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

Abstract

BackgroundCombining 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 methodsIn 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.ResultsMedian 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).ConclusionsAdding 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.

A rapidly evolving landscape: immune checkpoint inhibitors in pretreated metastatic endometrial cancer

“…Six investigated ICI monotherapy, including five phase I/II studies in MMRd/MSI-H selected populations 3 , 27 – 33 and one phase Ib study in patients with PD-L1-positive tumors. 34 Three studies also assessed ICI combinations in unselected patients, including one phase III trial and a randomized phase II study investigating ICI plus TKI combinations 35 , 36 and another assessing a dual ICI combination 37 (Preferred Reporting Items for Systematic Reviews and Meta-Analyses, Figure 1 ).…”

Current Approaches to the Management of Patients with Endometrial Cancer

“…Immunotherapy with a PD-1 inhibitor, combined with an antiangiogenic agent, when managing pretreated recurrent EC has been shown to be quite beneficial in patients’ survival. According to NCT03367741, a translational Phase II trial, cabozantinib-nivolumab combined therapy significantly improved PFS (5.3 vs. 1.9 months) [ 86 ]. Finally, a Phase III randomized placebo controlled trial aims to assess the addition of atezolizumab, an IgG1 PD-L1 inhibitor, to standard chemotherapy in advanced or recurrent EC; the results are expected in 2023 [ 87 , 88 ].…”

Mass cytometry immunostaining protocol for multiplexing clinical samples

“…Typically, high-dimensional data analysis tools are employed with CyTOF data, such as phenograph-based clustering ( Levine et al., 2015 ), t-Distributed Stochastic Neighbor Embedding ( Amir et al., 2013 ), and Uniform Manifold Approximation and Projection for dimension reduction (UMAP) ( Becht et al., 2018 ) to identify and visualize immune populations in different experimental groups and/or samples ( Mathew et al., 2020 ; Lheureux et al., 2022 ).…”

“…Therefore, only barcoded immune cell data will be acquired from any samples that also include non-immune cells, such as single-cell suspensions of tumor biopsies or ascites/pleural effusion fluids from cancer patients. If the non- immune components of the samples are of interest, then the same protocol can be used with DNA-based barcoding alone – without the use of multiple CD45 antibodies – and thus limiting the sample number to 20 per batch ( Zunder et al., 2015 ; Lheureux et al., 2022 ).…”