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Purpose: PD-1/PD-L1 inhibitors are approved for multiple tumor types. However, resistance poses substantial clinical challenges. Patients and Methods: We conducted a phase I trial of CD40 agonist APX005M (sotigalimab) and CSF1R inhibitor cabiralizumab with or without nivolumab using a 3+3 dose-escalation design (NCT03502330). Patients were enrolled from June 2018 to April 2019. Eligibility included patients with biopsy-proven advanced melanoma, non–small cell lung cancer (NSCLC), or renal cell carcinoma (RCC) who progressed on anti-PD-1/PD-L1. APX005M was dose escalated (0.03, 0.1, or 0.3 mg/kg i.v.) with a fixed dose of cabiralizumab with or without nivolumab every 2 weeks until disease progression or intolerable toxicity. Results: Twenty-six patients (12 melanoma, 1 NSCLC, and 13 RCC) were enrolled in six cohorts, 17 on nivolumab-containing regimens. Median duration of follow-up was 21.3 months. The most common treatment-related adverse events were asymptomatic elevations of lactate dehydrogenase (n = 26), creatine kinase (n = 25), aspartate aminotransferase (n = 25), and alanine aminotransferase (n = 19); periorbital edema (n = 17); and fatigue (n = 13). One dose-limiting toxicity (acute respiratory distress syndrome) occurred in cohort 2. The recommended phase 2 dose was APX005M 0.3 mg/kg, cabiralizumab 4 mg/kg, and nivolumab 240 mg every 2 weeks. Median days on treatment were 66 (range, 23–443). Median cycles were 4.5 (range, 2–21). One patient had unconfirmed partial response (4%), 8 stable disease (31%), 16 disease progression (62%), and 1 unevaluable (4%). Pro-inflammatory cytokines were upregulated 4 hours post-infusion. CD40 and MCSF increased after therapy. Conclusions: This first in-human study of patients with anti-PD-1/PD-L1–resistant tumors treated with dual macrophage-polarizing therapy, with or without nivolumab demonstrated safety and pharmacodynamic activity. Optimization of the dosing frequency and sequence of this combination is warranted.

clinical cancer research

A Phase I Study of APX005M and Cabiralizumab with or without Nivolumab in Patients with Melanoma, Kidney Cancer, or Non–Small Cell Lung Cancer Resistant to Anti-PD-1/PD-L1