Weiss et al. performed a phase 2 trial that combined the CD40 agonist sotigalimab with nivolumab in 38 patients with advanced melanoma who progressed on anti-PD-(L)1 therapy. Grade 3 adverse events (AEs) were observed in 29% of patients, with a low incidence of immune-related AEs. Efficacy could be assessed for 33 patients; 5 had partial responses with a median duration of at least 26 months, and 10 had stable disease, of which 2 lasted >6 months. The objective response rate was 15% and the median progression-free survival was 2 months. Treatment increased immune mediators associated with activation of dendritic, NK, and T cells.

Contributed by Maartje Wouters

PURPOSE: Disease progression during or after anti-PD-1-based treatment is common in advanced melanoma. Sotigalimab is a CD40 agonist antibody with unique epitope specificity and Fc-receptor binding profile optimized for activation of CD40-expressing antigen presenting cells. Preclinical data indicated that CD40 agonists combined with anti-PD1 could overcome resistance to anti-PD-1. METHODS: We conducted a multi-center, open-label, phase II trial to evaluate the combination of sotigalimab 0.3mg/kg and nivolumab 360mg q3wk in patients with advanced melanoma following confirmed disease progression on anti-PD-1. The primary objective was to determine the objective response rate (ORR). RESULTS: Thirty-eight subjects were enrolled and evaluable for safety. Thirty-three were evaluable for activity. Five confirmed partial responses (PR) were observed for an ORR of 15%. Two PRs are ongoing at 45.9+ and 26+ months while the other 3 responders relapsed at 41.1, 18.7, and 18.4 months. Median duration of response was at least 26 months. Two additional patients had stable disease for > 6 months. Thirty-four patients (89%) experienced at least one adverse event (AE) and 13% experienced a grade 3 AE related to sotigalimab. The most common AEs were pyrexia, chills, nausea, fatigue, pruritus, elevated liver function, rash, vomiting, headache, arthralgia, asthenia, myalgia, and diarrhea. There were no treatment-related SAEs, deaths, or discontinuation of sotigalimab due to AEs. CONCLUSIONS: Sotigalimab plus nivolumab had a favorable safety profile consistent with the toxicity profiles of each agent. The combination resulted in durable and prolonged responses in a subset of patients with anti-PD-1-resistant melanoma, warranting further evaluation in this setting.

Author Info: (1) Rutgers, The State University of New Jersey, New Brunswick, NJ, United States. (2) Yale University School of Medicine, New Haven, CT, United States. (3) The University of Texas

Author Info: (1) Rutgers, The State University of New Jersey, New Brunswick, NJ, United States. (2) Yale University School of Medicine, New Haven, CT, United States. (3) The University of Texas Health Science Center at San Antonio, San Antonio, United States. (4) Regional and Virgen de la Victoria University Hospitals. Institute of Biomedical Research in Malaga (IBIMA). 29010. Malaga. Spain, M‡laga, Spain. (5) Vall d'Hebron Institute of Oncology, barcelona, barcelona, spain, Spain. (6) Clinical Oncology Dept, Hospital Universitario Insular, Las Palmas de Gran Canaria, Spain, Las Palmas de Gran Canaria, Las Palmas, Spain. (7) NEXT Madrid, Madrid, Spain. (8) University of Pennsylvania, Philadelphia, PA, United States. (9) Quir—n Dexeus University Hospital, Barcelona, Spain. (10) Hospital Cl’nic de Barcelona, Barcelona, Spain. (11) Yale University, New Haven, CT, United States. (12) VA Nebraska Western Iowa Health Care System and University of Nebraska Medical Center, Omaha, NE, United States. (13) Nebraska Cancer Specialists, Omaha, NE, United States. (14) Hospital Universitario General de Valencia, Valencia, Spain. (15) Hematology Oncology Associates of the Treasure Coast, Port St. Lucie, FL, United States. (16) Apexigen America, Inc (current affiliation -- previously Immune Design), San Carlos, California, United States. (17) Yale School of Medicine, New Haven, CT, United States.