@article{39780df74b2d49a59028e5f4414d6d9c,
title = "Cabozantinib plus Nivolumab Phase I Expansion Study in Patients with Metastatic Urothelial Carcinoma Refractory to Immune Checkpoint Inhibitor Therapy",
abstract = "Purpose: This study investigated the efficacy and tolerability of cabozantinib plus nivolumab (CaboNivo) in patients with metastatic urothelial carcinoma (mUC) that progressed on checkpoint inhibition (CPI). Patients and Methods: A phase I expansion cohort of patients with mUC who received prior CPI was treated with cabozantinib 40 mg/day and nivolumab 3 mg/kg every 2 weeks until disease progression/unacceptable toxicity. The primary goal was objective response rate (ORR) per RECIST v.1.1. Secondary objectives included progression-free survival (PFS), duration of response (DoR), overall survival (OS), safety, and tolerability. Results: Twenty-nine out of 30 patients enrolled were evaluable for efficacy. Median follow-up was 22.2 months. Most patients (86.7%) received prior chemotherapy and all patients received prior CPI (median seven cycles). ORR was 16.0%, with one complete response and three partial responses (PR). Among 4 responders, 2 were primary refractory, 1 had a PR, and 1 had stable disease on prior CPI. Median DoR was 33.5 months [95% confidence interval (CI), 3.7–33.5], median PFS was 3.6 months (95% CI, 2.1–5.5), and median OS was 10.4 months (95% CI, 5.8–19.5). CaboNivo decreased immunosuppressive subsets such as regulatory T cells (Tregs) and increased potential antitumor immune subsets such as nonclassical monocytes and effector T cells. A lower percentage of monocytic myeloid-derived suppressor cells (M-MDSC) and polymorphonuclear MDSCs, lower CTLA-4 and TIM-3 expression on Tregs, and higher effector CD4{\th} T cells at baseline were associated with better PFS and/or OS. Conclusions: CaboNivo was clinically active, well tolerated, and favorably modulated peripheral blood immune subsets in patients with mUC refractory to CPI.",
author = "Girardi, {Daniel M.} and Niglio, {Scot A.} and Amir Mortazavi and Rosa Nadal and Primo Lara and Pal, {Sumanta K.} and Biren Saraiya and Lisa Cordes and Lisa Ley and Ortiz, {Olena Sierra} and Jacqueline Cadena and Carlos Diaz and Hadi Bagheri and Bernadette Redd and Steinberg, {Seth M.} and Rene Costello and Chan, {Keith S.} and Lee, {Min Jung} and Sunmin Lee and Yunkai Yu and Sandeep Gurram and Chalfin, {Heather J.} and Vladimir Valera and Figg, {William D.} and Maria Merino and Antoun Toubaji and Howard Streicher and Wright, {John J.} and Elad Sharon and Parnes, {Howard L.} and Ning, {Yang Min} and Bottaro, {Donald P.} and Liang Cao and Trepel, {Jane B.} and Apolo, {Andrea B.}",
note = "Funding Information: D.M. Girardi reports other support from Merck and personal fees from Pfizer outside the submitted work. A. Mortazavi reports other support from NIH during the conduct of the study, as well as other support from Seattle Genetics, Pfizer, Debiopharm Group, Acerta Pharma, Genentech, Roche, Merck, Novartis, Seattle Genetics, Astellas Pharma, Mirati Therapeutics, Bristol Myers Squibb, and Debiopharm Group outside the submitted work. S.K. Pal reports personal fees from F. Hoffman-La Roche outside the submitted work, as well as research funding to his institution from Eisai, Genentech, Roche, Exelixis, and Pfizer. B. Saraiya reports personal fees from Eisai, as well as grants from Merck and Advaxis outside the submitted work. D.P. Bottaro reports a patent for US 10,035,833 issued, a patent for US 9,550,818 and related international WO/2013/163606 issued, a patent for US 8,617,831 issued, a patent for US 7,964,365 and related international WO/2007/ 056523 issued, a patent for US 8,304,199 issued, a patent for US 8,569,360 and related international WO/2009/124024 and WO/2009/124013 issued, and a patent for US 7,871,981 and related international WO/2001/028577 issued. No disclosures were reported by the other authors. Funding Information: This research was supported by the Intramural Research Program of the Center for Cancer Research, NCI, NIH, and by a Cooperative Research and Development Agreement between Cancer Therapy Evaluation Program and the NCI. We thank the patients involved in this study and their families. We express appreciation to the nurses, medical oncology fellows, and consultation services at the NIH Clinical Center for their excellent patient care. We thank Bonnie L. Casey from the NCI for editorial assistance. Exelixis provided cabozantinib and Bristol Myers Squibb provided nivolumab. Publisher Copyright: {\textcopyright} 2022 The Authors.",
year = "2022",
month = apr,
day = "1",
doi = "10.1158/1078-0432.CCR-21-3726",
language = "English (US)",
volume = "28",
pages = "1353--1362",
journal = "Clinical Cancer Research",
issn = "1078-0432",
publisher = "American Association for Cancer Research Inc.",
number = "7",
}