NeoAdjuvant Therapy Comparing Sacituzumab Govitecan+Pembrolizumab vs. SoC Chemotherapy in Clinical Stage II-III, Triple-negative Early Breast Cancer

Summary

TNBC is a heterogeneous disease with distinct pathological, genetic, and clinical features among subtypes. Treatment results for high-risk primary TNBC remain poor compared to other breast cancer subtypes. Preoperative chemotherapy is the standard of care for patients with stage II or III primary TNBC. Multiple lines of clinical evidence demonstrate that TNBC patients who achieve a pCR to NACT, (ypT0/is ypN0), have an excellent long-term prognosis. A meta-analysis of individual patient data confirmed a strong association of pCR after NACT with improved long-term event-free survival (EFS, hazard ratio \[HR\] 0.24) and overall survival (OS, HR 0.16) benefit. Taxane- and anthracycline-based neoadjuvant regimens generally result in pCR rates between 25-50% \[REFs\], whereas the addition of platinum increases pCR rates to approximately 50-55%.

The KEYNOTE-522 trial has demonstrated that the addition of the immune-checkpoint inhibitor PEM to anthracycline- (AC), taxane- and platinum-based NACT resulted in a significant increase in pCR rates to nearly 65%, associated with a significant reduction of recurrences (EFS, HR 0.65 at 5 years) and improvement of OS (HR 0.66). Based on these results, the KEYNOTE-522 regimen has been approved by the FDA and EMA and has become the standard of care for patients with stage II or III TNBC.

Despite this significant progress, two major questions remain unresolved which will be investigated in the ADAPT-TN-IV trial:

1. Do all patients require the full 6 months of NACT as per KEYNOTE-522 or is there a subgroup of patients who are sufficiently treated with 12 weeks of NACT plus PEM?
2. Can incorporation of ADCs into the KEYNOTE-522 regimen improve response and outcomes in patients without an optimal early response? The outcome of patients with residual disease after 24 weeks of NACT and PEM remains suboptimal and there is an urgent need for more effective strategies. ADCs such as SG have demonstrated superior efficacy compared to standard chemotherapy in metastatic TNBC, resulting in substantially higher response rates and improved progression-free (PFS) and OS. Combination studies of ADCs and immunotherapy in metastatic TNBC have demonstrated significant activity, suggesting possible synergistic activity It is therefore a logical next step to investigate, whether the incorporation of SG in the NACT regimen can improve pCR rates and EFS results in patients who have residual clinical disease after 12 weeks of NACT with CARBO/PAC + PEM.

Conditions

• Breast Cancer
• Triple-negative Breast Cancer

Interventions

DRUG

Sacituzumab govitecan

SG is administered at 10 mg/kg as an intravenous (i.v.) infusion on Days 1 and 8 of a 21-day cycle. The dose of SG will be calculated based on actual weight at randomization (using weight obtained either at enrolment or on Cycle 1 Day 1) and remains constant throughout the study, unless there is a \> 10% change in body weight from baseline. Modifications to the study drug doses administered should be made for a \> 10% change in body weight from baseline and according to local and regional prescribing standards. Dose modifications for changes in body weight \< 10% may be made according to local institutional guidelines. SG is administered via i.v. infusion as described below with additional information available in the current version of the SmPC.

DRUG

Pembrolizumab 25 mg/1 ML Intravenous Solution [KEYTRUDA]

Pembrolizumab 200 mg will be administered as a 30-minute i.v. infusion every 3 weeks.

DRUG

SoC Chemotherapy

Standard of care chemotherapy as per common treatment guidelines and recommendations

Sponsors & Collaborators

• Gilead Sciences

  collaborator INDUSTRY

• West German Study Group

  lead OTHER

Principal Investigators

• Peter Schmid, PHD Dr · Westdeutsche Studiengruppe GmbH

• Nadia Harbeck, Prof Dr · Breast Centre, Dept. Obstetrics & Gynaecology and CCC Munich LMU University Hospital Munich Germany

• Oleg Gluz, Prof Dr · Breast Centre, Evang. Bethesda-Hospital Moenchengladbach Germany

• Sherko Kuemmel, Prof Dr · Breast Centre, Kliniken Essen Mitte Essen Germany

• Monika Graeser, PD Dr · Breast Centre, Marien-Hospital Witten Germany

Study Design

Allocation

RANDOMIZED

Purpose

TREATMENT

Masking

NONE

Model

PARALLEL

Eligibility

Min Age

18 Years

Sex

ALL

Healthy Volunteers

No

Timeline & Regulatory

Start

2026-06-30

Primary Completion

2033-03-31

Completion

2033-03-31