@article{33c895e57954467db1ff6fdb058b0151,
title = "Translational randomized phase II trial of cabozantinib in combination with nivolumab in advanced, recurrent, or metastatic endometrial cancer",
abstract = "Background Combining immunotherapy and antiangiogenic agents is a promising treatment strategy in endometrial cancer. To date, no biomarkers for response have been identified and data on post-immunotherapy progression are lacking. We explored the combination of a checkpoint inhibitor (nivolumab) and an antiangiogenic agent (cabozantinib) in immunotherapy-na{\"i}ve endometrial cancer and in patients whose disease progressed on previous immunotherapy with baseline biopsy for immune profiling. Patients and methods In this phase II trial (ClinicalTrials.gov NCT03367741, registered December 11, 2017), women with recurrent endometrial cancer were randomized 2:1 to nivolumab with cabozantinib (Arm A) or nivolumab alone (Arm B). The primary endpoint was Response Evaluation Criteria in Solid Tumors-defined progression-free survival (PFS). Patients with carcinosarcoma or prior immune checkpoint inhibitor received combination treatment (Arm C). Baseline biopsy and serial peripheral blood mononuclear cell (PBMC) samples were analyzed and associations between patient outcome and immune data from cytometry by time of flight (CyTOF) and PBMCs were explored. Results Median PFS was 5.3 (90% CI 3.5 to 9.2) months in Arm A (n=36) and 1.9 (90% CI 1.6 to 3.4) months in Arm B (n=18) (HR=0.59, 90% CI 0.35 to 0.98; log-rank p=0.09, meeting the prespecified statistical significance criteria). The most common treatment-related adverse events in Arm A were diarrhea (50%) and elevated liver enzymes (aspartate aminotransferase 47%, alanine aminotransferase 42%). In-depth baseline CyTOF analysis across treatment arms (n=40) identified 35 immune-cell subsets. Among immunotherapy-pretreated patients in Arm C, non-progressors had significantly higher proportions of activated tissue-resident (CD103+CD69+) I δT cells than progressors (adjusted p=0.009). Conclusions Adding cabozantinib to nivolumab significantly improved outcomes in heavily pretreated endometrial cancer. A subgroup of immunotherapy-pretreated patients identified by baseline immune profile and potentially benefiting from combination with antiangiogenics requires further investigation.",
keywords = "biomarkers, clinical trials, combination, drug therapy, female, genital neoplasms, immunotherapy, phase II as topic, tumor",
author = "Stephanie Lheureux and Matei, {Daniela E.} and Konstantinopoulos, {Panagiotis A.} and Wang, {Ben X.} and Ramy Gadalla and Block, {Matthew S.} and Andrea Jewell and Gaillard, {Stephanie L.} and Michael McHale and Carolyn McCourt and Sarah Temkin and Eugenia Girda and Backes, {Floor J.} and Werner, {Theresa L.} and Linda Duska and Siobhan Kehoe and Ilaria Colombo and Lisa Wang and Xuan Li and Rachel Wildman and Shirin Soleimani and Scott Lien and John Wright and Trevor Pugh and Ohashi, {Pamela S.} and Brooks, {David G.} and Fleming, {Gini F.}",
note = "Funding Information: 1Drug Development Program, Department of Medical Oncology and Hematology, Princess Margaret Cancer Centre, Toronto, Ontario, Canada 2Department of Obstetrics and Gynecology, Indiana University Melvin and Bren Simon Cancer Center, Indianapolis, Illinois, USA 3Department of Gynecologic Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA 4Immune Profiling Team – Tumor Immunotherapy Program, Princess Margaret Cancer Centre, Toronto, Ontario, Canada 5Department of Medical Oncology, Mayo Clinic, Rochester, Minnesota, USA 6Department of Gynecologic Oncology, University of Kansas Medical Center, Kansas City, Kansas, USA 7Department of Gynecology and Obstetrics, Johns Hopkins School of Medicine, Baltimore, Maryland, USA 8Department of Obstetrics and Gynecology, Moores Cancer Centre, UC San Diego Health, La Jolla, California, USA 9Department of Gynecology Oncology, Washington University School of Medicine, St Louis, Missouri, USA 10Department of Gynecology Oncology, Virginia Commonwealth University, Richmond, Virginia, USA 11Department of Gynecology Oncology, Rutgers Cancer Institute of New Jersey, New Brunswick, New Jersey, USA 12Department of Gynecologic Oncology, Ohio State University, Columbus, Ohio, USA 13Division of Oncology, Department of Medicine, Huntsman Cancer Institute, University of Utah, Salt Lake City, Utah, USA 14Department of Gynecology Oncology, University of Virginia, Charlottesville, Virginia, USA 15Department of Gynecology Oncology, NYU Langone, New York City, New York, USA 16Department of Statistics, Princess Margaret Cancer Centre, Toronto, Ontario, Canada 17Department of Medical Biophysics, University of Toronto, Toronto, Ontario, Canada 18Cancer Genomics Program, Princess Margaret Cancer Centre, Toronto, Ontario, Canada 19Department of Immunology, University of Toronto, Toronto, Ontario, Canada 20Investigational Drug Branch, Cancer Therapy Evaluation Program, National Cancer Institute, Bethesda, Maryland, USA 21Department of Immunology, Princess Margaret Cancer Centre, Toronto, Ontario, Canada 22Department of Medicine, University of Chicago Medicine, Chicago, Illinois, USA Acknowledgements We thank the patients and their families for participating in the study. Our gratitude also goes to our nurses, coordinators, and entire study teams across all of the participating sites for their dedication and support. A special message of gratitude to Drs Elise Kohn and Amit Oza for their mentorship. This project was possible thanks to the support of the 2019 Career Development Award from the American Society of Clinical Oncology/Conquer Cancer Foundation awarded to Dr Lheureux. The CyTOF panel and analysis was also supported by the Canadian Institutes of Health Research Foundation Grant FDN148386 and Scotiabank Research. We would like to thank the Family of Marion Margaret McCormick for their support in research for endometrial cancer and the correlative analyses performed as part of this trial. Funding Information: This is a National Cancer Institute-sponsored trial run through Experimental Therapeutics Clinical Trials Network centers in the USA and Canada. The Conquer Cancer ASCO Foundation and Princess Margaret Cancer Foundation (Family of Marion Margaret McCormick) supported the CyTOF analysis. Publisher Copyright: {\textcopyright} ",
year = "2022",
month = mar,
day = "14",
doi = "10.1136/jitc-2021-004233",
language = "English",
volume = "10",
journal = "Journal for ImmunoTherapy of Cancer",
issn = "2051-1426",
number = "3",
}