This is a phase II, multicentre, open-label, randomised controlled trial (patients are randomly assigned to one treatment arm or the other) evaluating two treatment strategies (sacituzumab govitecan and trastuzumab deruxtecan in an alternative schema or sacituzumab govitecan alone) in patients with locally advanced or metastatic triple-negative breast cancer. The goal is to answer the question: Does alternating sacituzumab goveitecan (SG) and trastuzumab deruxtecan (T-DXd) improve survival in patients with HER2-low metastatic triple-negative breast cancer compared to continuing treatment with SG alone?
Patients with locally advanced or metastatic triple-negative breast cancer (mTNBC) have poor survival outcomes Among mTNBC, about 40% of tumors have a low expression of HER2 (HER2-low; defined as IHC 2+/ISH or IHC 1+). Two antibody-drug conjugates (ADCs) have been approved for HER2-low mTNBC: sacituzumab govitecan (SG) and trastuzumab deruxtecan (T-DXd) that target TROP2 and HER2 at the tumor cell surface, respectively. Each of these ADCs, used as monotherapy, outperformed conventional chemotherapy according to the ASCENT and DESTINY-Breast 04 trials and thereby have become the new second or third line standard of care for HER2-low mTNBC. However, as with other types of treatments, resistance is inescapable mostly due to intra-tumor heterogeneity. In the case of ADCs, resistance mechanisms involve changes in tumor antigen expression, ADC intracellular uptake and processing, and efflux of the ADC cytotoxic payload. Consequently, SG and T-DXd are used sequentially after progression even though the most effective sequence has so far been scarcely investigated and remains to be established The ASCENT trial was designed to compare the efficacy of SG with chemotherapy in patients with mTNBC and reported significantly greater progression-free and overall survival compared with the physician's choice of chemotherapy. On the other hand, the DESTINY-Breast-04 compared the efficacy of T-DXd with chemotherapy but included just 63 patients with HER2-low mTNBC. Despite a significantly longer progression-free and overall survival were observed compared with the physician's choice of chemotherapy the efficacy analysis of T-DXd in this subpopulation was not a prespecified endpoint of the trial. Even though, collectively these results have contributed to a treatment paradigm shift for mTNBC, the superiority to chemotherapy can only be formally claimed for SG in mTNBC patients and for T-DXd in HER2-low metastatic breast cancer patients We hypothesize that an upfront alternating SG and T-DXd regimen would have a greater antitumor effect compared with their prescription at progression while limiting the emergence of drug resistance. Hence, the ALTER trial aims to compare the efficacy and safety of an upfront alternating SG and T-DXd regimen with SG alone in HER2-low mTNBC patients
Study Type
INTERVENTIONAL
Allocation
RANDOMIZED
Purpose
TREATMENT
Masking
NONE
Enrollment
260
Sacituzumab govitecan is administered intravenously at a dose of 10 mg/kg on Day 1 and Day 8 of each 3-week cycle. In this study, patients receive two cycles of sacituzumab govitecan followed by two cycles of trastuzumab deruxtecan, alternating throughout the study. Trastuzumab deruxtecan is administered intravenously at a dose of 5.4 mg/kg on Day 1 of each 3-week cycle. In this study, patients receive two cycles of trastuzumab deruxtecan followed by two cycles of sacituzumab govitecan, alternating throughout the study. Both Treatment are continued until disease progression as defined by RECIST 1.1, unacceptable toxicity, withdrawal of consent, or the end of the study.
institut Paoli calmette
Marseille, France
Gustave Roussy
Villejuif, France
Overall survival (OS)
The overall survival is the length of time from randomization that patients enrolled in the study are still alive
Time frame: From randomization to death from any cause, up to 4 years.
Clinical Benefit Rate (CBR)
Clinical Benefit Rate is defined as the percentage of patients with complete response (CR), partial response (PR), or stable disease (SD)for at least 24 weeks, as assessed by RECIST 1.1
Time frame: Time from randomization to disease progression, up to 4 years.
Objective response rate (ORR)
The objective response rate is defined as the percentage of patients with a complete response (CR) or a partial response (PR) as assessed by RECIST 1.1
Time frame: Time from randomization to disease progression, up to 4 years.
Progression-free survival (PFS),
The progression-free survival is the length of time during and after the treatment of a disease that a patient lives with the disease but it does not get worse.
Time frame: From randomization to disease progression or death, up to 4 years.
Quality-Adjusted progression free survival (QA-PFS)
Quality-Adjusted progression free survival is calculated as the product of the progression free survival function and the overall health utility index EQ-5D-5L.
Time frame: From randomization to disease progression or death, up to 4 years.
Incidence of Treatment-Emergent Adverse Events (TEAEs)
Frequency and severity of treatment-emergent adverse events (TEAEs), serious adverse events (SAEs), and adverse events of special interest (AESIs), graded per NCI-CTCAE v5.0. The proportion of patients with treatment discontinuations, interruptions, or dose reductions due to adverse events will also be reported
Time frame: From first dose through 30 days after the last dose of study treatment
Quality of Life questionnaire - EORTC QLQ-C30
Mean change from baseline in the EORTC QLQ-C30 Global Health Status/Quality of Life (GHS/QoL) score at Week 24. The QLQ-C30 is a 30-item questionnaire scored according to the EORTC scoring manual on 0-100 scales; higher GHS/QoL scores indicate better quality of life.
Time frame: Baseline to Week 24
Alexandre TASSIN DE NONNEVILLE
CONTACT
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