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

Author:

Rotow Julia1ORCID,Patel Jyoti D.2ORCID,Hanley Matthew P.3ORCID,Yu Helena4ORCID,Awad Mark1ORCID,Goldman Jonathan W.5ORCID,Nechushtan Hovav6ORCID,Scheffler Matthias7ORCID,Kuo Chih-Hsi S.8ORCID,Rajappa Senthil9ORCID,Harada Guilherme4ORCID,Clifford Sarah1ORCID,Santucci Alison1ORCID,Silva Laura3ORCID,Tupper Rebecca3ORCID,Oxnard Geoffrey R.1ORCID,Kherani Jennifer3ORCID,Drilon Alexander4ORCID

Affiliation:

1. 1Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts.

2. 2Department of Medicine, Northwestern University, Chicago, Illinois.

3. 3Loxo Oncology at Lilly, Indianapolis, Indiana.

4. 4Department of Medicine, Memorial Sloan Kettering Cancer Center and Weill Cornell Medical College, New York, New York.

5. 5University of California Los Angeles, Los Angeles, California.

6. 6Hadassah Medical Center, Jerusalem, Israel.

7. 7University of Cologne, Köln, Germany.

8. 8Chang Gung Memorial Hospital, Taoyuan City, Taiwan.

9. 9Basavatarakam Indo-American Cancer Hospital and Research Institute, Nandi Nagar, Banjara Hills, Hyderabad, Telangana, India.

Abstract

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 = 12], 83% (95% CI, 55%–95%), and 7.9 months (range, 0.8–25+), 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. See related commentary by Krebs and Popat, p. 2951

Funder

National Cancer Institute

LUNGevity Foundation

Publisher

American Association for Cancer Research (AACR)

Subject

Cancer Research,Oncology

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