2. Academic Validation
  3. Safety, tolerability and efficacy of agonist anti-CD27 antibody (varlilumab) administered in combination with anti-PD-1 (nivolumab) in advanced solid tumors

Safety, tolerability and efficacy of agonist anti-CD27 antibody (varlilumab) administered in combination with anti-PD-1 (nivolumab) in advanced solid tumors

  • J Immunother Cancer. 2022 Aug;10(8):e005147. doi: 10.1136/jitc-2022-005147.
Rachel E Sanborn 1,  Michael J Pishvaian 2,  Margaret K Callahan 3,  Amy Weise 4,  Branimir I Sikic 5,  Osama Rahma 6,  Daniel C Cho 7,  Naiyer A Rizvi 8,  Mario Sznol 9,  Jose Lutzky 10,  Julie E Bauman 11,  Rhonda L Bitting 12,  Alexander Starodub 13,  Antonio Jimeno 14,  David A Reardon 15,  Thomas Kaley 16,  Fabio Iwamoto 17,  Joachim M Baehring 18,  Deepa S Subramaniam 19,  Jeanny B Aragon-Ching 20,  Thomas R Hawthorne 21,  Tracey Rawls 22,  Michael Yellin 22,  Tibor Keler 23
Affiliations

Affiliations

  • 1 Providence Cancer Institute, Earle A. Chiles Research Institute, Portland, Oregon, USA [email protected].
  • 2 Department of Oncology, Georgetown-Lombardi Comprehensive Cancer Center, Washington, District of Columbia, USA.
  • 3 Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York, USA.
  • 4 Karmanos Cancer Institute, Detroit, Michigan, USA.
  • 5 Clinical and Translational Research Unit, Stanford Cancer Institute, Stanford, California, USA.
  • 6 Department of Medical Oncology, Dana Farber Cancer Institute, Boston, Massachusetts, USA.
  • 7 Perlmutter Cancer Center, NYU Langone Medical Center, New York, New York, USA.
  • 8 Division of Hematology/Oncology, Columbia University Medical Center, New York, New York, USA.
  • 9 Smilow Cancer Hospital, New Haven, Connecticut, USA.
  • 10 Mount Sinai Comprehensive Cancer Center, Miami Beach, Florida, USA.
  • 11 University of Arizona Cancer Center, Tuscon, Arizona, USA.
  • 12 Wake Forest Baptist Health, Winston-Salem, North Carolina, USA.
  • 13 Parkview Research Center, Fort Wayne, Indiana, USA.
  • 14 Department of Medicine, University of Colorado Anschutz Medical Campus, Aurora, Colorado, USA.
  • 15 Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA.
  • 16 Department of Neurology, Memorial Sloan Kettering Cancer Center, New York, New York, USA.
  • 17 Department of Neurology, Columbia Presbyterian Medical Center, New York, New York, USA.
  • 18 Department of Neurosurgery, Yale New Haven Health Smilow Cancer Hospital, New Haven, Connecticut, USA.
  • 19 Department of Oncology, Georgetown Lombardi Comprehensive Cancer Center, Washington, District of Columbia, USA.
  • 20 Inova Schar Cancer Institute, Fairfax, Virginia, USA.
  • 21 Celldex Therapeutics Inc New Haven, New Haven, Connecticut, USA.
  • 22 Celldex Therapeutics Inc, Hampton, New Jersey, USA.
  • 23 R & D, Celldex Therapeutics Inc, Hampton, New Jersey, USA.
PMID: 35940825 DOI: 10.1136/jitc-2022-005147
Abstract

Background: Phase 1/2 dose-escalation and expansion study evaluating varlilumab, a fully human agonist anti-CD27 mAb, with nivolumab in anti-PD-1/L1 naïve, refractory solid tumors.

Methods: Phase 1 evaluated the safety of varlilumab (0.1-10 mg/kg) with nivolumab (3 mg/kg) administered once every 2 weeks. Phase 2 evaluated varlilumab regimens (3 mg/kg once every 2 weeks, 3 mg/kg once every 12 weeks, and 0.3 mg/kg once every 4 weeks) with nivolumab 240 mg once every 2 weeks in tumor-specific cohorts. Primary objective was safety; key clinical endpoints included objective response rate (ORR) and overall survival rate at 12 months (OS12) (glioblastoma (GBM) only). Exploratory objectives included determination of effects on peripheral blood and intratumoral immune signatures.

Results: 175 patients were enrolled (36 in phase 1 and 139 in phase 2). Phase 1 dose-escalation proceeded to the highest varlilumab dose level without determining a maximum tolerated dose. In phase 2, ORR were ovarian 12.5%, squamous cell carcinoma of the head and neck 12.5%, colorectal Cancer 5%, and renal cell carcinoma 0%; GBM OS12 was 40.9%. Increased tumor PD-L1 and intratumoral T cell infiltration were observed in ovarian Cancer patients, with increases of ≥5% associated with better progression-free survival. The most common treatment related adverse events were fatigue (18%), pruritus (16%), and rash (15%).

Conclusion: Varlilumab and nivolumab were well tolerated, without significant toxicity beyond that expected for each agent alone. Clinical activity was observed in patients that are typically refractory to anti-PD-1 therapy, however, overall was not greater than expected for nivolumab monotherapy. Treatment was associated with proinflammatory changes in the tumor microenvironment, particularly in ovarian Cancer where the changes were associated with better clinical outcomes.

Trial registration number: NCT02335918.

Keywords

clinical trials as topic; combined modality therapy; immunotherapy.

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