KEY TAKEAWAYS
- The MK-3475-756/KEYNOTE-756 phase III trial aimed to present the primary outcomes of achieving a pCR.
- The dual primary endpoints were pCR and EFS. Secondary endpoints include OS, pCR, and safety.
- The result demonstrated that combining pembro with chemo substantially enhanced pCR rates in early-stage high-risk ER+/HER2– BC, maintaining consistent safety profiles with each regimen.
KEYNOTE-756 (NCT03725059) is a phase 3 global study investigating neoadjuvant pembrolizumab(pembro) or placebo(pbo) in combination with chemotherapy(chemo), followed by adjuvant pembro or pbo with endocrine therapy(ET) in patients with early-stage high-risk ER+/HER2– breast cancer(BC).
In this study, researchers aimed to present the primary outcomes of achieving a pathological complete response(pCR).
Eligible patients with centrally confirmed grade 3, invasive ductal ER+/HER2– BC (T1c-2 [≥2 cm] cN1-2 or T3-4 cN0-2) were randomized 1:1 to receive neoadjuvant pembro 200 mg Q3W or pbo, both in conjunction with paclitaxel QW for 12 weeks, followed by 4 cycles of doxorubicin or epirubicin + cyclophosphamide.
Post-definitive surgery (± radiation therapy), patients received pembro or pbo for 9 cycles alongside standard ET. Stratification factors encompassed 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).
The dual primary endpoints were pCR defined as ypT0/Tis ypN0 and event-free survival (EFS), with secondary endpoints including overall survival (OS), pCR defined as ypT0 ypN0 and ypT0/Tis, and safety.
Of 1278 participants, pembro + chemo (n=635), pbo + chemo (n=643), as of the May 25, 2023, median follow-up was 33.2 mo (range, 9.7-51.8),the interim analysis, pembro + chemo demonstrated a statistically significant improvement in pCR (ypT0/Tis ypN0) over pbo + chemo in the intention-to-treat (ITT) population: 24.3% (95% CI, 21.0-27.8) vs 15.6% (95% CI, 12.8-18.6), with an estimated difference of 8.5 percentage points (95% CI, 4.2-12.8); P=0.00005.
Similar benefits were observed in secondary pCR definitions ypT0, ypN0,(21.3% vs 12.8%) and ypT0/Tis(29.4% vs 18.2%). The pCR benefit was consistent across prespecified subgroups. In the neoadjuvant phase, grade ≥3 treatment-related adverse events occurred in 52.5% with pembro + chemo and 46.4% with pbo + chemo, leading to one death (acute myocardial infarction) in the pembro arm. Event-free survival results are still under evaluation.
The result demonstrated that combining pembro with chemo substantially enhanced pCR rates in early-stage high-risk ER+/HER2– BC, maintaining consistent safety profiles with each regimen.
Clinical Trial: https://clinicaltrials.gov/study/NCT03725059
Cardoso F, McArthur HL, Schmid P, Cortés J, Harbeck N, Telli ML, Cescon DW, O’Shaughnessy J, Fasching P, Shao Z, Loirat D, Park YH, González Fernández ME, Liu Z, Yasojima H, Ding Y, Jia L, Karantza VV, Tryfonidis KE, Bardia A. Phase III Study of Neoadjuvant Pembrolizumab (Pembro) or Placebo (Pbo) + Chemotherapy (Chemo) Followed by Adjuvant Pembro or Pbo. Annals of Oncology. 2023;34(suppl_2):S1254-S1335. doi:10.1016/annonc/annonc1358.
