A Phase II Open-Label Trial of Binimetinib and Hydroxychloroquine in Patients With Advanced KRAS-Mutant Non-Small Cell Lung Cancer

• Published in: The oncologist (Dayton, Ohio) Ohio), 2023-07, Vol.28 (7), p.644-e564
• Main Authors: Aggarwal, Charu, Maity, Alisha P, Bauml, Joshua M, Long, Qi, Aleman, Tomas, Ciunci, Christine, D’Avella, Christopher, Volpe, Melissa, Anderson, Evan, Jones, Lisa McCormick, Sun, Lova, Singh, Aditi P, Marmarelis, Melina E, Cohen, Roger B, Langer, Corey J, Amaravadi, Ravi
• Format: Article
• Language: English
• Subjects: Antimitotic agents; Antineoplastic agents; Antineoplastic Combined Chemotherapy Protocols - adverse effects; Antineoplastic Combined Chemotherapy Protocols - therapeutic use; Carcinoma, Non-Small-Cell Lung - drug therapy; Carcinoma, Non-Small-Cell Lung - genetics; Care and treatment; Clinical Trial Results; Clinical trials; Diagnosis; Dosage and administration; Drug therapy; Female; Humans; Hydroxychloroquine; Hydroxychloroquine - adverse effects; Hydroxychloroquine - therapeutic use; Lung cancer, Non-small cell; Lung cancer, Small cell; Lung Neoplasms - drug therapy; Lung Neoplasms - genetics; Male; Middle Aged; Mitogen-Activated Protein Kinase Kinases; Mutation; Patient outcomes; Pharmaceutical industry; Product development; Proto-Oncogene Proteins p21(ras) - genetics; Smoking and women; Testing
• ISSN: 1083-7159; 1549-490X
• DOI: 10.1093/oncolo/oyad106

Abstract Background In RAS-mutant tumors, combined MEK and autophagy inhibition using chloroquine demonstrated synthetic lethality in preclinical studies. This phase II trial evaluated the safety and activity of the MEK inhibitor binimetinib combined with hydroxychloroquine (HCQ) in patients with advanced KRAS-mutant non-small cell lung cancer (NSCLC). Methods Eligibility criteria included KRAS-mutant NSCLC, progression after first-line therapy, ECOG PS 0-1, and adequate end-organ function. Binimetinib 45 mg was administered orally (p.o.) bid with HCQ 400 mg p.o. bid. The primary endpoint was objective response rate (ORR). A Simon’s 2-stage phase II clinical trial design was used, with an α error of 5% and a power β of 80%, anticipating an ORR of 30% to proceed to the 2-stage expansion. Results Between April 2021 and January 2022, 9 patients were enrolled to stage I: median age 64 years, 44.4% females, 78% smokers. The best response was stable disease in one patient (11.1%). The median progression free survival (PFS) was 1.9 months, and median overall survival (OS) was 5.3 months. Overall, 5 patients (55.6%) developed a grade 3 adverse event (AE). The most common grade 3 toxicity was rash (33%). Pre-specified criteria for stopping the trial early due to lack of efficacy were met. Conclusion The combination of B + HCQ in second- or later-line treatment of patients with advanced KRAS-mutant NSCLC did not show significant antitumor activity. (ClinicalTrials.gov Identifier: NCT04735068). This phase II trial evaluated the safety and activity of the MEK inhibitor binimetinib combined with hydroxychloroquine in patients with advanced KRAS-mutant non-small cell lung cancer.