A Phase II Study of Potentiation of Pembrolizumab with Binimetinib and Bevacizumab in Refractory Microsatellite-Stable Colorectal Cancer

• Published in: Clinical cancer research Vol. 30; no. 17; pp. 3768 - 3778
• Main Authors: Lentz, Robert W, Friedrich, Tyler J, Blatchford, Patrick J, Jordan, Kimberly R, Pitts, Todd M, Robinson, Hannah R, Davis, S Lindsey, Kim, Sunnie S, Leal, Alexis D, Lee, Mathew R, Waring, Meredith R N, Martin, Anne C, Dominguez, Adrian T A, Bagby, Stacey M, Hartman, Sarah J, Eckhardt, S Gail, Messersmith, Wells A, Lieu, Christopher H
• Format: Journal Article
• Language: English
• Published: United States American Association for Cancer Research 03.09.2024
• Subjects: Adult; Aged; Antibodies, Monoclonal, Humanized - administration & dosage; Antibodies, Monoclonal, Humanized - adverse effects; Antineoplastic Combined Chemotherapy Protocols - adverse effects; Antineoplastic Combined Chemotherapy Protocols - therapeutic use; Benzimidazoles - administration & dosage; Benzimidazoles - adverse effects; Benzimidazoles - therapeutic use; Bevacizumab - administration & dosage; Bevacizumab - adverse effects; Bevacizumab - therapeutic use; Clinical Trial Results; Clinical Trials: Immunotherapy; Colorectal Neoplasms - drug therapy; Colorectal Neoplasms - genetics; Colorectal Neoplasms - mortality; Colorectal Neoplasms - pathology; Drug Resistance, Neoplasm - genetics; Female; Gastrointestinal Cancers; Humans; Immunotherapy; Male; Microsatellite Repeats; Middle Aged; Treatment Outcome
• ISSN: 1078-0432; 1557-3265; 1557-3265
• DOI: 10.1158/1078-0432.CCR-24-0090

In this single-institution phase II investigator-initiated study, we assessed the ability of MAPK and VEGF pathway blockade to overcome resistance to immunotherapy in microsatellite-stable metastatic colorectal cancer (MSS mCRC). Patients with MSS, BRAF wild-type mCRC who progressed on ≥2 prior lines of therapy received pembrolizumab, binimetinib, and bevacizumab until disease progression or unacceptable toxicity. After a safety run-in, patients were randomized to a 7-day run-in of binimetinib or simultaneous initiation of all study drugs, to explore whether MEK inhibition may increase tumor immunogenicity. The primary endpoint was objective response rate (ORR) in all patients combined (by Response Evaluation Criteria in Solid Tumors v1.1). Fifty patients received study drug treatment; 54% were male with a median age of 55 years (range, 31-79). The primary endpoint, ORR, was 12.0% [95% confidence interval (CI) 4.5%-24.3%], which was not statistically different than the historical control data of 5% (P = 0.038, exceeding prespecified threshold of 0.025). The disease control rate was 70.0% (95% CI, 55.4%-82.1%), the median progression-free survival 5.9 months (95% CI, 4.2-8.7 months), and the median overall survival 9.3 months (95% CI, 6.7-12.2 months). No difference in efficacy was observed between the randomized cohorts. Grade 3 and 4 adverse events were observed in 56% and 8% of patients, respectively; the most common were rash (12%) and increased aspartate aminotransferase (12%). Pembrolizumab, binimetinib, and bevacizumab failed to meet its primary endpoint of higher ORR compared with historical control data, demonstrated a high disease control rate, and demonstrated acceptable tolerability in refractory MSS mCRC.