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

  • Clin Cancer Res. 2021 Sep 1;27(17):4757-4767. doi: 10.1158/1078-0432.CCR-21-0903.
Sarah A Weiss  1 ,  Dijana Djureinovic  2 ,  Shlomit Jessel  2 ,  Irina Krykbaeva  3 ,  Lin Zhang  2 ,  Lucia Jilaveanu  2 ,  Amanda Ralabate  2 ,  Barbara Johnson  2 ,  Neta Shanwetter Levit  2 ,  Gail Anderson  2 ,  Daniel Zelterman  4 ,  Wei Wei  4 ,  Amit Mahajan  5 ,  Ovid Trifan  6 ,  Marcus Bosenberg  3  7  8 ,  Susan M Kaech  9 ,  Curtis J Perry  10 ,  William Damsky  7 ,  Scott Gettinger  2 ,  Mario Sznol  2 ,  Michael Hurwitz  2 ,  Harriet M Kluger  2
Affiliations
  • 1. Department of Medicine (Medical Oncology), Yale University School of Medicine, New Haven, Connecticut. [email protected].
  • 2. Department of Medicine (Medical Oncology), Yale University School of Medicine, New Haven, Connecticut.
  • 3. Department of Pathology, Yale University School of Medicine, New Haven, Connecticut.
  • 4. Department of Biostatistics, Yale School of Public Health, New Haven, Connecticut.
  • 5. Department of Radiology and Biomedical Imaging, Yale University School of Medicine, New Haven, Connecticut.
  • 6. Apexigen, Inc., San Carlos, California.
  • 7. Department of Dermatology, Yale University School of Medicine, New Haven, Connecticut.
  • 8. Department of Immunobiology, Yale University School of Medicine, New Haven, Connecticut.
  • 9. NOMIS Center for Immunobiology and Microbial Pathogenesis, Salk Institute, La Jolla, California.
  • 10. Department of Medicine, Yale University School of Medicine, New Haven, Connecticut.
PMID: 34140403 DOI: 10.1158/1078-0432.CCR-21-0903
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.

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