Abstract PS1-10-19: Palbociclib, pembrolizumab, and endocrine therapy in HR+/HER2- metastatic breast cancer: Updated results from a phase I/II trial

Abstract Background: The role of immune checkpoint inhibitors (ICIs) in HR+/HER2- metastatic breast cancer (MBC) has yet to be defined. We enrolled patients (pts) in a clinical trial testing the addition of pembrolizumab to palbociclib and endocrine therapy (ET) with the ICI administered concurrently or sequentially. Here, we present updated trial results for the addition of pembrolizumab to palbociclib and ET. Methods: In this single-center, open-label, phase I/II study, pts with HR+/HER2- MBC were treated with palbociclib, pembrolizumab, and ET. Cohort 1 enrolled pts with stable disease on palbociclib + ET for at least 6 months (Cohort 1 closed early due to limited accrual, data previously reported). Cohort 2 and 3 enrolled pts in the first-line (1L) setting to ET + palbociclib with concurrent ICI (Cohort 2, data previously reported) or sequential ICI following a 28 day lead-in. The primary endpoint was overall response rate (ORR). Secondary endpoints included progression free survival (PFS), overall survival (OS), and treatment-related adverse events (TRAEs). Results: Between March 2017 and November 2024, 47 pts were accrued, with 4, 19, and 24 pts in cohorts 1, 2 and 3, respectively. All but 1 were female, with a median age of 55 years (range 33-75). With a median follow-up of 42.6 months (95% CI, 30.8-53.4) for patients treated in the 1L setting, the ORR was 62.8% (95% CI, 47.7-77.8). ORR of cohorts 2 and 3 was 57.9% and 66.7%, respectively. The median PFS of patients treated in the 1L setting was 27.1 months (95% CI, 13.9-42.5). PFS of cohorts 2 and 3 was 25.2 months and 29.1 months, respectively. The median OS in the 1L setting was 56.8 months (95% CI, 37.6-80.6). In the 1L setting, grade 2 or higher TRAEs occurred in 97.7% of pts, with the most common being leukopenia (95.3%), neutropenia (93.0%), lymphopenia (62.8%), fatigue (27.9%), upper respiratory infection (27.9%), anemia (25.6%), elevated alanine aminotransferase (ALT, 25.6%), and elevated aspartate aminotransferase (AST, 23.3%). In the 1L setting, grade 3 hematologic and non-hematologic TRAEs occurred in 90.7% and 30.2% of pts, with the most common non-hematologic TRAEs being pneumonitis (14.3%), nausea (9.5%), and diarrhea (9.5%). Grade 4 hematologic TRAEs occurred in 16.3% of pts in the 1L setting. There were no non-hematologic grade 4 TRAEs or treatment-related deaths. Conclusions: The combination of palbociclib, pembrolizumab, and ET in the 1L setting was tolerable in pts with HR+/HER2- MBC with no unexpected TRAEs. We report an improved ORR compared to PALOMA-2 of 62.8% vs. 55.3%, respectively; with a comparable PFS of 27.1 months vs. 24.8 months, respectively. Correlative studies are currently underway to explore immune biomarkers including tumor-infiltrating lymphocytes scoring and tumor immune microenvironment composition to identify pts who may have an improved response to this combination treatment leading to improved PFS and OS rates in some pts. Citation Format: A. LeVee, C. Egelston, S. E. Yost, P. Frankel, N. Ruel, C. Ruel, D. Schmolze, P. Lee, C. Yeon, Y. Yuan, J. Waisman, J. Mortimer. Palbociclib, pembrolizumab, and endocrine therapy in HR+/HER2- metastatic breast cancer: Updated results from a phase I/II trial [abstract]. In: Proceedings of the San Antonio Breast Cancer Symposium 2025; 2025 Dec 9-12; San Antonio, TX. Philadelphia (PA): AACR; Clin Cancer Res 2026;32(4 Suppl):Abstract nr PS1-10-19.