Durvalumab and Tremelimumab in Metastatic Breast Cancer (MBC): Immunotherapy and Immunopharmacogenomic Dynamics.

3052 Background: PD-1/PD-L1 inhibitors produce modest responses in MBC; adding CTLA-4 inhibitors can augment anti-tumor activity in other cancers. Immunopharmacogenomics characterize immune-cancer cell interactions and may predict response. Methods: A single arm study was designed to determine the efficacy of durvalumab (PD-L1 inhibitor) and tremelimumab (CTLA-4 inhibitor), and immunopharmacogenomics in pts with metastatic ER+ or TNBC. The primary clinical endpoint was to assess ORR using a Simon 2-stage design (28 pts needed for type 1 error rate of 4%, 80% power). 18 pts were enrolled in the first stage; ≥4 responses were needed to proceed with the second stage. Pts were treated with durvalumab 1500mg IV and tremelimumab 75mg IV monthly for 4 doses, then durvalumab 750mg every 2 weeks to complete 1 year of therapy (option to renew for an additional year); biopsies at baseline and 2 months were collected. T-cell receptor (TCR) sequencing using mRNA isolates was conducted at baseline and 2 months, whole exome sequencing and immune-gene expression profiling were conducted at baseline. Results: From 01-09/2016, 18 evaluable pts were accrued (11 ER+; 7 TNBC). Responses are shown in the table below; the ORR did not meet criteria to proceed to the second stage. Notably, one pt with TNBC with PD had pseudoprogression, thus 5/7 (71%) pts with TNBC had clinical benefit. Median PFS was 3.8 months (95%CI 2.2-11.2) for the entire cohort (TNBC not reached), and median OS has not been reached. No grade 4 AEs were observed; grade 3 immune-related AEs included hepatitis (n = 3), nephritis (n = 1), and myocarditis (n = 1). Proportions of abundant TCR-β clonotypes (≥ 0.5% frequency) were increased in 2-month samples compared to baseline in TNBC compared to ER+, p = 0.004, and associated with responses. Remaining correlative analysis is ongoing and will be presented at ASCO. Conclusions: Response rates to PDL-1 and CTLA-4 inhibition were low in unselected MBC, however, high rates of clinical benefit were observed in TNBC. Immunopharmacogenomic may help identify phenotypes most likely to respond. Future studies in TNBC are warranted to confirm findings. Clinical trial information: NCT02536794. [Table: see text]