Background
Phase III, double-blind, placebo-controlled RCT. 1174 patients with early-stage TNBC (T1c-T2 N1-2, or T3-4 N0-2; stage II–III) without prior treatment for early BC. Pembrolizumab added to neoadjuvant paclitaxel-based chemotherapy (paclitaxel+carboplatin × 4 followed by AC × 4) then continued as adjuvant monotherapy vs standard chemotherapy + placebo. Dual primary endpoints: pCR and event-free survival (EFS).
Interventions and follow up
Arm A: Neoadjuvant pembrolizumab 200mg q3wk + paclitaxel/carboplatin × 4 → pembrolizumab + doxorubicin/cyclophosphamide × 4 → adjuvant pembrolizumab q3wk × 9 cycles (1 year)
Arm B: Neoadjuvant placebo + chemotherapy → adjuvant placebo × 9 cycles
Primary endpoint: pCR (ypT0/is ypN0) and EFS
mFollow up: 63.1 months (EFS analysis)
Arm B: Neoadjuvant placebo + chemotherapy → adjuvant placebo × 9 cycles
Primary endpoint: pCR (ypT0/is ypN0) and EFS
mFollow up: 63.1 months (EFS analysis)
Results
pCR: 64.8% vs 51.2%, difference +13.6%, P<.001
3-yr EFS: 84.5% vs 76.8%, HR 0.63, 95% CI 0.48–0.82, P<.001
OS (5-yr): 86.6% vs 81.7%, HR 0.66, 95% CI 0.50–0.87
3-yr EFS: 84.5% vs 76.8%, HR 0.63, 95% CI 0.48–0.82, P<.001
OS (5-yr): 86.6% vs 81.7%, HR 0.66, 95% CI 0.50–0.87
Adverse events
Overall: Grade ≥3 any AE 78.8% vs 73.0%; adjuvant pembrolizumab discontinuation 23.5%.
Immune-mediated: Any grade 36.5% vs 9.1%; grade ≥3 15.0% vs 2.1%; adrenal insufficiency 1.4%.
Pulmonary/cutaneous: Pneumonitis grade ≥3 0.5%; severe cutaneous reactions 0.4%.
Immune-mediated: Any grade 36.5% vs 9.1%; grade ≥3 15.0% vs 2.1%; adrenal insufficiency 1.4%.
Pulmonary/cutaneous: Pneumonitis grade ≥3 0.5%; severe cutaneous reactions 0.4%.
Conclusions
Pembrolizumab + neoadjuvant chemotherapy → adjuvant pembrolizumab significantly improved both pCR (by ~14%) and EFS (HR 0.63) in early TNBC. EFS and emerging OS benefits establish pembrolizumab + chemotherapy as a new standard of care in stage II–III TNBC regardless of PD-L1 status.
Key Limitations
Benefit was demonstrated across PD-L1 expression levels, but degree of EFS benefit appeared greater in PD-L1-positive tumors — subgroup analyses not powered for definitive stratification. High rate of immune-mediated AEs (36.5% any-grade) and the addition of 1 year of adjuvant pembrolizumab adds significant cost and monitoring burden. Optimal patient selection within TNBC (e.g., BRCA-mutated, tumor mutational burden) not established. Patients with de novo stage IV disease were excluded — a distinct population sometimes treated similarly in practice.
Clinical Context
KEYNOTE-522 established pembrolizumab + chemotherapy (neoadjuvant) followed by adjuvant pembrolizumab as the standard of care for stage II–III TNBC (FDA approved 2021; ESMO-MCBS score: 5). It is the most significant advance in TNBC in the curative setting in decades. PD-L1 testing is not required for eligibility. CREATE-X (capecitabine for residual disease) may still be used in patients with residual disease after KEYNOTE-522-type regimens, though the optimal approach is evolving.