LBA21 KEYNOTE-756: Phase III study of neoadjuvant pembrolizumab (pembro) or placebo (pbo) + chemotherapy (chemo), followed by adjuvant pembro or pbo + endocrine therapy (ET) for early-stage high-risk ER+/HER2– breast cancer

KEYNOTE-756 (NCT03725059) is a global phase 3 study of neoadjuvant pembro or pbo + chemo followed by adjuvant pembro or pbo + ET in patients (pts) with early-stage high-risk ER+/HER2– breast cancer. Here, we report primary pCR results. Eligible pts with T1c-2 (≥2 cm) cN1-2 or T3-4 cN0-2, centrally confirmed, grade 3, invasive ductal ER+/HER2– breast cancer were randomized 1:1 to neoadjuvant pembro 200 mg Q3W or pbo, both given with paclitaxel QW for 12 wk, then 4 cycles of doxorubicin or epirubicin + cyclophosphamide (neoadjuvant treatment). After definitive surgery (± radiation therapy), pts received pembro or pbo for 9 cycles + standard ET. Stratification factors include region (Eastern Europe, China, or Other), tumor PD-L1 status (CPS ≥1 [+] vs CPS <1 [–]), nodal involvement (+ vs –), ER positivity (≥10% vs <10%) and anthracycline schedule (Q3W vs Q2W). Dual primary endpoints are pCR (ypT0/Tis ypN0) and EFS. Secondary endpoints include OS, pCR defined as ypT0 ypN0 and ypT0/Tis and safety. 1278 pts were randomized to pembro + chemo (n=635) or pbo + chemo (n=643). At the final pCR analysis (May 25, 2023, first interim analysis data cutoff), median follow-up was 33.2 mo (range, 9.7-51.8). In the ITT population, pembro + chemo showed a statistically significant improvement in pCR (ypT0/Tis ypN0) vs pbo + chemo: 24.3% (95% CI, 21.0-27.8) vs 15.6% (95% CI, 12.8-18.6); estimated difference, 8.5 percentage points (95% CI, 4.2-12.8); P=0.00005; results were consistent for the secondary pCR definitions, ypT0 ypN0 (21.3% vs 12.8%) and ypT0/Tis (29.4% vs 18.2%). The benefit of pembro + chemo on pCR was generally consistent in the prespecified subgroups. In the neoadjuvant phase, grade ≥3 treatment-related AE rates were 52.5% with pembro + chemo and 46.4% with pbo + chemo, with 1 death in the pembro arm due to acute myocardial infarction. EFS results are still immature and continue to be evaluated. The addition of pembro to chemo significantly increased the pCR rate in pts with early-stage high-risk ER+/HER2– breast cancer. Safety was consistent with the known profiles of each regimen.