Updated results from the KEYNOTE-756 trial show benefits of the chemoimmunotherapy across subgroups of patients with ER+/HER2− breast cancer
Updated results from the phase III, randomised, double-blind KEYNOTE-756 trial were published in the Nature Medicine, reporting that the addition of the anti-PD-1 monoclonal antibody pembrolizumab to neoadjuvant chemotherapy significantly improved the pathological complete response (pCR) rate in patients with high-risk, early-stage ER+/HER2− breast cancer (Nature Medicine 2025 Jan 21).
The trial involved a total of 1,278 patients with grade 3 invasive, nonmetastatic (T1c–2 (≥2 cm), cN1–2 or T3–4, cN0–2) ductal breast carcinoma who were newly diagnosed and previously untreated. Patients, recruited from 222 global sites, were randomised to receive four cycles of either intravenous pembrolizumab (200 mg) or placebo plus paclitaxel once every three weeks, followed by four cycles of pembrolizumab or placebo in combination with either doxorubicin or epirubicin plus cyclophosphamide every two or three weeks. After surgery, patients received pembrolizumab or placebo once every three weeks for up to nine cycles (up to 6 months), plus the investigator’s choice of endocrine therapy (per institutional guidelines) for up to 10 years.
The percentage of patients who had a pCR – one of the primary endpoints of the study - was significantly higher in the pembrolizumab‒chemotherapy arm (24.3%) than in the placebo‒chemotherapy arm (15.6%). Benefits of adding the anti-PD-1 to chemotherapy in terms of pCR were generally consistent across subgroups defined by demographics and baseline clinical characteristics, and a numerically higher rate of pCR difference was observed with higher tumor PD-L1 expression and in the subgroup of patients with ER positivity <10%. However, the study authors highlight that the subgroups were underpowered, so the results from the subgroup analysis should be interpreted with caution.
The addition of pembrolizumab to chemotherapy did not show to exacerbate chemotherapy-associated toxicity, and no new safety concerns were reported.
Early results of the study were first reported at the ESMO Congress 2023. ER+/HER2− breast cancer is a heterogeneous disease, and patients with high-risk disease have usually poor long-term outcomes despite (neo) adjuvant chemotherapy and adjuvant endocrine therapy: for these patients, reported pCR rates range from 0% to 18%. In the KEYNOTE-756 trial, adding pembrolizumab to neoadjuvant chemotherapy led to a statistically significant increase in pCR, however it is not yet known if this is predictive of enhanced post-surgical event-free survival (EFS). EFS data, which are still immature as reported in the paper, will show the overall effect of the treatment regimen.
