Molecular correlates of response to eribulin and pembrolizumab in hormone receptor-positive metastatic breast cancer
Tanya E. Keenan, Jennifer L. Guerriero, Romualdo Barroso‐Sousa, Tianyu Li, Tess A. O’Meara, Anita Giobbie‐Hurder, Nabihah Tayob, Jiani Hu, Mariano Severgnini, Judith Agudo, Inês Vaz-Luís, Leilani Anderson, Victoria Attaya, Jihye Park, Jake R. Conway, Meng Xiao He, Brendan Reardon, Erin Shannon, Gerburg M. Wulf, Laura M. Spring, Rinath Jeselsohn, Ian E. Krop, Nancy U. Lin, Ann Partridge, Eric P. Winer, Elizabeth A. Mittendorf, David Liu, Eliezer M. Van Allen, Sara M. Tolaney
Abstract
Immune checkpoint inhibitors (ICIs) have minimal therapeutic effect in hormone receptor-positive (HR+ ) breast cancer. We present final overall survival (OS) results (n = 88) from a randomized phase 2 trial of eribulin ± pembrolizumab for patients with metastatic HR+ breast cancer, computationally dissect genomic and/or transcriptomic data from pre-treatment tumors (n = 52) for molecular associations with efficacy, and identify cytokine changes differentiating response and ICI-related toxicity (n = 58). Despite no improvement in OS with combination therapy (hazard ratio 0.95, 95% CI 0.59-1.55, p = 0.84), immune infiltration and antigen presentation distinguished responding tumors, while tumor heterogeneity and estrogen signaling independently associated with resistance. Moreover, patients with ICI-related toxicity had lower levels of immunoregulatory cytokines. Broadly, we establish a framework for ICI response in HR+ breast cancer that warrants diagnostic and therapeutic validation. ClinicalTrials.gov Registration: NCT03051659.