A Phase II Trial of the CD40 Agonistic Antibody Sotigalimab (APX005M) in Combination with Nivolumab in Subjects with Metastatic Melanoma with Confirmed Disease Progression on Anti-PD-1 Therapy

Abstract

Purpose: Disease progression during or after anti-PD-1-based treatment is common in advanced melanoma. Sotigalimab is a CD40 agonist antibody with a 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.

Patients and methods: We conducted a multicenter, open-label, phase II trial to evaluate the combination of sotigalimab 0.3 mg/kg and nivolumab 360 mg every 3 weeks in patients with advanced melanoma following confirmed disease progression on a PD-1 inhibitor. 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, whereas the other three responders relapsed at 41.1, 18.7, and 18.4 months. The 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. See related commentary by Wu and Luke, p. 9.

Figure 1.

A, Mechanism of action of sotigalimab (APX005M). Sotigalimab is a humanized IgG₁ mAb targeting CD40 that uniquely binds within the human CD40 L binding domain on CD40 with high affinity. Sotigalimab stimulates both innate and adaptive immune responses, activates antigen presenting cells, primes antitumor T cells, and targets TAMs. B, Study schema. Nivolumab 360 mg as a 30-minute i.v. infusion was administered first on day 1 of each cycle, followed by sotigalimab 0.3 mg/kg as a 60-minute i.v. infusion. Cycles were every 3 weeks. C, Low incidence of reported infusion reactions and no reported cytokine release syndrome (CRS). The incidence of infusion reactions decreased with subsequent doses, and a similar trend has been seen in other studies. Other AEs reported as at least possibly related to sotigalimab and considered possibly part of an infusion reaction or CRS (which was a separate question to investigators in the database) but not reported as such (preferred term) include pyrexia (grade 1/2), hypotension (grade 1, 1 event), and rash/rash maculopapular (grade 1/2, all transient <1 day).

Figure 2.

A, Spider plot showing change in target tumor size over time. B, Waterfall plot demonstrating maximal change in sum of target lesions by RECIST v1.1 in 33 evaluable subjects. C, Swimmer plot showing tumor response per subject until end of study. Duration of prior anti-PD-1, whether prior anti-CTLA-4 therapy was received, and LDH level at baseline are reported for each patient and responses are documented through the end of the study as of November 2020. D, Response in a mucosal melanoma patient. This patient was previously treated with ipilimumab and nivolumab, became resistant to anti-PD-1 monotherapy, and has had an ongoing response to sotigalimab/nivolumab as of July 2022. E, Swimmer plot showing DOR and time off systemic therapy for patients with PR beyond end of study. Two patients have an ongoing response as of July 2022.