De‑escalation of Neoadjuvant Carboplatin‑Paclitaxel Plus Pembrolizumab in Stage II Triple‑Negative Breast Cancer with High Tumor‑Infiltrating Lymphocytes

The primary objective is to evaluate the efficacy of a neoadjuvant chemotherapy regimen comprising four 12‑week cycles of carboplatin, paclitaxel, and pembrolizumab in patients with stage II triple‑negative breast cancer whose tumor‑infiltrating lymphocytes are ≥30%, thereby determining whether a de‑escalated protocol can achieve adequate pathologic response. Secondary objectives include assessment of three‑year event‑free survival, three‑year overall survival, tumor response as measured by residual cancer burden (RCB), safety and toxicity profiling, quality‑of‑life outcomes, fear of recurrence, correlation of breast MRI response with the RCB‑0 rate, correlation of the percentage of tumor‑infiltrating lymphocytes with the RCB‑0 rate, and identification of circulating and/or tissue biomarkers associated with therapeutic efficacy.

The trial enrolled adult males and females, all aged over 18 years, with a diagnosis of triple‑negative breast cancer meeting stage II criteria (T2‑T3N0M0 or T1‑T2N1M0) and tumor‑infiltrating lymphocytes ≥ 30% on initial biopsy. Participants were required to have a WHO performance status of ≤ 1 and no contraindications to neoadjuvant chemotherapy or pembrolizumab. Adequate bone‑marrow, hepatic, renal, and cardiac function were confirmed by laboratory tests and echocardiography within 21 days prior to screening. Women of childbearing potential needed a negative pregnancy test and effective contraception. All subjects had to be able to understand French and be affiliated with a social security system. The sponsor did not provide information on the total number of participants enrolled. No specific lifestyle restrictions such as diet or physical activity were reported in the available data.

The study is a prospective, multicenter, phase II, open‑label trial evaluating a neoadjuvant chemo‑immunotherapy regimen in patients with triple‑negative breast cancer meeting specific inclusion criteria. After an initial screening visit to confirm histology, stage II disease, tumor‑infiltrating lymphocyte (TIL) percentage ≥30 % and required laboratory parameters, participants receive four 21‑day cycles of intravenous carboplatin (800 mg), paclitaxel (160 mg) and pembrolizumab (200 mg) over a 12‑week treatment period. Study visits occur prior to each infusion for safety assessments, laboratory tests, performance status evaluation, and completion of quality‑of‑life questionnaires; a breast MRI and core‑needle biopsy are performed at the end of week 12 to determine the primary endpoint of pathological complete response (ypT0/Tis ypN0). Following the neoadjuvant phase, patients undergo definitive surgery, after which an end‑of‑study visit records surgical pathology, residual cancer burden and any adverse events. Participants remain under observation for up to three years to capture secondary endpoints such as event‑free survival, overall survival, toxicity, and patient‑reported outcomes. Early termination may occur if disease progression renders surgery impossible, if grade 3 or higher treatment‑related toxicity arises, if the patient withdraws consent, or if major protocol violations are identified.

The study evaluates a neoadjuvant chemotherapy protocol in patients with early triple-negative breast cancer (TNBC) characterized by tumor‑infiltrating lymphocytes ≥ 30%, comprising four 3‑week cycles administered over a 12‑week period.

PACLITAXEL HOSPIRA is supplied as a 6 mg/mL solution for dilution for infusion. The prescribed dose is 160 mg administered by IV infusion on day 1 of each cycle.

CARBOPLATINE ACCORD is provided as a 10 mg/mL solution for infusion. The assigned dose is 800 mg given by IV infusion on day 1 of each cycle, concurrent with paclitaxel.

KEYTRUDA (pembrolizumab) is a 25 mg/mL concentrate for solution for infusion. A fixed dose of 200 mg is administered by IV infusion on day 1 of each cycle, in combination with carboplatin and paclitaxel.

Endoxan (cyclophosphamide monohydrate) is a solution for injection. The dosage is 1200 mg delivered by IV infusion according to the protocol‑specified schedule.

DOXORUBICINE ARROW (doxorubicin hydrochloride) is a 2 mg/mL solution for infusion. The dose is 120 mg administered by IV infusion as defined in the treatment plan.

EPIRUBICINE MEDAC (epirubicin hydrochloride) is a 2 mg/mL solution for infusion. The assigned dose is 180 mg given by IV infusion per the protocol instructions.

All study medications are prepared and administered in a clinical setting under controlled conditions. Dosing intervals, infusion start and end times, and any dose modifications are documented in case report forms. Compliance monitoring includes verification of infusion completion, assessment of adverse events, and regular review of adherence to the 3‑week cycle schedule.

The primary efficacy assessment will be the proportion of participants achieving pathological complete response (ypT0/Tis ypN0) as determined by the absence of suspected residual tumor on breast MRI and core‑needle biopsy after 12 weeks of neoadjuvant treatment, confirmed by histological examination of the definitive surgical specimen (breast and axillary nodes) according to the AJCC 8th edition.

Secondary efficacy parameters include:

• Event‑free survival, calculated from the date of inclusion to the first occurrence of disease progression precluding surgery, local or distant recurrence, second primary cancer, or death from any cause.
• Overall survival, measured from inclusion to death from any cause.
• Residual cancer burden (RCB) index, derived from pathological measurements of tumor size, cellularity, and nodal involvement per the Symmans methodology; RCB‑0 corresponds to the primary endpoint, while RCB‑1, RCB‑2, and RCB‑3 reflect increasing levels of residual disease.
• Toxicity assessment based on the incidence and grade of adverse events attributable to chemotherapy and pembrolizumab.
• Quality of life evaluated with the EORTC QLQ‑C30 at inclusion, pre‑surgery, and three months post‑surgery, and with the EQ‑5D‑5L at each follow‑up visit over three years.
• Fear of recurrence measured by the French version of the FCRI‑SF at inclusion, pre‑surgery, and at each post‑treatment follow‑up visit for three years.
• Radiologic complete response on MRI, compared with RCB‑0, RCB‑1, and combined RCB‑2/RCB‑3 categories.
• Pre‑treatment tumor‑infiltrating lymphocyte (TIL) percentage, quantified as a continuous and dichotomous variable according to the 2014 International TILs Working Group recommendations and correlated with RCB categories.
• Exploratory biomarker analyses, including RNA expression profiling, spatial transcriptomics, proteomics, and immunomonitoring.

Imaging (breast MRI) and biopsy will be performed at baseline and at week 12. Histopathological evaluation of the surgical specimen will occur after definitive surgery. Patient‑reported outcomes (EORTC QLQ‑C30, EQ‑5D‑5L, FCRI‑SF) will be collected at the specified timepoints using standardized questionnaires. Toxicity will be recorded continuously and graded per established criteria. All efficacy data will be analyzed using appropriate statistical methods to estimate response rates, survival curves, and associations between biomarkers and clinical outcomes.