In a phase II trial reported in the Journal of Clinical Oncology, Schneider et al found that genomically directed therapy did not improve 2-year disease-free survival vs treatment of physician’s choice in patients with residual triple-negative breast cancer following neoadjuvant chemotherapy.
Study Details
The U.S. multicenter trial enrolled 193 patients with residual tumors. Tumors were analyzed via next-generation sequencing, with a molecular tumor board adjudicating all results. A total of 144 patients with a genomically defined target were randomly allocated between April 2014 and March 2019 to receive four cycles of genomically directed therapy (n = 71) or treatment of physician’s choice (n = 73); patients with no defined target (n = 47) were assigned to the physician’s choice group. The primary endpoint was 2-year disease-free survival among randomly assigned patients.
Key Findings
Patients in the directed-therapy group received 1 of 11 different therapies. Among all patients in the treatment of physician’s choice group, six different regimens or no therapy were given, with capecitabine being the most commonly used treatment.
Median follow-up was 34.2 months. In the randomly assigned population, estimated 2-year disease-free survival was 56.6% (95% confidence interval [CI] = 0.45%–0.70%) in the directed-therapy group vs 62.4% (95% CI = 0.52%–0.75%) in the treatment of physician’s choice group. No significant differences between the directed-therapy group vs the treatment of physician’s choice group were observed for disease-free survival, distant disease–free survival, or overall survival.
Genomically directed therapy was not superior to treatment of physician’s choice for patients with residual triple-negative breast cancer after neoadjuvant chemotherapy. Capecitabine should remain the standard of care; however, the activity of other agents in this setting provides rationale for testing optimal combinations to improve outcomes. ctDNA should be considered a standard covariate for trials in this setting.— Schneider et al
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No differences in outcomes were observed between the directed therapy group vs the entire treatment of physician’s choice group, or between the randomly allocated and assigned patients in the treatment of physician’s choice group.
The use of capecitabine for treatment of physician’s choice increased over time, from 2 (11.1%) of 18 patients up to December 2015, to 18 (50%) of 36 patients up to June 2017, and to 50 (79.4%) of 63 patients enrolled thereafter. In analysis of early vs later random assignment (cutpoint = median date for random assignment in July 2017), early random assignment was associated with significantly poorer distant disease–free survival (HR = 1.81, 95% CI = 1.04–3.13, P = .035).
Treatments used in ≥ 10 patients in the directed therapy group were pembrolizumab (n = 18), olaparib (n = 12), and gemcitabine (n = 10). No significant differences in disease-free, distant disease–free, or overall survival were observed for pembrolizumab or gemcitabine vs capecitabine in the treatment of physician’s choice group; inferior outcomes were observed with olaparib vs capecitabine.
Among all patients, circulating tumor DNA (ctDNA)-positive status was associated with significantly poorer disease-free survival (HR = 1.93, P = .03), distant disease–free survival (HR = 2.68, P = .0065), and overall survival (HR = 2.64, P = .02). Among 45 patients in the directed-therapy group assessed at completion of therapy, 8 were ctDNA-positive at baseline and negative at follow-up; of these, 5 have not had distant disease recurrence.
The investigators concluded, “Genomically directed therapy was not superior to treatment of physician’s choice for patients with residual triple-negative breast cancer after neoadjuvant chemotherapy. Capecitabine should remain the standard of care; however, the activity of other agents in this setting provides rationale for testing optimal combinations to improve outcomes. ctDNA should be considered a standard covariate for trials in this setting.”
Bryan P. Schneider, MD, of Indiana University Melvin and Bren Simon Comprehensive Cancer Center, Indianapolis, is the corresponding author for the Journal of Clinical Oncology article.
Disclosure: The study was supported by the Vera Bradley Foundation for Breast Cancer Research, Walther Cancer Foundation, and Indiana University Grand Challenge Precision Health Initiative. For full disclosures of the study authors, visit ascopubs.org.
