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-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 (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+) ɣδ T 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.

• Authors: 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 Wildman, Shirin Soleimani, Scott Lien, John Wright, Trevor Pugh, Pamela S Ohashi, David G Brooks, Gini F Fleming
• Journal: Journal for immunotherapy of cancer (J Immunother Cancer) Vol. 10 Issue 3 (03 2022) ISSN: 2051-1426 [Electronic] England
• PMID: 35288469 (Publication Type: Clinical Trial, Phase II, Journal Article, Randomized Controlled Trial, Research Support, Non-U.S. Gov't)
• Copyright: © Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY. Published by BMJ.

Chemical References

• Anilides
• Pyridines
• cabozantinib
• Nivolumab

Topics

• Anilides (pharmacology, therapeutic use)
• Endometrial Neoplasms (drug therapy)
• Female
• Humans
• Leukocytes, Mononuclear
• Nivolumab (pharmacology, therapeutic use)
• Pyridines