MRI-Guided Neoadjuvant Treatment De-Escalation in Stage II-III TNBC

Summary

Breast cancer is the most common malignancy among women worldwide. Triple-negative breast cancer (TNBC), defined by the lack of estrogen receptor, progesterone receptor, and HER2 expression, comprises approximately 15% of all breast cancers and is the most aggressive subtype, associated with a higher risk of early recurrence and death compared to other breast cancer subtypes. Neoadjuvant chemotherapy (NACT), administered before definitive surgery, is the standard of care for stage II-III TNBC (eTNBC), and pathological complete response (pCR), defined as the absence of invasive cancer in the breast and lymph nodes at surgery, following neoadjuvant systemic therapy, is strongly associated with improved survival in this population.

In the pivotal phase 3 KEYNOTE-522 study, the addition of Pembrolizumab (an immune checkpoint inhibitor (ICI), a PD-1 inhibitor) to NACT significantly improved both pCR rates and survival in patients with eTNBC , establishing a new standard of care for these patients. The KEYNOTE-522 regimen is a five-drug regimen administered in two distinct phases: in the first phase, Paclitaxel and Carboplatin are administered with Pembrolizumab for four cycles (TCa+P) and in the second phase, Adriamycin and Cyclophosphamide are administered with Pembrolizumab for an additional four cycles (AC+P). This regimen carries a high toxicity burden, particularly due to anthracyclines, which are associated with late cardiotoxicity and increased risk of therapy-related leukemias.

Many patients, however, achieve an excellent response after only the first phase of treatment (paclitaxel-carboplatin + pembrolizumab), raising the question of whether treatment can be safely de-escalated in selected responders. Emerging evidence from the NeoPACT and NEO-N studies suggests that pCR rates of 55-58% can be achieved with taxane-carboplatin-pembrolizumab regimen, even in the absence of anthracyclines. Moreover, the recently published TRAIN-3 study in HER2+ breast cancer demonstrated that radiologic complete response on MRI (MRI-CR) strongly correlates with pCR in hormone receptor-negative disease, with 87% concordance.

Building on this rationale, we propose a prospective, investigator-initiated, multicenter, phase II clinical trial in Israel to evaluate the feasibility and efficacy of MRI-guided de-escalation of NACT plus immunotherapy in patients with eTNBC. All enrolled patients will receive four cycles (12 weeks) of paclitaxel-carboplatin with pembrolizumab (TCa+P), followed by breast MRI to assess treatment response. Patients achieving MRI-CR will proceed directly to surgery, omitting the second phase of anthracycline-containing chemotherapy (AC+P). Patients with radiologic residual disease (MRI-RD) will complete the full KEYNOTE-522 regimen. Adjuvant therapy, including pembrolizumab continuation and/or additional chemotherapy, will be administered based on pathological findings and physician and patient discretion.

The primary endpoint is pCR rate among patients who achieve MRI-CR and undergo early surgery. The trial uses a Simon's two-stage optimal design and aims to test whether the observed pCR rate in MRI-CR patients exceeds the benchmark of 65% (based on KEYNOTE-522), with a target of 87% as suggested by TRAIN-3. Based on this approach, to reject the null hypothesis, a pathologic complete response (pCR) must be achieved in at least 22 of the 27 patients with MRI-CR who are referred to early surgery. Overall, Approximately 54 patients will be enrolled in the study to reach this goal. Key secondary endpoints include recurrence-free survival (RFS), overall survival (OS), and patient-reported quality of life (QoL). Patient-reported outcomes (PROs) will be collected longitudinally throughout the study to assess physical symptoms, psychological well-being, treatment-related toxicities, and functional recovery, helping to evaluate how treatment de-escalation impacts patient's experience.

In addition, the study will prospectively collect blood samples for circulating tumor DNA (ctDNA) analysis, creating a unique biorepository of biologic material for translational research. ctDNA dynamics will be evaluated as a complementary biomarker to MRI, enabling assessment of early treatment response, molecular residual disease, and mechanisms of resistance. Samples will be collected at multiple timepoints, before treatment, during therapy, and prior to surgery, providing a rich dataset for future genomic, epigenetic, and immune profiling studies.

This study represents an innovative, precision-driven approach to treatment de-escalation in eTNBC, with the potential to influence clinical practice and redefine the standard of care by identifying patients who can safely avoid anthracycline-based chemotherapy without compromising efficacy.

Conditions

• TNBC, Triple Negative Breast Cancer
• Early Breast Cancer

Interventions

OTHER

Treatment De-Escalation and Early Surgery

Patients with MRI-CR after the first phase of the KEYNOTE-522 regimen will be referred for early surgery without completing the AC+P phase.

Sponsors & Collaborators

• Sheba Medical Center

  collaborator OTHER_GOV

• Tel-Aviv Sourasky Medical Center

  lead OTHER_GOV

Study Design

Allocation

NON_RANDOMIZED

Purpose

TREATMENT

Masking

NONE

Model

SEQUENTIAL

Eligibility

Min Age

18 Years

Sex

ALL

Healthy Volunteers

No

Timeline & Regulatory

Start

2025-11-11

Primary Completion

2028-02-01

Completion

2030-11-01

Countries

• Israel

Study Locations