Randomized Phase III Postoperative Trial of Platinum-Based Chemotherapy Versus Capecitabine in Patients With Residual Triple-Negative Breast Cancer Following Neoadjuvant Chemotherapy: ECOG-ACRIN EA1131

Abstract

Purpose: Patients with triple-negative breast cancer (TNBC) and residual invasive disease (RD) after completion of neoadjuvant chemotherapy (NAC) have a high-risk for recurrence, which is reduced by adjuvant capecitabine. Preclinical models support the use of platinum agents in the TNBC basal subtype. The EA1131 trial hypothesized that invasive disease-free survival (iDFS) would not be inferior but improved in patients with basal subtype TNBC treated with adjuvant platinum compared with capecitabine.

Patients and methods: Patients with clinical stage II or III TNBC with ≥ 1 cm RD in the breast post-NAC were randomly assigned to receive platinum (carboplatin or cisplatin) once every 3 weeks for four cycles or capecitabine 14 out of 21 days every 3 weeks for six cycles. TNBC subtype (basal v nonbasal) was determined by PAM50 in the residual disease. A noninferiority design with superiority alternative was chosen, assuming a 4-year iDFS of 67% with capecitabine.

Results: Four hundred ten of planned 775 participants were randomly assigned to platinum or capecitabine between 2015 and 2021. After median follow-up of 20 months and 120 iDFS events (61% of full information) in the 308 (78%) patients with basal subtype TNBC, the 3-year iDFS for platinum was 42% (95% CI, 30 to 53) versus 49% (95% CI, 39 to 59) for capecitabine. Grade 3 and 4 toxicities were more common with platinum agents. The Data and Safety Monitoring Committee recommended stopping the trial as it was unlikely that further follow-up would show noninferiority or superiority of platinum.

Conclusion: Platinum agents do not improve outcomes in patients with basal subtype TNBC RD post-NAC and are associated with more severe toxicity when compared with capecitabine. Participants had a lower than expected 3-year iDFS regardless of study treatment, highlighting the need for better therapies in this high-risk population.

Trial registration: ClinicalTrials.gov NCT02445391.

FIG 1.

CONSORT diagram. All patients (308 basal subtype and 88 nonbasal subtype) enrolled after Protocol Amendment 3, June 2016 (which incorporated capecitabine as the control arm instead of observation based on CREATE-X trial results), were included in efficacy analyses. A total of 391 patients started protocol therapy and 382 of them submitted AE data and were included in toxicity analysis. Patients enrolled to platinum and capecitabine arms but not treated (n = 21, 16 basal subtype) were followed for recurrence and survival and were included in the intention-to-treat efficacy analysis. Patients enrolled to observation arm were excluded from the report. AE, adverse event; PD, disease progression.

FIG 2.

Kaplan-Meier estimates of iDFS. Three-year iDFS (A) patients with basal subtype TNBC were similar across both arms, and (B and C) patients with basal subtype TNBC had poor prognosis (worse iDFS) regardless of treatment arm compared to patients with nonbasal subtype. (B) Patients with nonbasal subtype TNBC appear to have better iDFS when treated with capecitabine than with a platinum agent, but this finding is not statistically significant. HR, hazard ratio; iDFS, invasive disease-free survival; RCI, repeated CI; TNBC, triple-negative breast cancer.

FIG 3.

Kaplan-Meier estimates of RFS and OS. Three-year (A) RFS and (B) OS for patients with basal subtype triple-negative breast cancer were similar across both treatment arms and lower than originally anticipated. HR, hazard ratio; OS, overall survival; RFS, recurrence-free survival.

FIG A1.

EA1131 interim analysis monitoring (futility and efficacy). The graph outlines the range of possible outcomes for EA1131, designed to demonstrate noninferiority with superiority alternative (hybrid design). The primary analysis for the primary objective tested the hypothesis that platinum chemotherapy was not inferior to capecitabine. The null hypothesis of inferiority of platinum was defined as an HR = 1.154 (noninferiority margin). If noninferiority was demonstrated, the secondary hypothesis of no difference versus superiority of platinum would then be tested. At each interim analysis, if the conditional power (ie, probability of eventually rejecting the null of inferiority) of the assigned treatment analysis was < 10% and the lower boundary of the two-sided 95% RCI was > 0.754 (ie, the alternative hypothesis for the noninferiority test), the trial would then be stopped because of futility. As the HR for platinum versus capecitabine was 1.09 (95% RCI, 0.62 to 1.90) and the conditional power was 6%, the trial was stopped by the Data Safety Monitoring Committee because of futility, since it was unlikely that the trial would be able to show noninferiority or superiority of the platinum arm. HR, hazard ratio; RCI, repeated CI.