Abstract PS1-11-05: Phase II trial of pembrolizumab in combination with paclitaxel in the hormone receptor-positive metastatic breast cancer enriched with tumor mutational burden determined by whole exome sequencing: Korean Cancer Study Group trial (

Abstract Background: In hormone receptor-positive (HR+)/human epidermal growth factor receptor 2-negative (HER2-) metastatic breast cancer (MBC), chemotherapy is considered for patients resistant to endocrine therapies including CDK4/6 inhibitors (CDK4/6i) or those with visceral crisis. Pembrolizumab, a PD-1 inhibitor, has not shown its efficacy in unselected HR+/HER2- MBC patient population. This study evaluated pembrolizumab in combination with weekly paclitaxel as first-line chemotherapy in HR+/HER2- MBC patients enriched with tumor mutational burden (TMB), assessed as an integral biomarker. Methods: In this multicenter, single-arm, phase II trial, patients with HR+/HER2- MBC considered resistant to endocrine therapy were prescreened to determine TMB. Fresh tissue was procured through tumor biopsy and was sent to central laboratory for whole-exome sequencing (WES). TMB was calculated as the number of high-confidence nonsynonymous somatic single nucleotide variants detected by MuTect2(GATK v3.5) from WES of tumor-normal pairs. Inclusion criteria for TMB counts were initially defined as ≥70 nonsynonymous mutations for the first 30 prescreened patients and subsequently redefined upper 20% counts with every 30 patients by that time. Prior chemotherapy in the metastatic setting was not allowed. Patients received pembrolizumab (200 mg every 3 weeks) plus paclitaxel (80 mg/m2 on days 1, 8, and 15 of a 28-day cycle) until disease progression or unacceptable toxicity. The primary endpoint was investigator-assessed objective response rate (ORR) per RECIST v1.1. Secondary endpoints included progression-free survival (PFS), overall survival (OS), duration of response (DoR), and safety. Results: Between March 2022 and December 2024, 105 patients were prescreened across 18 centers. The trial was terminated early due to slow recruitment after enrollment of 23 patients. The median age was 59 years (range, 32-74). All patients had prior exposure to CDK4/6 inhibitors, and approximately half (n=11, 47.8%) of patients had received two lines of endocrine therapy before enrollment. The investigator-assessed ORR was 65.2% (95% CI, 42.7-83.6%). At a median follow-up of 13.5 months, median PFS (mPFS) was 7.5 months (95% CI, 6.0-11.6), and median DoR was 4.3 months (95% CI, 3.9-not reached). Patients who experienced any grade of immune-related adverse events (irAEs) (n=9) demonstrated significantly longer mPFS compared to those without irAEs (9.1 vs. 5.8 months; HR=0.25; 95% CI, 0.08-0.77; P=0.016). An increase in TMB was positively correlated with the extent of tumor reduction, suggesting that patients with higher TMB experienced more pronounced tumor shrinkage by RECIST (R=-0.42, P=0.048). Median overall survival (OS) was not reached at the time of data cutoff. In terms of adverse events (AEs), peripheral neuropathy was the most frequent non-hematologic AE (n=15, 65.2%), and hypothyroidism was the most common immune-related AE (n=3, 13%). One patient discontinued treatment due to grade 3 irAE. Conclusion: Integration of biopsy followed by TMB determination through bioinformatic process as a biomarker-integral trial was feasible. Pembrolizumab in combination with weekly paclitaxel demonstrated promising clinical activity and manageable safety as first-line chemotherapy in TMB-enriched HR+/HER2- MBC patients. Citation Format: J. Sohn, Y. Moon, J. Lee, J. Kim, K. Lee, M. Ahn, H. Ahn, Y. Park, S. Kim, A. Kim, E. Kim, Y. Yang, Y. Cha, J. Byun, K. Lee, J. Kim, H. Kim, I. Woo, S. Koh, K. Lee, M. Lee, J. Jung, Y. Chae, G. Kim, M. Kim, K. Kim. Phase II trial of pembrolizumab in combination with paclitaxel in the hormone receptor-positive metastatic breast cancer enriched with tumor mutational burden determined by whole exome sequencing: Korean Cancer Study Group trial (KCSG BR20-16) [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 PS1-11-05.