Neoplasms

Skin and Connective Tissue Diseases

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Symptoms and General Pathology

Breast Neoplasms

Triple Negative Breast Neoplasms

Recurrence

Breast Diseases

Skin Diseases

All Drugs and Chemicals

Antineoplastic Agents

Sacituzumab govitecan

Pembrolizumab

Antineoplastic Agents, Immunological

Immune Checkpoint Inhibitors

Immunoconjugates

Immunologic Factors

* Cohort 1a: In case of (near) cCR: end of treatment, followed by surgery
* Cohort 1b: In case of cPR after 12 weeks: further 6 weeks (2 cycles) SG i.v., followed by surgery (use of core biopsy is allowed per investigator´s decision, if further NACT is planned) pCR dependent post-neoadjuvant treatment
* In case of pCR: no further systemic treatment
* In case of non-pCR: chemotherapy according to investigators decision, e.g., AC/EC q3w x 4, PAC/Carbo q1w x 12

* Cohort 2a: In case of (near) cCR: end of treatment, followed by surgery
* Cohort 2b: In case of cPR after 12 weeks: 6 weeks (2 cycles) SG+PEM i.v., followed by surgery (use of core biopsy is allowed per investigator´s decision, if further NACT is planned) pCR dependent post-neoadjuvant treatment
* In case of pCR: no further systemic treatment
* In case of non-pCR: chemotherapy according to investigators decision, e.g., AC/EC q3w x 4, PAC/Carbo q1w x 12

10 mg/kg twice on Days 1 and 8 of a continuous 21-day treatment cycle

Oleg Gluz, PD Dr.

Anja Braschoß

Peter Schmid, Prof Dr PHD

Nadia Harbeck, Prof Dr

Oleg Gluz, PD Dr

Sherko Kuemmel, Prof Dr

Monika Graeser, PD Dr..

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?

This is a multicentre, interventional, prospective, two-arm, randomised, open-label, neoadjuvant, phase-II-trial evaluating the efficacy and safety of SG alone vs. SG+PEM in low-risk early TNBC in pre- and postmenopausal women.

NeoAdj. Therapy Comparing Sacituzumab Govitecan (SG) vs. SG+Pembrolizumab in Low-risk, Triple-neg. EBC (ADAPT-TN-III)

NeoAdjuvant Dynamic Marker - Adjusted Personalized Therapy Comparing Sacituzumab Govitecan Versus Sacituzumab Govitecan+Pembrolizumab in Low-risk, Triple-negative Early Breast Cancer (ADAPT-TN-III)

ypT0/is, any ypN

* ypT0, ypN0
* near pCR (ypT1a/is, any ypN)

no invasive tumour in breast and lymph nodes (ypT0/is and ypN0)

time from date of first diagnosis to any invasive breast cancer event, death or secondary malignancy according to STEEP 2.0 criteria

change in QLQ-C30-Score; min 0 - max 100 points; the higher the better quality of life

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.

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization	Link
NeoAdj. Therapy Comparing Sacituzumab Govitecan (SG) vs. SG+Pembrolizumab in Low-risk, Triple-neg. EBC (ADAPT-TN-III)	NCT06081244	Triple Negative...	Sacituzumab gov... Pembrolizumab	18 Years -	West German Study Group
NeoAdj. Therapy Comparing Sacituzumab Govitecan (SG) vs. SG+Pembrolizumab in Low-risk, Triple-neg. EBC (ADAPT-TN-III)	NCT06081244	Triple Negative...	Sacituzumab gov... Pembrolizumab	18 Years -	West German Study Group

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