Journal
CLINICAL CANCER RESEARCH
Volume 27, Issue 17, Pages 4757-4767Publisher
AMER ASSOC CANCER RESEARCH
DOI: 10.1158/1078-0432.CCR-21-0903
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Funding
- Yale Cancer Center
- Bristol Myers Squibb
- Apexigen
- Yale Calabresi Immuno-oncology Training Program [K12CA215110]
- Yale SPORE in Lung Cancer [P50 CA196530]
- NIH NRSA [F30 GR10226]
- Wenner-Gren Foundations
- Yale SPORE in Skin Cancer [P50 CA121974]
- [R01-CA227432]
- [R01-CA216846]
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This first in-human study of patients with anti-PD-1/PD-Li-resistant tumors treated with dual macrophage polarizing therapy, with or without nivolumab, demonstrated safety and pharmacodynamic activity. Further optimization of the dosing frequency and sequence of this combination is warranted.
Purpose: PD-i/PD-Li 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 CSFIR 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-Li. 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 asymptom atic 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 i 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-Li-resistant tumors treated with dual macrophagepolarizing therapy, with or without nivolumab demonstrated safety and pharmacodynamic activity. Optimization of the dosing frequency and sequence of this combination is warranted.
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