A phase I study of APX005M and cabiralizumab with/without nivolumab in patients with melanoma, kidney cancer or non-small cell lung cancer resistant to anti-PD-(L)1


Purpose: PD-1/PD-L1 inhibitors are approved for multiple tumor types. However, resistance poses substantial clinical challenges.

Methods: We conducted a phase I trial of CD40 agonist APX005M (sotigalimab) and CSF1R inhibitor cabiralizumab with/without nivolumab using a 3+3 dose escalation design (NCT03502330). Patients were enrolled from June 2018-April 2019. Eligibility included biopsy-proven advanced melanoma, non-small cell lung cancer (NSCLC), or renal cell carcinoma (RCC) patients who progressed on anti-PD-1/PD-L1. APX005M was dose escalated (0.03, 0.1, or 0.3 mg/kg IV) with a fixed dose of cabiralizumab with/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 TRAEs were asymptomatic elevations of LDH (n=26), CK (n=25), AST (n=25), and ALT (n=19); periorbital edema (n=17), and fatigue (n=13). One DLT (acute respiratory distress syndrome) occurred in Cohort 2. RP2D was APX005M 0.3 mg/kg, cabiralizumab 4 mg/kg, and nivolumab 240 mg q2wk. Median days on treatment was 66 (range 23-443). Median cycles was 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 M-CSF 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.