Neoadjuvant dose-dense anthracycline and cyclophosphamide in combination with carboplatin, paclitaxel, and pembrolizumab for triple-negative breast cancer: A systematic review and meta-analysis.

Abstract

e12606 Background: Pembrolizumab in combination with carboplatin and paclitaxel (CT), followed by 3-weekly anthracycline and cyclophosphamide (AC), or administered in the reverse order, has become the standard neoadjuvant regimen for early triple negative breast cancer (eTNBC). However, the KEYNOTE-522 trial did not evaluate the use of dose dense (dd) AC as part of the chemotherapy backbone, a regimen that had showed survival gains in eTNBC before introduction of immunotherapy. This meta-analysis assesses the efficacy and safety of ddAC in combination with CT and pembrolizumab. Methods: A systematic search was conducted in PubMed, EMBASE and Cochrane databases to identify randomized or retrospective studies evaluating the efficacy and safety of ddAC in combination with CT and pembrolizumab, with or without comparisons to 3-weekly AC combined with CT and pembrolizumab in eTNBC. There were no restrictions with the order of administration of chemotherapeutics. Studies with overlapping populations or alternative chemo-immunotherapeutics regimens were excluded. Endpoints accessed were pathological complete response (pCR), grade III-IV toxicities, dose modifications and treatment delays associated with neoadjuvant protocols. Statistical analysis was performed using random-effects model in Review Manager Version 5.4 for studies comparing two schedules, and single-arm proportional meta-analysis was conducted in RStudio Version 12.0 to summarize safety and pCR for dose dense regimen. Heterogeneity was assed using I 2 statistic. This protocol was registered in PROSPERO (CRD42024583795). Results: Four observational studies, comprising a total of 535 patients (329 receiving ACdd and 206 receiving 3-weekly AC), met the inclusion criteria. Three studies compared ddAC with 3-weekly AC, while one evaluated ddAC in combination with CT and pembrolizumab. No significant differences in pCR were observed between ddAC and 3-weekly AC (RR 1.10; 95% CI 0.94-1.28; p=0.25; i 2 0%). However, patients receiving ddAC experienced a higher incidence of grade III-IV adverse events (RR 1.65; 95% CI 1.15-2.37; p=0.007; i 2 36%). No differences were found in dose modifications or treatment delays between the two schedules. In the combined analysis of studies evaluating ddAC, the overall pCR was 63% (95% CI 0.55-0.71; i 2 31.3%), with a 33% incidence of treatment delays (95% CI 0.11-0.59; i 2 82.1%). Conclusions: ddAC in combination with CT and pembrolizumab demonstrated a pCR incidence comparable to that reported in the KEYNOTE-522 trial. When compared to 3-weekly AC, ddAC was associated with a higher incidence of grade III-IV adverse events, with no observed difference in pCR. At the current state, in the absence of survival data, neoadjuvant ddAC combined with pembrolizumab does not appear to offer additional benefit for eTNBC.