Osimertinib and selpercatinib efficacy, safety, and resistance in a multicenter, prospectively treated cohort of EGFR-mutant and RET fusion-positive lung cancers Journal Article
| Authors: | Rotow, J.; Patel, J. D.; Hanley, M. P.; Yu, H.; Awad, M.; Goldman, J. W.; Nechushtan, H.; Scheffler, M.; Kuo, C. H. S.; Rajappa, S.; Harada, G.; Clifford, S.; Santucci, A.; Silva, L.; Tupper, R.; Oxnard, G. R.; Kherani, J.; Drilon, A. |
| Article Title: | Osimertinib and selpercatinib efficacy, safety, and resistance in a multicenter, prospectively treated cohort of EGFR-mutant and RET fusion-positive lung cancers |
| Abstract: | Purpose: Acquired RET fusions have been reported at resistance to treatment with EGFR inhibitors in EGFR-mutant non-small cell lung cancer (NSCLC); however, a multicenter cohort of patients with EGFR-mutant lung cancers treated with osimertinib and selpercatinib for RET fusion-mediated osimertinib resistance has not previously been published. Patients and Methods: Patients who received selpercatinib in combination with osimertinib on a prospective expanded access clinical trial (NCT03906331) and single-patient compassionate use programs across five countries were centrally analyzed. All patients had advanced EGFR-mutant NSCLC with a RET fusion detected from tissue or plasma following osimertinib therapy. Clinicopathologic and outcomes data were collected. Results: Fourteen patients with EGFR-mutant and RET fusion-positive lung cancers who experienced prior progression on osimertinib received osimertinib and selpercatinib. EGFR exon 19 deletions (±T790M, 86%) and non-KIF5B fusions (CCDC6-RET 50%, NCOA4-RET 36%) predominated. Osimertinib 80 mg daily and selpercatinib 80 mg twice daily were the most commonly administered dosages. The response rate, disease control rate, and median treatment duration were 50% [95% confidence interval (CI), 25%-75%, n 1⁄4 12], 83% (95% CI, 55%-95%), and 7.9 months (range, 0.8-25þ), respectively. Resistance was complex, involving EGFR on-target (EGFR C797S), RET on-target (RET G810S), and off-target (EML4-ALK/STRN-ALK, KRAS G12S, BRAF V600E) mechanisms; RET fusion loss; or polyclonal mechanisms. Conclusions: For patients with EGFR-mutant NSCLC with an acquired RET fusion as a mechanism of EGFR inhibitor resistance, the addition of selpercatinib to osimertinib was feasible and safe and offered clinical benefit, supporting the prospective evaluation of this combination. © 2023 American Association for Cancer Research. |
| Keywords: | genetics; mutation; protein kinase inhibitor; carcinoma, non-small-cell lung; lung neoplasms; epidermal growth factor receptor; drug effect; pathology; protein kinase inhibitors; lung tumor; aniline compounds; protein ret; ret protein, human; proto-oncogene proteins c-ret; egfr protein, human; non small cell lung cancer; aniline derivative; erbb receptors; humans; human; osimertinib; selpercatinib |
| Journal Title: | Clinical Cancer Research |
| Volume: | 29 |
| Issue: | 16 |
| ISSN: | 1078-0432 |
| Publisher: | American Association for Cancer Research |
| Date Published: | 2023-08-15 |
| Start Page: | 2979 |
| End Page: | 2987 |
| Language: | English |
| DOI: | 10.1158/1078-0432.Ccr-22-2189 |
| PUBMED: | 36996322 |
| PROVIDER: | scopus |
| PMCID: | PMC10524391 |
| DOI/URL: | |
| Notes: | The MSK Cancer Center Support Grant (P30 CA008748) is acknowledged in the PDF -- Corresponding author is MSK author: Alexander Drilon -- Source: Scopus |
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