Phase II Clinical Trial of Pembrolizumab and Chemotherapy Reveals Distinct Transcriptomic Profiles by Radiologic Response in Metastatic Triple-Negative Breast Cancer.

Purpose A single arm, Phase II trial of carboplatin, nab-paclitaxel, and pembrolizumab (CNP) in metastatic triple negative breast cancer (mTNBC) was designed to evaluate overall response rate (ORR), progression-free survival (PFS), duration of response (DOR), safety/tolerability, overall survival (OS), and identify pathologic and transcriptomic correlates of response to therapy. Patients/Methods Patients with ≤2 prior therapies for metastatic disease were treated with CNP regardless of tumor PD-L1 status. Core tissue biopsies were obtained prior to treatment initiation. ORR was assessed using a binomial distribution. Survival was analyzed via the Kaplan Meier method. Bulk RNA-sequencing was employed for correlative studies. Results Thirty patients were enrolled. The ORR was 48.0%: 2 (7%) complete responses (CR), 11 (41%) partial responses (PR), and 8 (30%) stable disease (SD). The median DOR for patients with CR or PR was 6.4 months (95% confidence interval [CI], 4 to 8.5 months). For patients with CR, DOR was > 24 months. Overall median PFS and OS were 5.8 (95% CI 4.7 - 8.5 months) and 13.4 months (8.9 - 17.3 months), respectively. We identified unique transcriptomic landscapes associated with each RECIST category of radiographic treatment response. In CR and durable PR, IGHG1 expression was enriched. IGHG1high tumors were associated with improved overall survival (p=0.045) and were concurrently enriched with B cells and follicular helper T cells, indicating IGHG1 as a promising marker for lymphocytic infiltration and robust response to chemo-immunotherapy. Conclusions Pre-treatment tissue sampling in mTNBC treated with CNP reveals transcriptomic signatures that may predict radiographic responses to chemo-immunotherapy.