TNBC is known for poor prognosis, aggressive patterns of disease, and significant molecular heterogeneity. (Neo)adjuvant chemotherapy (NACT) is standard of care in all node-positive and in node-negative patients with a tumour size \>5 mm according to current National Comprehensive Cancer Network (NCCN) guidelines. However, TNBC patients with lower stage disease do clearly have a better prognosis compared to more advanced stages. Patients with stage I-II node-negative disease have 3-5 year iDFS rates of 80-90% (with majority of relapses within the first three years) as shown in several trials.Although survival results appear much better in the lower vs. higher stages, there is a high clinical need in this most common group of TNBC patients in Western Europe and USA.
About 15% of breast cancers lack both, expression of ER and PR receptors, and amplification/over-expression of HER2 receptors, and are thus described as triple negative breast cancer (TNBC). TNBC is known for poor prognosis, aggressive patterns of disease, and significant molecular heterogeneity. (Neo)adjuvant chemotherapy (NACT) is standard of care in all node-positive and in node-negative patients with a tumour size \>5 mm according to current National Comprehensive Cancer Network (NCCN) guidelines. However, TNBC patients with lower stage disease do clearly have a better prognosis compared to more advanced stages. Patients with stage I-II node-negative disease have 3-5 year iDFS rates of 80-90% (with majority of relapses within the first three years) as shown in several trials. Our own results from the PlanB- and ADAPT-trials, and pooled analysis with SUCCESS C-trials show 3-year iDFS of 86-90% in node-negative TNBC with a tumour size \< 3 cm. Although survival results appear much better in the lower vs. higher stages, there is a high clinical need in this most common group of TNBC patients in Western Europe and USA. In the neoadjuvant setting, it has been shown that the prognosis of patients with TNBC is strongly dependent on their response to NACT: Patients achieving pathological complete response (pCR), or a near pCR (an excellent response after NACT (residual cancer burden (RCB) score 0-1), in some studies do have an excellent prognosis that is not significantly different from that observed in other breast cancer subtypes. However, patients with a less responsive disease (i.e., with RCB Score 2-3) suffer from a significantly worse prognosis compared to non-TNBC. Chemotherapy in TNBC The optimal chemotherapy regimen for patients with TNBC remains to be identified. Standard anthracycline-taxane (A/T)-based NACT combinations render pCR rates between 25-50%. However, the survival impact of anthracyclines remains controversial due to conflicting results of different randomized trials. Adding carboplatin (carbo) to A/T-containing poly-NACT or use of dose-intensified poly-NACT significantly increases pCR-rates up to 49-60% in mostly stage II-III disease with conflicting survival results and higher toxicity. Hence, use of pragmatic taxane-carboplatin anthracycline-free combinations appears as an effective treatment option in TNBC instead of further treatment escalation. This probably is independent of the germline BRCA (gBRCA) status, due to its general chemo-predictive effect. Unfortunately, no prospective phase-III-data are available so far. However, indirect comparison between trials renders similar pCR rates in taxane-carboplatin based vs. A/T+/-carbo-based regimens in early TNBC. In the ADAPT-TN neoadjuvant trial, the taxane-carbo arm (12-week nab-paclitaxel (nab-pac)+carbo) was well tolerable (only 10% SAE-rate), highly effective (pCR, ypT0/is/ypN0, of 46%) and superior to the gemcitabine (gem)-arm (nab-pac+gem, pCR of 29%). In this study, omission of further chemotherapy was allowed in patients with pCR after 12 weeks of therapy and was not associated with decreased survival after 3 years \[5\] and longer follow up. Although a standard chemotherapy as well as optimal therapy duration are still to be defined, several studies are showing a comparable efficacy for longer vs. shorter adjuvant treatments in TNBC \[3\], as well as a similar efficacy regarding pCR in HR-negative (in contrast to HR-positive) early breast cancer (eBC) \[26\]. Moreover 6 vs. 4 cycles of the same chemotherapy (AC or pac weekly) yielded a similar survival outcome in eBC despite of HR-status. No such comparison regarding treatment duration is available for modern antibody-drug conjugates like sacituzumab govitecan (SG). Therefore, an examination of shorter (12 weeks vs. 18 weeks) regimen as neoadjuvant treatment appears to be a very promising strategy at least in patients with lower risk disease or in elderly patients, who do not qualify for polychemotherapy treatments. In the Keynote-522 trial combination of carboplatin/taxane-anthracycline NACT with the anti-PD1-antibody pembrolizumab (PEM) has been shown to be associated with a significantly higher pCR and clinically meaningful better EFS and a trend to better OS. Noteworthy only patients with more advanced stages IIa-III TNBC were included into the Keynote-522 trial. Although this effect was independent of clinically assessed nodal status, there is still some uncertainty on the optimal treatment in patients with clinical stage I. In the metastatic setting, SG as a Trop-2-antibody-drug-conjugate has been shown to be highly efficacious in severely pre-treated patients (all with A/T pre-treated tumours, most of them carboplatin and 1/3 also anti-PD1 pre-treated) compared to chemotherapy of investigator´s choice. Treatment with SG was associated with significant longer median PFS (5.5 vs. 1.7 months) and longer median OS (12.1 vs. 6.7 months). Objective response was dramatically higher in the SG group vs. treatment by physician´s choice group (34.9 vs. 4.7%), in particular in the 2nd-3rd-line therapy (40% vs. 4%). Moreover, Tropics-02 trial has shown higher efficacy of SG vs. chemotherapy of investigator´s choice in patients with HR-positive/HER2-negative metastatic breast cancer. In the neoadjuvant setting, recently presented results from the NeoSTAR trial show a promising pCR-rate of 30% and RCB 0-1-rate of 36% in TNBC patients with mostly stage II-III-disease (about 80%) after only 4 cycles of SG. The following clinical questions are of highest medical need 1. Can 12-18 weeks neoadjuvant treatment with SG alone or in combination with PEM be associated with comparable pCR-rates (but more favourable safety profile) as shown for polychemotherapy in TNBC patients at lower relapse risk in historical controls? 2. Can SG-based therapy, as the most promising agent in patients with chemo-resistant disease, be associated with a such better prognosis (measured by 3-year-iDFS) compared to historical controls, which would make a randomized phase III-trial obsolete?
