Clinical and Biomarker Findings of Neoadjuvant Pembrolizumab and Carboplatin Plus Docetaxel in Triple-Negative Breast Cancer: NeoPACT Phase 2 Clinical Trial.

Importance: Addition of pembrolizumab to anthracycline-based chemotherapy improves pathologic complete response (pCR) and event-free survival (EFS) in triple-negative breast cancer (TNBC). The efficacy of anthracycline-free chemoimmunotherapy in TNBC has not been assessed. Objective: To assess the efficacy of the anthracycline-free neoadjuvant regimen of carboplatin and docetaxel plus pembrolizumab in TNBC. Design, Setting, and Participants: This was an open-label phase 2 clinical trial including a single group of patients with stage I to III TNBC enrolled at 2 sites who received neoadjuvant carboplatin and docetaxel plus pembrolizumab every 21 days for 6 cycles. Participants were enrolled from 2018 to 2022. Intervention or Exposure: Carboplatin (with an area under the free carboplatin plasma concentration vs time curve of 6) and docetaxel (75 mg/m2) plus pembrolizumab (200 mg) every 21 days for 6 cycles. Myeloid growth factor support was administered with all cycles. Main Outcomes and Measures: Primary end point was pathologic complete response (pCR) defined as no evidence of invasive tumor in breast and axilla. The secondary end points were residual cancer burden, EFS, toxicity, and immune biomarkers. RNA isolated from pretreatment tumor tissue was subjected to next-generation sequencing. Specimens were classified as positive or negative for the 44-gene DNA damage immune response (DDIR) signature and for the 27-gene tumor immune microenvironment (TIM; DetermaIO) signature using predefined cutoffs. Stromal tumor-infiltrating lymphocytes (sTILs) were evaluated using standard criteria. Programmed cell death-ligand 1 (PD-L1) testing was performed using a standard immunohistochemical assay. Results: Among the eligible study population of 115 female patients (median [range] age, 50 [27-70] years) who enrolled from September 2018 to January 2022, 39% had node-positive disease. pCR and residual cancer burden 0 + 1 rates were 58% (95% CI, 48%-67%) and 69% (95% CI, 60%-78%), respectively. Grade 3 or higher immune-mediated adverse events were observed in 3.5% of patients. sTILs, PD-L1, DDIR, and TIM were each predictive of pCR in multivariable analyses. The areas under curve for pCR were 0.719, 0.740, 0.699, and 0.715 for sTILs, PD-L1, DDIR, and TIM, respectively. Estimated 3-year EFS was 86% in all patients; 98% in pCR group and 68% in no-pCR group. Conclusions and Relevance: The findings of the phase 2 clinical trial indicate that neoadjuvant carboplatin and docetaxel plus pembrolizumab shows encouraging pCR and 3-year EFS. The regimen was well tolerated, and immune enrichment as identified by various biomarkers was independently predictive of pCR. These results provide data on an alternative anthracycline-free chemoimmunotherapy regimen for patients who are not eligible for anthracycline-based regimens and support further evaluation of this regimen as a chemotherapy de-escalation strategy in randomized studies for TNBC. Trial Registration: ClinicalTrials.gov Identifier: NCT03639948.

Randomized Phase II Trial of Anthracycline-free and Anthracycline-containing Neoadjuvant Carboplatin Chemotherapy Regimens in Stage I-III Triple-negative Breast Cancer (NeoSTOP).

PURPOSE: Addition of carboplatin (Cb) to anthracycline chemotherapy improves pathologic complete response (pCR), and carboplatin plus taxane regimens also yield encouraging pCR rates in triple-negative breast cancer (TNBC). Aim of the NeoSTOP multisite randomized phase II trial was to assess efficacy of anthracycline-free and anthracycline-containing neoadjuvant carboplatin regimens. PATIENTS AND METHODS: Patients aged ≥18 years with stage I-III TNBC were randomized (1:1) to receive either paclitaxel (P) weekly × 12 plus carboplatin AUC6 every 21 days × 4 followed by doxorubicin/cyclophosphamide (AC) every 14 days × 4 (CbP → AC, arm A), or carboplatin AUC6 + docetaxel (D) every 21 days × 6 (CbD, arm B). Stromal tumor-infiltrating lymphocytes (sTIL) were assessed. Primary endpoint was pCR in breast and axilla. Other endpoints included residual cancer burden (RCB), toxicity, cost, and event-free (EFS) and overall survival (OS). RESULTS: One hundred patients were randomized; arm A (n = 48) or arm B (n = 52). pCR was 54% [95% confidence interval (CI), 40%-69%] in arm A and 54% (95% CI, 40%-68%) in arm B. RCB 0+I rate was 67% in both arms. Median sTIL density was numerically higher in those with pCR compared with those with residual disease (20% vs. 5%; P = 0.25). At median follow-up of 38 months, EFS and OS were similar in the two arms. Grade 3/4 adverse events were more common in arm A compared with arm B, with the most notable differences in neutropenia (60% vs. 8%; P < 0.001) and febrile neutropenia (19% vs. 0%; P < 0.001). There was one treatment-related death (arm A) due to acute leukemia. Mean treatment cost was lower for arm B compared with arm A (P = 0.02). CONCLUSIONS: The two-drug CbD regimen yielded pCR, RCB 0+I, and survival rates similar to the four-drug regimen of CbP → AC, but with a more favorable toxicity profile and lower treatment-associated cost.