Pembrolizumab Plus Chemotherapy Demonstrates a Statistically Significant PFS Benefit in PD-L1-Positive HR+/HER2− Advanced Breast Cancer, Without Improving Overall Survival

KEYNOTE-B49 (NCT04895358) is a randomized, double-blind, placebo-controlled Phase III study evaluating pembrolizumab plus chemotherapy versus placebo plus chemotherapy in patients with locally recurrent inoperable or metastatic HR+/HER2− advanced breast cancer with PD-L1 CPS ≥1, whose disease had progressed following endocrine-based therapy. A total of 342 patients were randomized in a 1:1 ratio to receive pembrolizumab plus chemotherapy (n=171) or placebo plus chemotherapy (n=171). Pembrolizumab was administered at 200 mg every three weeks for up to 35 cycles, alongside physician's choice of paclitaxel, nab-paclitaxel, liposomal doxorubicin, or capecitabine. The primary endpoint was PFS assessed by blinded independent central review (BICR) according to RECIST v1.1 in the CPS ≥1 population, while OS was a key secondary endpoint. At the primary PFS analysis (September 22, 2025 data cutoff), median follow-up was 29.1 months. The final OS KEYNOTE-B49 (NCT04895358) is a randomized, double-blind, placebo-controlled Phase III study evaluating pembrolizumab plus chemotherapy versus placebo plus chemotherapy in patients with locally recurrent inoperable or metastatic HR+/HER2− advanced breast cancer with PD-L1 CPS ≥1, whose disease had progressed following endocrine-based therapy. A total of 342 patients were randomized in a 1:1 ratio to receive pembrolizumab plus chemotherapy (n=171) or placebo plus chemotherapy (n=171). Pembrolizumab was administered at 200 mg every three weeks for up to 35 cycles, alongside physician's choice of paclitaxel, nab-paclitaxel, liposomal doxorubicin, or capecitabine. The primary endpoint was PFS assessed by blinded independent central review (BICR) according to RECIST v1.1 in the CPS ≥1 population, while OS was a key secondary endpoint. At the primary PFS analysis (September 22, 2025 data cutoff), median follow-up was 29.1 months. The final OS analysis was conducted using a March 16, 2026 data cutoff, with a median follow-up of 34.9 months. The study met its primary PFS endpoint, demonstrating a statistically significant improvement with pembrolizumab plus chemotherapy. However, the final analysis did not demonstrate a statistically significant OS benefit.

Conclusion-

The Phase III KEYNOTE-B49 findings demonstrate that pembrolizumab plus chemotherapy can improve disease control in patients with PD-L1-positive HR+/HER2− advanced breast cancer following endocrine-based therapy. Although the combination achieved a statistically significant PFS benefit, the absolute improvement in median PFS was modest (0.7 months), and no corresponding OS advantage was observed. The numerically greater PFS benefit in the CPS ≥10 subgroup warrants further investigation but does not establish a definitive biomarker threshold for selecting patients. Additionally, increased treatment-related toxicity and discontinuation rates highlight the need to carefully evaluate the benefit–risk profile of immunotherapy in this population. Overall, KEYNOTE-B49 provides evidence supporting the activity of pembrolizumab in a subset of HR+/HER2− advanced breast cancer; however, the lack of an OS benefit and modest median PFS improvement may limit its potential to change the standard treatment paradigm.