Clinical and Biomarker Findings of Neoadjuvant Pembrolizumab and Carboplatin Plus Docetaxel in Triple-Negative Breast Cancer

Abstract

ImportanceAddition 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.ObjectiveTo assess the efficacy of the anthracycline-free neoadjuvant regimen of carboplatin and docetaxel plus pembrolizumab in TNBC.Design, Setting, and ParticipantsThis 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 ExposureCarboplatin (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 MeasuresPrimary 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.ResultsAmong 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 RelevanceThe 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 RegistrationClinicalTrials.gov Identifier: NCT03639948

Safety and efficacy of anlotinib combined with taxane and lobaplatin in neoadjuvant treatment of clinical stage II/III triple-negative breast cancer in China (the neoALTAL trial): a single-arm, phase 2 trial

“…In the NeoPACT study, 83 patients with stage II to III disease and ER and PR less than 1% achieved a pCR rate of 58% using taxane and platinum-based agent combined with pembrolizumab for six cycles. 27 Our study used taxane and lobaplatin combined with anlotinib for 6 cycles, and obtained a pCR rate of 57.8%, which is similar to the NeoPACT study. According to the results of pCR rate, it could be interesting to further evaluate of neoadjuvant anlotinib plus taxane and platinum as an alternative regimen for patients with TNBC, who are not eligible for chemoimmunotherapy or anthracycline-based regimens in phase 2–3 randomized studies.…”

“… 9 These data also compare favorably with those from neoadjuvant chemoimmunotherapy regimens, in which toxic effects related treatment discontinuation rates of 23%, 23%, and 12% were reported by the KEYNOTE-522, Impassion031, and NeoPACT trials. 25 , 26 , 27 The hematological toxicities and gastrointestinal reactions are the most common AEs shared by neoadjuvant chemotherapy. The anthracycline drug increases the cardiotoxicity.…”

Stromal tumor-infiltrating lymphocytes and pathologic response to neoadjuvant chemotherapy with the addition of platinum and pembrolizumab in TNBC: A single-center real-world study

“…It is well established that TNBC tumors exhibit a tumor microenvironment (TME) enriched with immune cells, characterized by high levels of sTILs, PD-L1-positivity and up-regulated immune gene signatures [13,14,19,20]. These immune biomarkers exhibit correlations [13,20].…”

“…In addition, robust evidence suggests that a high level of stromal tumor-in ltrating lymphocytes (sTILs) in pre-treatment biopsied samples correlates with an increased rate of pCR in TNBC patients undergoing neoadjuvant chemotherapy [9][10][11][12][13][14]. However, there has been limited data regarding the impact of sTILs on response to different neoadjuvant chemotherapy regimens with or without pembrolizumab in TNBC patients.…”

Expert consensus on the clinical application of immunotherapy in breast cancer: 2024

“…There is still controversy of whether need to combine anthracycline in TNBC therapy. phase II NeoPACT study ( 15 ) showed patients treated with preoperative anthracycline-free chemotherapy (carboplatin and docetaxel) with pembrolizumab achieved a pCR rate of 58% and a 3-year EFS of 86%. cTRIO study showed patients treated with 6 cycles of non-anthracycline (nab-paclitaxel + carboplatin + tislelizumab) achieved a pCR of 56.5% ( 11 ).…”