PMID- 34006498 OWN - NLM STAT- MEDLINE DCOM- 20211022 LR - 20221003 IS - 1938-0682 (Electronic) IS - 1558-7673 (Print) IS - 1558-7673 (Linking) VI - 19 IP - 5 DP - 2021 Oct TI - A Phase I/II Study to Assess the Safety and Efficacy of Pazopanib and Pembrolizumab Combination Therapy in Patients with Advanced Renal Cell Carcinoma. PG - 434-446 LID - S1558-7673(21)00092-6 [pii] LID - 10.1016/j.clgc.2021.04.007 [doi] AB - BACKGROUND: This study assessed whether antiangiogenic treatment may potentiate immune checkpoint blockade in patients with advanced renal cell carcinoma. PATIENTS AND METHODS: This was an open-label, two-part, multicenter study involving treatment-naive patients with advanced renal cell carcinoma. Part 1 consisted of a phase I dose escalation and expansion of pazopanib plus pembrolizumab (combination therapy). Cohorts A and B received pazopanib in combination with pembrolizumab, whereas Cohort C received pazopanib monotherapy for 9 weeks before receiving the combination therapy. Part 2 was planned as a randomized three-arm study but was not conducted. RESULTS: Overall, 42 patients were enrolled (10 each in Cohorts A and B, 22 in Cohort C). The maximum tolerated dose was not reached and the recommended phase II dose was not declared, as Cohort C was closed early because of safety concerns. The overall response rates were 60% and 20% in Cohorts A and B, respectively. In Cohort C, the overall response rates were 33%, 25%, and 0% in the combination therapy, pembrolizumab monotherapy, and pazopanib monotherapy groups, respectively. The median progression-free survival rates were 21.95 months and 41.40 months in Cohorts A and B, respectively. Grade 3 or 4 adverse events (AEs) were observed in 90% of patients in Cohorts A and B. In Cohort C, the frequencies of grade 3 or 4 AEs, serious adverse events, and AEs leading to dose reduction were typically high in the combination therapy group. CONCLUSIONS: Despite preliminary signs of efficacy, significant hepatotoxicity was observed in Cohorts A and B. The sequential schedule of pazopanib followed by pazopanib plus pembrolizumab showed reduced hepatotoxicity; however, other safety issues emerged with this approach. CI - Copyright (c) 2021 Elsevier Inc. All rights reserved. FAU - Chowdhury, Simon AU - Chowdhury S AD - Sarah Cannon Research Institute, London, United Kingdom; Guy's Hospital, London, United Kingdom. FAU - Infante, Jeffery R AU - Infante JR AD - Sarah Cannon Research Institute/Tennessee Oncology, Nashville, TN. FAU - Hawkins, Robert AU - Hawkins R AD - Institute of Cancer Sciences, Manchester, United Kingdom. FAU - Voss, Martin H AU - Voss MH AD - Memorial Sloan-Kettering Cancer Center, New York, New York. FAU - Perini, Rodolfo AU - Perini R AD - Merck & Co., Inc., Kenilworth, NJ. FAU - Arkenau, Tobias AU - Arkenau T AD - Sarah Cannon Research Institute and Cancer Institute, University College, London, United Kingdom. FAU - Voskoboynik, Mark AU - Voskoboynik M AD - Alfred Health Melbourne, Monash University, Melbourne, Australia. FAU - Aimone, Paola AU - Aimone P AD - Novartis Pharma AG, Basel, Switzerland. FAU - Naeije, Isabelle AU - Naeije I AD - Novartis Pharma AG, Basel, Switzerland. FAU - Reising, Albert AU - Reising A AD - Novartis Oncology, East Hanover, NJ. FAU - McDermott, David F AU - McDermott DF AD - Beth Israel Deaconess Medical Center, Boston, MA. Electronic address: dmcdermo@bidmc.harvard.edu. LA - eng GR - P30 CA008748/CA/NCI NIH HHS/United States PT - Clinical Trial, Phase I PT - Clinical Trial, Phase II PT - Journal Article PT - Multicenter Study DEP - 20210420 PL - United States TA - Clin Genitourin Cancer JT - Clinical genitourinary cancer JID - 101260955 RN - 0 (Antibodies, Monoclonal, Humanized) RN - 0 (Indazoles) RN - 0 (Pyrimidines) RN - 0 (Sulfonamides) RN - 7RN5DR86CK (pazopanib) RN - DPT0O3T46P (pembrolizumab) SB - IM MH - Antibodies, Monoclonal, Humanized MH - Antineoplastic Combined Chemotherapy Protocols/adverse effects MH - *Carcinoma, Renal Cell/drug therapy MH - Humans MH - Indazoles MH - *Kidney Neoplasms/drug therapy MH - Pyrimidines MH - Sulfonamides MH - Treatment Outcome PMC - PMC9494291 MID - NIHMS1827582 OTO - NOTNLM OT - Antiangiogenic OT - Immune checkpoint inhibitor OT - Immuno-oncology OT - TKI/IO OT - VEGF-TKI COIS- Declaration of interests MHV reports grants from BMS; personal fees from Corvus, Exelixis, and Eisai; and grants and personal fees from Pfizer, outside the submitted work. DFMcD reports grants from BMS, Pfizer, Merck, Alkemes, Genetech, Exelixis, and X4 Pharma and personal fees from BMS, EMP Sereno, Eli Lilly Company, Merck, Pfizer, and Alkemes, outside the submitted work. TA reports personal fee from Bayer, Biontech, Beigene, Servier, Roche, outside the submitted work. MV reports personal fees from MSD, AstraZeneca, and BMS, outside the submitted work. PA and IN are employees of Novartis Pharma AG, Basel, Switzerland. AR is an employee of Novartis Pharmaceuticals Corporation, East Hanover, NJ, USA. EDAT- 2021/05/20 06:00 MHDA- 2022/09/25 06:00 PMCR- 2022/10/01 CRDT- 2021/05/19 05:49 PHST- 2020/11/26 00:00 [received] PHST- 2021/03/31 00:00 [revised] PHST- 2021/04/05 00:00 [accepted] PHST- 2021/05/20 06:00 [pubmed] PHST- 2022/09/25 06:00 [medline] PHST- 2021/05/19 05:49 [entrez] PHST- 2022/10/01 00:00 [pmc-release] AID - S1558-7673(21)00092-6 [pii] AID - 10.1016/j.clgc.2021.04.007 [doi] PST - ppublish SO - Clin Genitourin Cancer. 2021 Oct;19(5):434-446. doi: 10.1016/j.clgc.2021.04.007. Epub 2021 Apr 20.