What is the design and outcome of the CREATE‑X phase III trial of adjuvant capecitabine versus observation in adult patients with HER2‑negative (triple‑negative) breast cancer who have residual invasive disease after neoadjuvant anthracycline‑ and taxane‑based chemotherapy?

CREATE-X Trial Overview for Triple-Negative Breast Cancer

Trial Design and Population

CREATE-X was a multicenter, open-label, randomized phase III trial that enrolled 910 Asian patients with stages I to IIIB, HER2-negative breast cancer who had centrally confirmed residual invasive disease after standard neoadjuvant anthracycline and/or taxane-based chemotherapy. 1

Key Eligibility Criteria

• Patients required centrally confirmed residual invasive disease at surgery in the breast and/or axillary nodes following standard combination chemotherapy 1
• Approximately 95% of patients received sequential or concurrent anthracycline- and taxane-based neoadjuvant therapy 1
• The trial enrolled 68% hormone receptor-positive patients (n=601) and 32% hormone receptor-negative/triple-negative patients (n=286) 1
• 57% of patients were premenopausal at study entry 1

Treatment Arms

Capecitabine Arm

• Patients received 6 to 8 cycles of oral capecitabine at 1,250 mg/m² twice daily on days 1-14 of each 21-day cycle 1

Control Arm

• Observation only (no additional adjuvant treatment) 1

Primary Outcomes: Overall Population

At a median follow-up of 3.6 years, the 5-year disease-free survival rate was 74.1% in the capecitabine arm versus 67.6% in the control arm (HR 0.70; 95% CI 0.53-0.92; P=0.01), representing an absolute benefit of 6.5%. 1, 2

Overall survival at 5 years was significantly improved: 89.2% in the capecitabine group versus 83.6% in the control group (HR 0.59; 95% CI 0.39-0.90; P=0.01), with an absolute difference of 5.6%. 1, 2

Triple-Negative Subgroup Analysis: The Most Compelling Results

In the triple-negative breast cancer subgroup specifically, capecitabine demonstrated even greater benefit with 5-year disease-free survival of 69.8% versus 56.1% (HR 0.58; 95% CI 0.39-0.87) and overall survival of 78.8% versus 70.3% (HR 0.52; 95% CI 0.30-0.90). 1, 2

Extended Follow-Up Data

• In an exploratory analysis after a median follow-up of 10.3 years, patients with triple-negative breast cancer maintained improved recurrence-free survival (HR 0.53, P=0.02) and overall survival (HR 0.55, P=0.03) with capecitabine 1

Hormone Receptor-Positive Subgroup

Hormone receptor-positive patients also derived benefit, though numerically smaller: disease-free survival 76.4% versus 73.5% (HR 0.81; 95% CI 0.55-1.17) and overall survival 93.4% versus 90% (HR 0.73; 95% CI 0.38-1.40). 1, 2

The interaction test for treatment effect by hormone receptor status was not statistically significant (P=0.21), though the effect size was numerically larger in hormone receptor-negative disease. 1

Safety Profile

Hand-foot syndrome was the most frequent adverse event, occurring in 73.4% of patients, with 11.1% experiencing grade 3 events in the capecitabine group versus 0% across all grades in the standard therapy group. 1

• Diarrhea and hematologic toxicities were also common and required routine monitoring 3
• The capecitabine dosage of 1,250 mg/m² twice daily is associated with higher toxicity in patients ≥65 years old 1

Current Guideline Recommendations Based on CREATE-X

NCCN 2024 guidelines include adjuvant capecitabine as an adjuvant therapy option for those with triple-negative breast cancer and residual disease after preoperative therapy, based on CREATE-X trial results showing improved disease-free survival (HR 0.70; 95% CI 0.53-0.92; P=0.01) and overall survival (HR 0.59; 95% CI 0.39-0.90; P=0.01). 1

ASCO recommends that patients with early-stage, HER2-negative breast cancer with pathologic invasive residual disease at surgery following standard anthracycline- and taxane-based preoperative therapy may be offered up to 6-8 cycles of adjuvant capecitabine (Type: Evidence-based, benefits outweigh harms; Evidence quality: intermediate; Strength of recommendation: moderate). 1

The ASCO Expert Panel preferentially supports the use of adjuvant capecitabine in patients with hormone receptor-negative, HER2-negative (triple-negative) breast cancer. 1, 2

Practical Dosing Modifications

For patients ≥65 years old, reduce the starting dose to 1,000 mg/m² twice daily without escalation due to higher toxicity risk. 3

Real-world data from a US population showed a mean relative dose intensity of only 60.2% across eight cycles, significantly lower than the CREATE-X trial (60.2% vs 78.7%, p<0.001), indicating that the full CREATE-X dose is often not well tolerated in non-Asian populations. 4

Important Clinical Context

CREATE-X established the paradigm of residual disease-guided therapy, demonstrating that patients with extensive residual invasive cancer after neoadjuvant chemotherapy are at high risk of recurrence and benefit from additional post-operative treatment. 5

The value of adjuvant capecitabine after the use of a platinum compound in the neoadjuvant setting is currently unknown, as this was not studied in CREATE-X. 3