RT Journal Article
SR Electronic
T1 Translational randomized phase II trial of cabozantinib in combination with nivolumab in advanced, recurrent, or metastatic endometrial cancer
JF Journal for ImmunoTherapy of Cancer
JO J Immunother Cancer
FD BMJ Publishing Group Ltd
SP e004233
DO 10.1136/jitc-2021-004233
VO 10
IS 3
A1 Lheureux, Stephanie
A1 Matei, Daniela E
A1 Konstantinopoulos, Panagiotis A
A1 Wang, Ben X
A1 Gadalla, Ramy
A1 Block, Matthew S
A1 Jewell, Andrea
A1 Gaillard, Stephanie L
A1 McHale, Michael
A1 McCourt, Carolyn
A1 Temkin, Sarah
A1 Girda, Eugenia
A1 Backes, Floor J
A1 Werner, Theresa L
A1 Duska, Linda
A1 Kehoe, Siobhan
A1 Colombo, Ilaria
A1 Wang, Lisa
A1 Li, Xuan
A1 Wildman, Rachel
A1 Soleimani, Shirin
A1 Lien, Scott
A1 Wright, John
A1 Pugh, Trevor
A1 Ohashi, Pamela S
A1 Brooks, David G
A1 Fleming, Gini F
YR 2022
UL http://jitc.bmj.com/content/10/3/e004233.abstract
AB 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.All data relevant to the study are included in the article or uploaded as supplementary information.