What were the design, patient eligibility, treatment regimen, and outcomes of the KEYNOTE‑756 trial evaluating pembrolizumab (Keytruda) plus chemotherapy in high‑risk early‑stage estrogen‑receptor‑positive/HER2‑negative breast cancer?

KEYNOTE-756 Trial Overview

KEYNOTE-756 is a phase 3, double-blind, placebo-controlled trial that demonstrated pembrolizumab plus neoadjuvant chemotherapy significantly improved pathological complete response (pCR) rates in high-risk, early-stage ER+/HER2- breast cancer, though event-free survival data remain immature. 1

Trial Design

The study randomized 1,278 patients (1:1 ratio) with previously untreated, high-risk ER+/HER2- breast cancer to receive:

Treatment Arms:

• Pembrolizumab arm (n=635): Pembrolizumab 200 mg IV every 3 weeks
• Placebo arm (n=643): Matching placebo every 3 weeks

Treatment Sequence:

1. Neoadjuvant phase: Pembrolizumab/placebo + paclitaxel weekly for 12 weeks
2. Followed by 4 cycles of doxorubicin or epirubicin plus cyclophosphamide (every 2-3 weeks)
3. Surgery (with or without adjuvant radiation)
4. Adjuvant phase: Pembrolizumab/placebo for 9 additional cycles + mandatory endocrine therapy 1

Patient Eligibility

Inclusion criteria required ALL of the following:

• Grade 3 invasive breast cancer
• ER+/HER2- status
• High-risk disease defined as:
  • T1c-2 (≥2 cm) with cN1-2, OR
  • T3-4 with cN0-2
• Previously untreated
• Postmenopausal status (based on study population) 1

Primary Outcomes

At the prespecified first interim analysis:

Pathological Complete Response (pCR):

• Pembrolizumab-chemotherapy: 24.3% (95% CI: 21.0-27.8%)
• Placebo-chemotherapy: 15.6% (95% CI: 12.8-18.6%)
• Absolute difference: 8.5 percentage points (95% CI: 4.2-12.8; P = 0.00005)

This represents a statistically significant and clinically meaningful improvement in pCR rates. 1

Event-Free Survival (EFS):

• Data not yet mature at the time of the first interim analysis
• Follow-up continues for this co-primary endpoint 1

Safety Profile

Neoadjuvant phase adverse events:

• Grade ≥3 treatment-related adverse events:
  • Pembrolizumab-chemotherapy: 52.5%
  • Placebo-chemotherapy: 46.4%
• Safety profile consistent with known toxicities of pembrolizumab and chemotherapy
• The 6% absolute increase in grade ≥3 events represents manageable toxicity given the pCR benefit 1

Clinical Context and Limitations

Critical caveats:

1. Immature survival data: While pCR improved significantly, the ultimate clinical benefit depends on EFS and overall survival data, which are still being collected. pCR is a surrogate endpoint that doesn't always translate to survival benefit in ER+ disease.

2. ER+ disease biology: Unlike triple-negative breast cancer where pembrolizumab is established (KEYNOTE-522), ER+ tumors are generally less immunogenic. The 24.3% pCR rate, while improved, is still modest compared to TNBC outcomes.

3. Not yet guideline-endorsed: Current ESMO 2 and NCCN 3 guidelines do not include pembrolizumab for ER+/HER2- breast cancer. Guidelines currently recommend immunotherapy only for triple-negative disease.

4. Competing strategies: For high-risk ER+/HER2- disease, CDK4/6 inhibitors (abemaciclib in monarchE, ribociclib in NATALEE) are established adjuvant options with mature survival data 2. The role of pembrolizumab versus these agents remains undefined.

5. Patient selection: The trial enrolled only grade 3, high-risk tumors. Applicability to lower-grade or lower-risk ER+ disease is unknown and likely inappropriate.

Real-world considerations: A Japanese single-institution study showed pembrolizumab plus chemotherapy may have particular efficacy in ER-low (1-9%) HER2- tumors, with 87.5% pCR rates, suggesting this subset may derive greater benefit 4. However, this was a small retrospective series requiring validation.