Translational randomized phase II trial of cabozantinib in combination with nivolumab in advanced, recurrent, or metastatic endometrial cancer

Stephanie Lheureux, Daniela E. Matei, Panagiotis A. Konstantinopoulos, Ben X. Wang, Ramy Gadalla, Matthew S. Block, Andrea Jewell, Stephanie L. Gaillard, Michael McHale, Carolyn McCourt, Sarah Temkin, Eugenia Girda, Floor J. Backes, Theresa L. Werner, Linda Duska, Siobhan Kehoe, Ilaria Colombo, Lisa Wang, Xuan Li, Rachel WildmanShirin Soleimani, Scott Lien, John Wright, Trevor Pugh, Pamela S. Ohashi, David G. Brooks, Gini F. Fleming

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29 Scopus citations


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-naïve 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 ( 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.

Original languageEnglish
Article numbere004233
JournalJournal for ImmunoTherapy of Cancer
Issue number3
StatePublished - Mar 14 2022


  • biomarkers
  • clinical trials
  • combination
  • drug therapy
  • female
  • genital neoplasms
  • immunotherapy
  • phase II as topic
  • tumor


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