Abstract P3-09-10: A phase II study of nivolumab in combination with cabozantinib for metastatic triple-negative breast cancer (mTNBC)
Authors: Barroso-Sousa Romualdo , Trippa Lorenzo , Li Tianyu , Keenan Tanya E , Winship Grace , Andrews Chelsea , Osmani Wafa , Overmoyer Beth , Winer Eric P , Mittendorf Elizabeth A , Duda Dan G , Tolaney Sara M 
Published: March 2020

Abstract
Background: Patients (pts) with mTNBC have a poor prognosis, and new therapies are needed. Cabozantinib is a multikinase inhibitor that blocks VEGF receptor 2, reduces myeloid-derived suppressor cells, and increases T cell infiltration, suggesting it may enhance the activity of the anti-PD-1 checkpoint blockade agent nivolumab. Here, we report the safety and efficacy of nivolumab plus cabozantinib in a phase II single-arm study in mTNBC pts.
Methods: Eligible pts had metastatic breast cancer that was estrogen and progesterone receptor &lt; 10% and HER2 negative, measurable disease, and received 0-3 prior lines of chemotherapy in the advanced setting. Pts received nivolumab (480 mg intravenously on day 1, every 28 days) plus cabozantinib (40 mg daily by mouth). The primary endpoint was objective response rate (ORR) by RECIST v1.1. Using the Simons “optimal” method, if ≥ 3/18 pts responded during the first stage, 17 more would be enrolled. If ≥ 7/35 responded, the null hypothesis (ORR=10%) would be rejected in favor of a 30% ORR. Predefined secondary endpoints included progression free survival (PFS), clinical benefit rate (CBR), and toxicity. CBR was defined as the fraction of pts with any objective response or stable disease (SD) ≥ 24 weeks. Analyses associating PD-L1 expression, tumor-infiltrating lymphocytes (TIL), and genomic alterations (assessed by next generation sequencing on archival tissue) with outcomes were exploratory.
Results: From 12/15/2017 to 01/24/2019, 18 pts were enrolled into the first stage of the trial; one partial response was seen (ORR 5.6%; 95% CI: 0.3-29.4), and the study was closed to further accrual. The median age was 58y, all pts had ECOG PS 0, and 7 (38.9%) had liver metastases. The median number of prior cytotoxic therapies for mTNBC pts was 1 (range 0 to 3). Three pts had SD ≥24 weeks and two had progressive disease best response. The CBR was 22.2%. After a median follow up of 3.7 months, the median PFS was 4.4 months (95% CI: 1.9-12.8), and the median OS was 6.9 months (95% CI: 3.4-NR). All-cause adverse events occurred in 100% of pts (G3-4, 78%) including elevated liver enzymes (any 50%; G3-4 16.7%), hand-foot syndrome (any 38.9%; G3-4 16.7%), fatigue (any 38.9%; G3-4 11.1%), and hypothyroidism (any 33.3%; no G3-4). Of the 9 pts with available genomic data, none had tumor mutational burden ≥ 10 mutations per megabase. Updated data with TIL, PD-L1, whole exome sequencing and RNA-sequencing results will be presented.
Conclusions: The combination of nivolumab plus cabozantinib was not associated with any unexpected adverse events, however, with an ORR of 5.6%, the study did not achieve its primary endpoint. Exploratory genomic and immunological correlative studies are ongoing. Clinical trial information: NCT03316586.
Citation Format: Romualdo Barroso-Sousa, Lorenzo Trippa, Tianyu Li, Tanya E Keenan, Grace Winship, Chelsea Andrews, Wafa Osmani, Beth Overmoyer, Eric P Winer, Elizabeth A Mittendorf, Dan G Duda, Sara M Tolaney. A phase II study of nivolumab in combination with cabozantinib for metastatic triple-negative breast cancer (mTNBC) [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P3-09-10.