As reported in the Journal of Clinical Oncology and during the 2021 ASCO Annual Meeting by Ingrid A. Mayer, MD, and colleagues, the phase III ECOG-ACRIN EA1131 trial investigated the use of adjuvant platinum vs capecitabine in patients with basal subtype triple-negative breast cancer and residual disease following neoadjuvant chemotherapy. The trial was stopped early due to the unlikelihood of showing noninferiority or superiority in terms of invasive disease–free survival.
The investigators stated: “Patients with triple-negative breast cancer and residual invasive disease after completion of neoadjuvant chemotherapy have a high risk for recurrence, which is reduced by adjuvant capecitabine. Preclinical models support the use of platinum agents in the triple-negative breast cancer basal subtype.”
Ingrid A. Mayer, MD
Study Details
In the trial, 410 of a planned 775 patients with clinical stage II or III triple-negative breast cancer with ≥ 1 cm residual disease were randomly assigned between June 2016 and March 2021 to receive platinum (carboplatin at AUC 6 or cisplatin at 75 mg/m2) once every 3 weeks for four cycles or capecitabine at 1,000 mg/m2 twice daily 14 out of 21 days every 3 weeks for six cycles. Among 308 patients (78%) with basal subtype triple-negative breast cancer (primary analysis population), 148 received platinum (88% carboplatin, 12% cisplatin) and 160 received capecitabine.
The primary endpoint was invasive disease–free survival in the basal subtype population, with an assumption of a 4-year rate of 67% in the capecitabine group based on recent clinical trial results. A noninferiority with superiority alternative design was used, with a hazard ratio of 1.154 for platinum vs capecitabine as the noninferiority margin and a hazard ratio of 0.754 for superiority.
Invasive Disease–Free Survival
At the fifth interim analysis (58% full information, 113 invasive disease–free survival events), the hazard ratio for platinum vs capecitabine was 1.09 (95% repeated confidence interval [CI] = 0.62–1.90; considered inconclusive for noninferiority) and grade 3 and 4 toxicities were more common in the platinum arm. In March 2021, the Data and Safety Monitoring Committee recommended stopping the trial due to the unlikelihood that further accrual would provide ability to show noninferiority or superiority of the platinum group.
At data cutoff for the current report in April 2021, median follow-up was 20 months; 120 events (61% of full information) had occurred. Invasive disease–free survival at 3 years was 42% (95% CI = 30%–53%) in the platinum group vs 49% (95% CI = 39%–59%) in the capecitabine group (hazard ratio [HR] = 1.06, 95% repeated CI = 0.62–1.81). No clinical factors identified a subset of patients with relative benefit with platinum treatment.
At 3 years, recurrence-free survival was 46% vs 49% (HR = 0.99, 95% CI = 0.67–1.45) and overall survival was 58% vs 66% (HR = 1.13, 95% CI = 0.71–1.79).
KEY POINTS
- The trial was stopped early due to unlikelihood of noninferiority or superiority of platinum vs capecitabine being shown and increased grade 3 and 4 toxicity in the platinum group.
- Invasive disease–free survival at 3 years was 42% in the platinum group vs 49% in the capecitabine group.
Adverse Events
Among a total of 184 patients in the platinum group and 198 in the capecitabine group who began treatment, grade 3 and 4 adverse events occurred in 26% vs 15%, with the most common in the platinum group being decreased white blood cell count (10% vs 3%) and anemia (7% vs 0%). Adverse events led to discontinuation of treatment in 21 vs 12 patients.
Common adverse events of any grade were myelosuppression and nausea in the platinum group, and myelosuppression, nausea, diarrhea, and palmar-plantar erythrodysesthesia in the capecitabine group. Peripheral sensory neuropathy of any grade occurred in 25% vs 28%. No grade 5 adverse events were observed.
The investigators concluded, “Platinum agents do not improve outcomes in patients with basal subtype triple-negative breast cancer [with] residual disease post–neoadjuvant chemotherapy and are associated with more severe toxicity when compared with capecitabine. Participants had a lower than expected 3-year invasive disease–free survival regardless of study treatment, highlighting the need for better therapies in this high-risk population.”
Dr. Mayer, of Vanderbilt University Medical Center, is the corresponding author for the Journal of Clinical Oncology article.
Disclosure: The study was supported by grants from the National Cancer Institute. For full disclosures of the study authors, visit ascopubs.org.
