Osimertinib and Selpercatinib Efficacy, Safety, and Resistance in a Multicenter, Prospectively Treated Cohort of EGFR-Mutant and RET Fusion-Positive Lung Cancers

Julia Rotow, Jyoti D. Patel, Matthew P. Hanley, Helena Yu, Mark Awad, Jonathan W. Goldman, Hovav Nechushtan, Matthias Scheffler, Chih Hsi S. Kuo, Senthil Rajappa, Guilherme Harada, Sarah Clifford, Alison Santucci, Laura Silva, Rebecca Tupper, Geoffrey R. Oxnard, Jennifer Kherani, Alexander Drilon*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

18 Scopus citations

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 ¼ 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.

Original languageEnglish (US)
Pages (from-to)2979-2987
Number of pages9
JournalClinical Cancer Research
Volume29
Issue number16
DOIs
StatePublished - Aug 15 2023

Funding

This article was supported in part by funding from the National Cancer Institute of the National Institute of Health: R01CA251591–01A1 and P30CA008748. Partial support was likewise provided by LUNGevity.

ASJC Scopus subject areas

  • General Medicine

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