Phase IB study of ziv-aflibercept plus pembrolizumab in patients with advanced solid tumors.

Autor:	Rahma OE; Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA osamae_rahma@dfci.harvard.edu.; Harvard Medical School, Boston, Massachusetts, USA., Tyan K; Harvard Medical School, Boston, Massachusetts, USA., Giobbie-Hurder A; Division of Biostatistics, Department of Data Sciences, Dana Farber Cancer Institute, Boston, Massachusetts, USA., Brohl AS; Sarcoma Department and Cutaneous Oncology, Moffitt Cancer Center, Tampa, Florida, USA., Bedard PL; Division of Medical Oncology and Hematology, University Health Network, Princess Margaret Cancer Centre, Toronto, Ontario, Canada., Renouf DJ; Cancer and Department of Medicine, University of British Columbia, Vancouver, British Columbia, Canada., Sharon E; Cancer Therapy Evaluation Program, National Cancer Institute, Bethesda, Maryland, USA., Streicher H; Cancer Therapy Evaluation Program, National Cancer Institute, Bethesda, Maryland, USA., Hathaway E; Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA.; Center for Immuno-Oncology, Dana Farber Cancer Institute, Boston, Massachusetts, USA., Cunningham R; Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA.; Center for Immuno-Oncology, Dana Farber Cancer Institute, Boston, Massachusetts, USA., Manos M; Center for Immuno-Oncology, Dana Farber Cancer Institute, Boston, Massachusetts, USA., Severgnini M; Center for Immuno-Oncology, Dana Farber Cancer Institute, Boston, Massachusetts, USA., Rodig S; Department of Pathology, Brigham and Women's Hospital, Boston, Massachusetts, USA., Stephen Hodi F; Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA.; Harvard Medical School, Boston, Massachusetts, USA.
Jazyk:	angličtina
Zdroj:	Journal for immunotherapy of cancer [J Immunother Cancer] 2022 Mar; Vol. 10 (3).
DOI:	10.1136/jitc-2021-003569
Abstrakt:	Background: The combination of antiangiogenic agents with immune checkpoint inhibitors could potentially overcome immune suppression driven by tumor angiogenesis. We report results from a phase IB study of ziv-aflibercept plus pembrolizumab in patients with advanced solid tumors. Methods: This is a multicenter phase IB dose-escalation study of the combination of ziv-aflibercept (at 2-4 mg/kg) plus pembrolizumab (at 2 mg/kg) administered intravenously every 2 weeks with expansion cohorts in programmed cell death protein 1 (PD-1)/programmed death-ligand 1(PD-L1)-naïve melanoma, renal cell carcinoma (RCC), microsatellite stable colorectal cancer (CRC), and ovarian cancer. The primary objective was to determine maximum tolerated dose (MTD) and recommended dose of the combination. Secondary endpoints included overall response rate (ORR) and overall survival (OS). Exploratory objectives included correlation of clinical efficacy with tumor and peripheral immune population densities. Results: Overall, 33 patients were enrolled during dose escalation (n=3) and dose expansion (n=30). No dose-limiting toxicities were reported in the initial dose level. Ziv-aflibercept 4 mg/kg plus pembrolizumab 2 mg/kg every 2 weeks was established as the MTD. Grade ≥3 adverse events occurred in 19/33 patients (58%), the most common being hypertension (36%) and proteinuria (18%). ORR in the dose-expansion cohort was 16.7% (5/30, 90% CI 7% to 32%). Complete responses occurred in melanoma (n=2); partial responses occurred in RCC (n=1), mesothelioma (n=1), and melanoma (n=1). Median OS was as follows: melanoma, not reached (NR); RCC, 15.7 months (90% CI 2.5 to 15.7); CRC, 3.3 months (90% CI 0.6 to 3.4); ovarian, 12.5 months (90% CI 3.8 to 13.6); other solid tumors, NR. Activated tumor-infiltrating CD8 T cells at baseline (CD8+PD1+), high CD40L expression, and increased peripheral memory CD8 T cells correlated with clinical response. Conclusion: The combination of ziv-aflibercept and pembrolizumab demonstrated an acceptable safety profile with antitumor activity in solid tumors. The combination is currently being studied in sarcoma and anti-PD-1-resistant melanoma. Trial Registration Number: NCT02298959. Competing Interests: Competing interests: OR has research support from Merck; educational grants from BMS and Merck; consulting agreements with Merck, Celgene, Five Prime Therapeutics, GSK, GFK, Defined Health INC, Roche/Genentech, Puretech, Leerink, and PRMA Consulting; and a pending patent, ‘Methods of Using Pembrolizumab and Trebananib’. ASB reports serving as a consultant or advisor for Bayer, Deciphera, EMD Serono, and PierianDx. PLB reports consulting or advisory role for Seattle Genetics, Lilly, Amgen, Merck, BMS, and Pfizer, and reports research funding from Bristol-Myers Squibb, Sanofi, AstraZeneca, Genentech/Roche, SERVIER, GlaxoSmithKline, Novartis, PTC Therapeutics, Nektar, Merck, Seattle Genetics, Mersana, Immunomedics, Lilly, Amgen, and Bicara. SR reports receiving commercial research grants from Bristol-Myers Squibb, Merck, and KITE/Gilead. SH reports the following: grants from BMS and Novartis; personal fees from BMS, Merck, Serono, Novartis, Takeda, Surface Pharmaceuticals, Genentech/Roche, Compass Therapeutics, Apricity, Bayer, Aduro, Partners Therapeutics, Sanofi, Pfizer, Pionyr Immunotherapeutics, 7 Hills Pharma, Verastem Oncology, Rheos Medicines, and Kairos Therapeutics; equity in Torque Therapeutics; and patents #20100111973 and #7250291 issued as well as #20170248603, #20160340407, #20160046716, #20140004112, #20170022275, and #20170008962, and ‘Methods of Using Pembrolizumab and Trebananib’ pending. (© Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)
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