Background
Phase III, open-label RCT. 910 patients with HER2-negative early breast cancer (HR+ or TNBC) who had residual invasive disease in the breast or axilla after NACT (paclitaxel-based ± anthracycline). Testing the hypothesis that capecitabine consolidation targets residual chemotherapy-resistant cells via oral fluoropyrimidine activity. Conducted in Japan.
Interventions and follow up
Arm A: Capecitabine 1250mg/m² BID days 1–14 of 21-day cycle × 8 cycles (6 months)
Arm B: Observation
Primary endpoint: Disease-free survival (DFS)
mFollow up: 3.6 years
Arm B: Observation
Primary endpoint: Disease-free survival (DFS)
mFollow up: 3.6 years
Results
DFS (all HER2-): HR 0.70, 95% CI 0.53–0.92, P=.005
OS (all HER2-): HR 0.59, 95% CI 0.39–0.90, P=.01
DFS (TNBC subgroup): HR 0.58, P=.003
OS (TNBC subgroup): HR 0.52, P=.008
OS (all HER2-): HR 0.59, 95% CI 0.39–0.90, P=.01
DFS (TNBC subgroup): HR 0.58, P=.003
OS (TNBC subgroup): HR 0.52, P=.008
Adverse events
Dermatologic: Grade ≥3 hand-foot syndrome 11.3% (rates may vary by dosing and ethnicity).
GI: Grade ≥3 diarrhea 1.3%; grade ≥3 nausea/vomiting 1.6%.
Dose management: Dose reduction 37%; discontinuation 6.9%; overall well-tolerated in this Asian population.
GI: Grade ≥3 diarrhea 1.3%; grade ≥3 nausea/vomiting 1.6%.
Dose management: Dose reduction 37%; discontinuation 6.9%; overall well-tolerated in this Asian population.
Conclusions
Adjuvant capecitabine significantly improved DFS and OS vs observation in HER2-negative early BC with residual disease after NACT, with the greatest benefit in the TNBC subgroup (~48% OS risk reduction). CREATE-X established capecitabine as a response-adapted therapy in this high-risk post-NACT population.
Key Limitations
Conducted in Japan — 72% of patients were Japanese; capecitabine pharmacokinetics, toxicity profiles, and dosing tolerability differ between Asian and Western populations (Western patients often require dose reductions). The trial predates pembrolizumab-based neoadjuvant regimens — optimal role of capecitabine in patients receiving KEYNOTE-522-style therapy with residual disease is unclear. The benefit in HR+ patients was less pronounced than in TNBC. Standard dosing (1250mg/m²) requires de-escalation to 1000mg/m² in many Western patients to reduce HFS rates.
Clinical Context
CREATE-X established capecitabine × 6–8 cycles as standard-of-care for HER2-negative residual disease post-NACT (ESMO/ASCO guideline-endorsed). For TNBC with residual disease, OlympiA olaparib (if gBRCA-mutated) and capecitabine are both active — their combination vs sequential use is unstudied. Pembrolizumab adjuvant therapy (KEYNOTE-522 paradigm) is now standard in stage II–III TNBC, and its interaction with capecitabine in residual disease is under investigation. ESMO-MCBS score: 4.
References