Safety, tolerability and efficacy of agonist anti-CD27 antibody (varlilumab) administered in combination with anti-PD-1 (nivolumab) in advanced solid tumors
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 week...
| Main Authors: | , , , , , , , , , , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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BMJ Publishing Group
2022-08-01
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| Series: | Journal for ImmunoTherapy of Cancer |
| Online Access: | https://jitc.bmj.com/content/10/8/e005147.full |
| _version_ | 1811322408559181824 |
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| author | Mario Sznol Michael Yellin Tibor Keler Jose Lutzky Amy Weise Margaret K Callahan Osama Rahma Rachel E Sanborn Alexander Starodub Deepa S Subramaniam Antonio Jimeno Tracey Rawls David A Reardon Daniel C Cho Rhonda L Bitting Michael J Pishvaian Branimir I Sikic Naiyer A Rizvi Julie E Bauman Thomas Kaley Fabio Iwamoto Joachim M Baehring Jeanny B Aragon-Ching Thomas R Hawthorne |
| author_facet | Mario Sznol Michael Yellin Tibor Keler Jose Lutzky Amy Weise Margaret K Callahan Osama Rahma Rachel E Sanborn Alexander Starodub Deepa S Subramaniam Antonio Jimeno Tracey Rawls David A Reardon Daniel C Cho Rhonda L Bitting Michael J Pishvaian Branimir I Sikic Naiyer A Rizvi Julie E Bauman Thomas Kaley Fabio Iwamoto Joachim M Baehring Jeanny B Aragon-Ching Thomas R Hawthorne |
| author_sort | Mario Sznol |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-04-13T13:35:54Z |
| format | Article |
| id | doaj.art-64a076a7b8714d66afa98dfcc1b8a9bc |
| institution | Directory Open Access Journal |
| issn | 2051-1426 |
| language | English |
| last_indexed | 2024-04-13T13:35:54Z |
| publishDate | 2022-08-01 |
| publisher | BMJ Publishing Group |
| record_format | Article |
| series | Journal for ImmunoTherapy of Cancer |
| spelling | doaj.art-64a076a7b8714d66afa98dfcc1b8a9bc2022-12-22T02:44:48ZengBMJ Publishing GroupJournal for ImmunoTherapy of Cancer2051-14262022-08-0110810.1136/jitc-2022-005147Safety, tolerability and efficacy of agonist anti-CD27 antibody (varlilumab) administered in combination with anti-PD-1 (nivolumab) in advanced solid tumorsMario Sznol0Michael Yellin1Tibor Keler2Jose Lutzky3Amy Weise4Margaret K Callahan5Osama Rahma6Rachel E Sanborn7Alexander Starodub8Deepa S Subramaniam9Antonio Jimeno10Tracey Rawls11David A Reardon12Daniel C Cho13Rhonda L Bitting14Michael J Pishvaian15Branimir I Sikic16Naiyer A Rizvi17Julie E Bauman18Thomas Kaley19Fabio Iwamoto20Joachim M Baehring21Jeanny B Aragon-Ching22Thomas R Hawthorne23Yale Cancer Center, Yale School of Medicine, New Haven, Connecticut, USAAff3 grid.417695.8Celldex Therapeutics, Inc. Charlottesville VA USA2Celldex Therapeutics, Inc., Hampton, NJ, USADepartment of Oncology, Sylvester Comprehensive Cancer Center, Miami, Florida, USAAff10 0000 0001 1456 7807grid.254444.7Department of Hematology & OncologyKarmanos Cancer Institute, Wayne State University Detroit MI USAAff1 grid.51462.340000000121719952Memorial Sloan-Kettering Cancer Center New York NY USACenter for Cancer Therapeutic Innovation, Gastrointestinal Cancer Center, Dana-Farber Cancer Institute, Boston, Massachusetts, USADepartment of Medical Oncology, Earle A. Chiles Research Institute, Providence Cancer Institute, Portland, Oregon, USA2Riverside Peninsula Cancer Institute, Goshen, IN, USADepartment of Oncology, Lombardi Comprehensive Cancer Center, Georgetown University, Washington, District of Columbia, USAMedicine, University of Colorado Anschutz Medical Campus, Aurora, Colorado, USACelldex Therapeutics, Hampton, NJ, USAHarvard Medical School, Boston, Massachusetts, USADepartment of Medicine, Perlmutter Cancer Center at NYU Langone Medical Center, New York, New York, USAWake Forest Baptist Health, Winston-Salem, North Carolina, USADepartment of Oncology, Georgetown-Lombardi Comprehensive Cancer Center, Washington, District of Columbia, USAClinical and Translational Research Unit, Stanford Cancer Institute, Stanford, California, USADivision of Hematology/Oncology, Columbia University Medical Center, New York, New York, USAUniversity of Arizona Cancer Center, Tuscon, Arizona, USADepartment of Neurology, Memorial Sloan Kettering Cancer Center, New York, New York, USADepartment of Neurology, Columbia Presbyterian Medical Center, New York, New York, USADepartment of Neurosurgery, Yale New Haven Health Smilow Cancer Hospital, New Haven, Connecticut, USAInova Schar Cancer Institute, Fairfax, Virginia, USACelldex Therapeutics Inc New Haven, New Haven, Connecticut, USABackground 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.https://jitc.bmj.com/content/10/8/e005147.full |
| spellingShingle | Mario Sznol Michael Yellin Tibor Keler Jose Lutzky Amy Weise Margaret K Callahan Osama Rahma Rachel E Sanborn Alexander Starodub Deepa S Subramaniam Antonio Jimeno Tracey Rawls David A Reardon Daniel C Cho Rhonda L Bitting Michael J Pishvaian Branimir I Sikic Naiyer A Rizvi Julie E Bauman Thomas Kaley Fabio Iwamoto Joachim M Baehring Jeanny B Aragon-Ching Thomas R Hawthorne Safety, tolerability and efficacy of agonist anti-CD27 antibody (varlilumab) administered in combination with anti-PD-1 (nivolumab) in advanced solid tumors Journal for ImmunoTherapy of Cancer |
| title | Safety, tolerability and efficacy of agonist anti-CD27 antibody (varlilumab) administered in combination with anti-PD-1 (nivolumab) in advanced solid tumors |
| title_full | Safety, tolerability and efficacy of agonist anti-CD27 antibody (varlilumab) administered in combination with anti-PD-1 (nivolumab) in advanced solid tumors |
| title_fullStr | Safety, tolerability and efficacy of agonist anti-CD27 antibody (varlilumab) administered in combination with anti-PD-1 (nivolumab) in advanced solid tumors |
| title_full_unstemmed | Safety, tolerability and efficacy of agonist anti-CD27 antibody (varlilumab) administered in combination with anti-PD-1 (nivolumab) in advanced solid tumors |
| title_short | Safety, tolerability and efficacy of agonist anti-CD27 antibody (varlilumab) administered in combination with anti-PD-1 (nivolumab) in advanced solid tumors |
| title_sort | safety tolerability and efficacy of agonist anti cd27 antibody varlilumab administered in combination with anti pd 1 nivolumab in advanced solid tumors |
| url | https://jitc.bmj.com/content/10/8/e005147.full |
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