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

Abstract

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.

Signal pathways of melanoma and targeted therapy

“…Another CD40 agonist, APX005M and the inhibitor of another macrophage polarizing regulator CSF1R, cabiraluzumab with or without nivolumab demonstrated tolerable safety profile, warranting further investigations into the optimization of the dosing and selection of patients. 686 The investigations on the combinations of APX005M and nivolumab or pembrolizumab are still ongoing. Other CD40 agonists entering the clinic including SEA-CD40, ADC-1013, and CDX-1140 are being tested for single use or in combination with either chemotherapy, vaccines, or ICBs in early clinical trials in patients with advanced melanoma.…”

Tumor Associated Macrophages: Origin, Recruitment, Phenotypic Diversity, and Targeting

“…A CSF-1R blocking monoclonal antibody RG7155 was shown to reduce CSF-1R+CD163+ TAMs and peripheral blood CCR2+ monocytes in phase I clinical trial in patients with diffuse-type giant cell tumor (ClinicalTrials.gov identifier NCT01494688) ( 147 ). Also, safety and pharmacodynamic activity of CSF1R inhibitor cabiralizumab was reported in phase I clinical trial testing a combination of CD40 agonist APX005M (sotigalimab) and cabiralizumab with or without PD-1/PD-L1 inhibitor nivolumab in PD-1/PD-L1 resistant advanced cancer patients (ClinicalTrials.gov Identifier: NCT03502330) ( 148 ).…”

CD40 Cross-Linking Induces Migration of Renal Tumor Cell through Nuclear Factor of Activated T Cells (NFAT) Activation

“…The knowledge of the different mechanisms activated by CD40 ligation in RCC patients will help us to identify novel approaches in the treatment of RCC. CD40 agonists represent today the novel frontier in the treatment of this carcinoma [32], since CD40 ligation plays an important role also in neo-vascularization of tumors [33] and anti-angiogenesis and immunotherapy represent next-generation approaches in the treatment of renal cell carcinoma [34]. Moreover, CD40 engagement can also enhance the immunostimulation of dendritic cells and effector cells against human RCC [24].…”