Efficacy of osimertinib in patients with lung cancer positive for uncommon EGFR exon 19 deletion mutations Journal Article
| Authors: | 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. |
| Article Title: | Efficacy of osimertinib in patients with lung cancer positive for uncommon EGFR exon 19 deletion mutations |
| Abstract: | PURPOSE: The uncommon EGFR exon 19 deletion (ex19del), L747_A750>P, demonstrates reduced sensitivity to osimertinib compared with the common ex19del, E746_A750del in preclinical models. The clinical efficacy of osimertinib in patients with non-small cell lung cancer harboring L747_A750>P and other uncommon ex19dels is not known. EXPERIMENTAL DESIGN: The AACR GENIE database was interrogated to characterize the frequency of individual ex19dels relative to other variants, and a multicenter 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). RESULTS: 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-institutional cohort (N = 200), E746_A750del was associated with significantly prolonged progression-free survival (PFS) with 1L osimertinib versus L747_A750>P [median 21.3 months (95% confidence interval, 17.0-31.7) vs. 11.7 months (10.8-29.4); adjusted HR 0.52 (0.28-0.98); P = 0.043]. Osimertinib efficacy in patients with other uncommon ex19dels varied on the basis of the specific mutation present. CONCLUSIONS: The ex19del L747_A750>P is associated with inferior PFS compared with the common E746_A750del mutation in patients treated with 1L osimertinib. Understanding differences in osimertinib efficacy among EGFR ex19del subtypes could alter management of these patients in the future. ©2023 American Association for Cancer Research. |
| Keywords: | retrospective studies; exon; gene deletion; genetics; mutation; exons; sequence deletion; clinical trial; protein kinase inhibitor; carcinoma, non-small-cell lung; lung neoplasms; epidermal growth factor receptor; pathology; retrospective study; protein kinase inhibitors; lung tumor; multicenter study; aniline compounds; egfr protein, human; non small cell lung cancer; aniline derivative; erbb receptors; humans; human; osimertinib |
| Journal Title: | Clinical Cancer Research |
| Volume: | 29 |
| Issue: | 11 |
| ISSN: | 1078-0432 |
| Publisher: | American Association for Cancer Research |
| Date Published: | 2023-06-01 |
| Start Page: | 2123 |
| End Page: | 2130 |
| Language: | English |
| DOI: | 10.1158/1078-0432.Ccr-22-3497 |
| PUBMED: | 36913537 |
| PROVIDER: | scopus |
| PMCID: | PMC10493186 |
| DOI/URL: | |
| Notes: | Article -- Source: Scopus |
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