New data from the phase 3 KEYNOTE-B49 trial show that adding pembrolizumab to chemotherapy delays disease progression in a specific group of patients with advanced hormone receptor–positive, HER2-negative breast cancer whose tumors express PD-L1. The findings were presented by Hope S. Rugo, MD, of City of Hope Comprehensive Cancer Center, at the 2026 European Society for Medical Oncology Congress in Madrid.
Trial Design and Patient Population
KEYNOTE-B49 enrolled 342 patients with endocrine-resistant, PD-L1–positive, HR-positive, HER2-negative metastatic breast cancer. PD-L1 positivity was defined as a combined positive score (CPS) of 1 or greater. Nearly all participants, 99 percent, had received a CDK4/6 inhibitor, and 85 percent had visceral metastases. The trial randomized patients to pembrolizumab or placebo plus physician-choice chemotherapy, which included capecitabine, paclitaxel, nab-paclitaxel, or liposomal doxorubicin.
Enrollment proved challenging. Approximately 59 percent of screened patients did not have PD-L1–positive tissue even at the CPS 1 cutoff. Slow accrual led investigators to reduce the planned sample size from 800 to 340 patients, which lowered statistical power for overall survival to approximately 65 percent while preserving adequate power for the primary endpoint of progression-free survival.
Progression-Free Survival Benefits
At the interim analysis, pembrolizumab plus chemotherapy reduced the relative risk of disease progression or death by 26 percent compared with chemotherapy alone, yielding a hazard ratio of 0.74. Median progression-free survival was 6.7 months in the pembrolizumab arm versus 6.0 months in the control group. The encouraging part is that the Kaplan-Meier curves separated over time, with 15 percent of patients in the pembrolizumab group remaining free from progression at 24 months compared with 4 percent in the placebo group.
Patients with a CPS of 10 or greater, representing 21 percent of the enrolled population, experienced a numerically greater benefit. In this subset, median progression-free survival reached 7.5 months with an unstratified hazard ratio of 0.59. Early findings suggest the magnitude of benefit increases with higher PD-L1 expression, a pattern consistent with observations in triple-negative breast cancer.
Overall Survival and Confounding Factors
Final overall survival assessments showed no statistically significant difference between the two arms. Median overall survival was 21.0 months with pembrolizumab plus chemotherapy versus 22.2 months with chemotherapy alone, producing a hazard ratio of 1.04. Subsequent therapeutic interventions, including widespread use of antibody-drug conjugates after study treatment discontinuation, occurred in a substantial majority of participants and likely confounded long-term survival metrics. Patients should understand that the lack of an overall survival signal does not erase the progression-free benefit, but it does frame the conversation about treatment goals.
Safety Profile
The safety profile aligned with known toxicities of the individual agents. Grade 3 or higher treatment-related adverse events occurred in 38 percent of patients receiving pembrolizumab plus chemotherapy compared with 33 percent in the control group. Immune-mediated adverse events were reported in 37 percent of combination recipients, most frequently involving endocrine or pulmonary toxicities. Discontinuation of any study agent due to treatment-related adverse events occurred in 11 percent of patients in the pembrolizumab arm and 5 percent in the placebo arm.
Future Directions
Next steps include the phase 3 TroFuse-010 trial evaluating the investigational TROP2-directed antibody-drug conjugate sacituzumab tirumotecan plus pembrolizumab. Investigators are also considering combination strategies with trastuzumab deruxtecan (Enhertu). Pending event-free survival data from the phase 3 KEYNOTE-756 trial in early-stage disease will further inform the role of immunotherapy in this breast cancer subtype.
These results offer a measured step forward for a defined patient population. The encouraging part is that we now have a biomarker-defined subset where immunotherapy adds value. Talk to your doctor or oncologist about whether this approach fits your treatment plan.
Sources
- KEYNOTE-B49 Points to a PD-L1-Defined Subset Benefiting From Immunotherapy in Breast Cancer | CancerNetwork
- Pembrolizumab Delays Progression in Advanced Breast Cancer
- Ribociclib Survival Data Anchor a Sobering ESMO 2026 for Breast Cancer | Pharmacy Times
Photo: Linda Bartlett (Photographer) (Public domain)
