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.
TNBC: ER = 0%, PR = 0%, and HER2- (i.e., immunohistochemistry [IHC] with DAKO score ≤ 1 or fluorescence in situ hybridization [FISH]-negative)
or TNBC-like: ER ≤ 10% positive cells in IHC, PR < 10% positive cells in IHC, and HER2- (i.e., IHC with DAKO score ≤ 1 or FISH negative)
All patients, independent from gender
≥18 years at diagnosis
Known hypersensitivity to the compounds or incorporated substances of the IMPs
Prior malignancy with a disease-free survival of < 5 years, except curatively treated basalioma of the skin or pTis of the cervix uteri
Any history of invasive breast cancer
Previous or concurrent treatment with cytotoxic agents for any non-oncological reason unless clarified with sponsor
Parallel
Sacituzumab govitecan
DrugSG 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.
Pembrolizumab 25 mg/1 ML Intravenous Solution [KEYTRUDA]
DrugPembrolizumab 200 mg will be administered as a 30-minute i.v. infusion every 3 weeks.
SoC Chemotherapy
DrugStandard of care chemotherapy as per common treatment guidelines and recommendations
Cohort I: 3-year event-free survival (EFS)
EFS after 36 months defined as time from registration to any invasive breast cancer event, death, or secondary malignancy (same definition as iDFS) according to STEEP 2.0 criteria \[103\]
Cohort II: superiority of neoadjuvant treatment with SG+PEM vs. SoC with regards to event-free survival (EFS)
EFS after 36 months defined as time from registration to any invasive breast cancer event, death, or secondary malignancy or local progress precluding surgery in neoadjuvant treated patients
Cohort II: superiority of neoadjuvant treatment with SG+PEM vs. SoC with regards to pathological complete response (pCR) rates
pCR defined as no invasive disease in breast and lymph nodes (ypT0/is, ypN0) in patients of both arms
clinical response after 12 weeks of neoadjuvant chemotherapy treatment (NACT)
Clinical response measured by tumour size in mm by palpation, ultrasound, mammography, or MRI
distant disease-free survival (dDFS)
distant disease-free survival (dDFS)
relapse-free survival (RFS)
relapse-free survival (RFS)
locoregional relapse-free survival (LRFS)
locoregional relapse-free survival (LRFS)
Click on the lead sponsor to view all of their trials.
Women's Cancer Study Group GmbH
Lead sponsor
Gilead Sciences
Collaborator
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