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.

©2021 American Association for Cancer Research.

Figures

Figure 1.

A, Study design: Patients in cohorts 1, 3, and 5 were treated with cabiralizumab and APX005M alone, as this doublet had not previously been administered to patients with cancer. Cohorts 2, 4, and 6 involved the addition of nivolumab to the other two drugs. Patients were enrolled concurrently in cohorts 2 and 3 and in cohorts 4 and 5. A standard 3+3 design was used. B–E, Example of tumor from a patient with melanoma treated on cohort 6 with increased CD4+ and CD8+ T-cell density in a right axillary lymph node at week 8 (C) compared with baseline (B). D shows baseline T-cell infiltration of tumor from a patient with RCC treated on cohort 1 in which there was a decrease in CD4+ and CD8+ T-cell density in a right flank mass at week 8 (E).

Figure 2.

A, Rises in levels of circulating cytokines or chemokines on-treatment compared with pre-treatment samples, showing nine cytokines or chemokines with highly significant differences (P < 0.001). In addition, levels of CD40 and the ligand of the cabiralizumab target, MCSF, were also significantly higher after treatment. B, Nine cytokines/chemokines, CD40, and MCSF, the ligand of cabiralizumab, were significantly increased (P < 0.001) by rank value after two cycles of therapy (samples available from 22/26 patients) compared to pre-treatment levels (samples available from 26/26 patients).

Figure 3.

A, More cytokines/chemokines were significantly upregulated by rank value at C2D2 compared with baseline in the triplet versus the doublet cohort. Some cytokines/chemokines were more significantly upregulated at C2D2 in triplet versus doublet cohorts, including IL10, CCL22, TNFα, CD40 and MCSF (P < 0.001), and CXCL10 (P = 0.002), CCL3 (P = 0.002), and CCL27 (P = 0.005). At baseline, samples were available from 9/9 and 17/17 patients on doublet and triplet therapy, respectively. At C2D2, samples were available from 6/9 and 16/17 patients on doublet and triplet therapy, respectively. B, Comparison of the fold change of cytokine/chemokine levels at C2D2 from baseline at different dose levels of APX005M demonstrated that CCL22, TNFα and CD40 were increased in patients at the highest APX005M dose (0.3 mg/kg) compared with the lowest dose (0.03 mg/kg; P < 0.001). CCL22 was the only chemokine significantly higher at the highest APX005M dose compared with the intermediate dose (0.1 mg/kg; P < 0.001).