Study Type
INTERVENTIONAL
Allocation
RANDOMIZED
Purpose
TREATMENT
Masking
NONE
Enrollment
348
10 mg/kg twice on Days 1 and 8 of a continuous 21-day treatment cycle
200 mg every 3 weeks (q3w)
Stadtklinik Baden-Baden / Brustzentrum
Baden-Baden, Baden-Wurttemberg, Germany
RECRUITINGKliniken Böblingen
Böblingen, Baden-Wurttemberg, Germany
RECRUITINGPraxis für interdisziplinäre Onkologie & Hämatologie
Freiburg im Breisgau, Baden-Wurttemberg, Germany
RECRUITINGSLK Kliniken Heilbronn, Frauenklinik
Heilbronn, Baden-Wurttemberg, Germany
pathological complete remission (pCR)
no invasive tumour in breast and lymph nodes (ypT0/is and ypN0)
Time frame: at surgery
invasive disease-free survival rate (iDFS),
time from date of first diagnosis to any invasive breast cancer event, death or secondary malignancy according to STEEP 2.0 criteria
Time frame: after 3 years
Overall survival (OS)
time from first diagnosis to death
Time frame: 6 years
distant disease-free survival (dDFS)
distant disease-free survival
Time frame: after 3 years
distant disease-free interval (dDFI)
distant disease-free interval
Time frame: after 3 years
recurrence-free survival (RFS)
recurrence-free survival
Time frame: after 3 years
local recurrence-free survival (LRFS)
local recurrence-free survival
Time frame: after 3 years
Breast cancer free interval (BCFI)
Breast cancer free interval
Time frame: after 3 years
Health-related Quality of Life: Quality of Life Questionnaire C30
change in QLQ-C30-Score; min 0 - max 100 points; the higher the better quality of life
Time frame: Baseline to end of cycle 2 (each cycle is 21 days)
Health-related Quality of Life: Quality of Life Questionnaire BR45
change in BR45-Score; min 0 - max 100 points; the higher points on functional scale the better the function; the higher points on symptom scale the higher the symptomatology.
Time frame: Baseline to end of cycle 2 (each cycle is 21 days)
Health-related Quality of Life: Quality of Life Questionnaire C30
change in QLQ-C30-Score; min 0 - max 100 points; the higher the better quality of life
Time frame: Baseline to end of cycle 4 (each cycle is 21 days)
Health-related Quality of Life: Quality of Life Questionnaire BR45
change in BR45-Score; min 0 - max 100 points; the higher points on functional scale the better the function; the higher points on symptom scale the higher the symptomatology.
Time frame: Baseline to end of cycle 4 (each cycle is 21 days)
Health-related QoL: EORTC QLQ-C30
change in QLQ-C30-Score; min 0 - max 100 points; the higher the better quality of life
Time frame: Baseline to end of cycle 6 (each cycle is 21 days)
Health-related Quality of Life: Quality of Life Questionnaire BR45
change in BR45-Score; min 0 - max 100 points; the higher points on functional scale the better the function; the higher points on symptom scale the higher the symptomatology.
Time frame: Baseline to end of cycle 6 (each cycle is 21 days)
Health-related QoL: EORTC QLQ-C30
change in QLQ-C30-Score; min 0 - max 100 points; the higher the better quality of life
Time frame: Baseline to timepoint before surgery
Health-related QoL: EORTC QLQ-BR45
change in QLQ-BR45-Score
Time frame: Baseline to timepoint before surgery
Health-related Quality of Life: Quality of Life Questionnaire C30
change in QLQ-C30-Score; min 0 - max 100 points; the higher the better quality of life
Time frame: Baseline to timepoint 1 year after surgery
Health-related Quality of Life: Quality of Life Questionnaire BR45
change in BR45-Score; min 0 - max 100 points; the higher points on functional scale the better the function; the higher points on symptom scale the higher the symptomatology.
Time frame: Baseline to timepoint 1 year after surgery
This platform is for informational purposes only and does not constitute medical advice. Always consult a qualified healthcare professional.
Universitätsklinikum Tübingen
Tübingen, Baden-Wurttemberg, Germany
RECRUITINGUniversitätsklinikum Ulm
Ulm, Baden-Wurttemberg, Germany
RECRUITINGGRN Klinik Weinheim
Weinheim, Baden-Württembergs, Germany
RECRUITINGHämatologie-Onkologie im Zentrum MVZ GmbH
Augsburg, Bavaria, Germany
RECRUITINGUniversitätsklinikum Augsburg A.ö.R.
Augsburg, Bavaria, Germany
RECRUITINGRotkreuzklinikum München
München, Bavaria, Germany
ACTIVE_NOT_RECRUITING...and 32 more locations