerelt van Rosenburgh, I. K., Wurtz, A., Piper-Valillo, A. J., Piotrowska, Z., Falcon, C., Yu, H. A., Aggarwal, C., Scholes, D., Patil, T., Nguyen, C., Phadke, M., Li, F. Y., Neal, J., Lemmon, M. A., Walther, Z., Politi, K., Goldberg, S. B. 2023


The uncommon EGFR exon 19 deletion (ex19del), L747_A750>P, demonstrates reduced sensitivity to osimertinib compared to the common ex19del, E746_A750del in preclinical models. The clinical efficacy of osimertinib in patients with non-small cell lung cancer (NSCLC) harboring L747_A750>P and other uncommon ex19dels is not known.The AACR GENIE database was interrogated to characterize the frequency of individual ex19dels relative to other variants, and a multi-center retrospective cohort was used to compare clinical outcomes for patients with tumors harboring E746_A750del, L747_A750>P, and other uncommon ex19dels who received osimertinib in the first line (1L) or in second or later lines of therapy and were T790M+ (=2L).Ex19dels comprised 45% of EGFR mutations, with 72 distinct variants ranging in frequency from 28.1% (E746_A750del) to 0.03%, with L747_A750>P representing 1.8% of the EGFR mutant cohort. In our multi-institution cohort (N=200), E746_A750del was associated with significantly prolonged progression free survival (PFS) with 1L osimertinib vs. L747_A750>P (median 21.3 months [95% CI 17.0-31.7] vs. 11.7 months [10.8-29.4], adjusted hazard ratio [HR] 0.52 [0.28-0.98] p=0.043). Osimertinib efficacy in patients with other uncommon ex19dels varied based on the specific mutation present.The ex19del L747_A750>P is associated with inferior PFS compared to the common E746_A750del mutation in patients treated with 1L osimertinib. Understanding differences in osimertinib efficacy among EGFR ex19del.

View details for DOI 10.1158/1078-0432.CCR-22-3497

View details for PubMedID 36913537