A Phase I/II Trial of Palbociclib, Pembrolizumab, and Endocrine Therapy for Patients with HR+/HER2- Locally Advanced or Metastatic Breast Cancer (MBC): Clinical Outcomes and Stool Microbial Profiling.

1038 Background: Based on preclinical data highlighting synergy between CDK4/6 inhibitors and immune checkpoint inhibitors (ICIs), we conducted a phase I/II study of palbociclib, pembrolizumab, and endocrine therapy (ET) in pts with HR+/HER2- MBC. Given evidence suggesting a correlation between ICI response and stool microbiome composition in a wide array of cancers, we sought to determine if this biomarker could segregate responders in our cohort. Methods: Pts with stage IV HR+/HER2- MBC were enrolled and treated with palbociclib, pembrolizumab, and ET. Cohort 1 enrolled pts with stable disease on palbociclib + ET for at least 6 months. Cohort 2 and 3 enrolled pts in the first-line (1L) setting, with cohort 3 designed with a palbociclib + ET lead-in to evaluate the immune potentiating effect of palbociclib (not included in this report). The primary endpoint was objective response rate (ORR); secondary endpoints included progression-free survival (PFS), overall survival (OS), and toxicity. Correlative studies assessed the association between the gut microbiome and response using previously published methods (1). Results: Between March 2017 and May 2022, 40 pts were accrued, with 4, 19 and 17 pts in cohorts 1, 2 and 3, respectively. There were 39 females and 1 male, with a median age of 51 (range 39-75). The ORR in cohorts 1, 2 and 3 were 2/4 (50%), 11/19 (58%) and 13/17 (76%), respectively. Median PFS across cohorts 2 and 3 (reflecting 1L therapy) was 25 mo (95% CI 21- not reached), and at a median follow-up of 35 mo, OS was 76% (95% CI 0.60-0.96). The most common grade 3/4 adverse events across all cohorts included neutropenia (83%), leukopenia (56%), elevated alanine aminotransferase (13%), elevated aspartate aminotransferase (13%), and thrombocytopenia (10%). Gut microbial profiling (total N=24 pts; Arm 2 N=7, Arm 3 N=17) demonstrated multiple species higher in abundance in pts with a response (p < 0.05), with notable species belonging to the families Lachnospiraceae, Ruminococcaceae, and Rikenellaceae. Several metabolic pathways were enriched in responders (p-value < 0.05), including pathways related to fatty acid biosynthesis and the tricarboxylic acid (TCA) cycle. Conclusions: Pembrolizumab added to palbociclib + ET in the 1L setting demonstrated a higher response rate compared to palbociclib + ET alone in HR+/HER2- MBC. Specific gut profiles were associated with response, with similar taxa of bacteria associated with ICI response in other tumor types (2). Enriched metabolic pathways may generate microbiota-derived metabolites that have an immunomodulatory effect. These results suggest that the gut microbiome may be associated with response to ICI combination therapy in MBC, which warrants further evaluation. 1. Dizman et al.,Nature Med 2022. 2. Spencer et al Science 2021. Clinical trial information: NCT02778685 .