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

Journal Article (Journal Article)

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.

Full Text

Duke Authors

Cited Authors

  • Sanborn, RE; Pishvaian, MJ; Callahan, MK; Weise, A; Sikic, BI; Rahma, O; Cho, DC; Rizvi, NA; Sznol, M; Lutzky, J; Bauman, JE; Bitting, RL; Starodub, A; Jimeno, A; Reardon, DA; Kaley, T; Iwamoto, F; Baehring, JM; Subramaniam, DS; Aragon-Ching, JB; Hawthorne, TR; Rawls, T; Yellin, M; Keler, T

Published Date

  • August 2022

Published In

Volume / Issue

  • 10 / 8

PubMed ID

  • 35940825

Pubmed Central ID

  • PMC9364417

Electronic International Standard Serial Number (EISSN)

  • 2051-1426

Digital Object Identifier (DOI)

  • 10.1136/jitc-2022-005147


  • eng

Conference Location

  • England