A Phase III, Open-label, Randomised Study of Neoadjuvant Datopotamab Deruxtecan (Dato-DXd) Plus Durvalumab Followed by Adjuvant Durvalumab With or Without Chemotherapy Versus Neoadjuvant Pembrolizumab Plus Chemotherapy Followed by Adjuvant Pembrolizumab With or Without Chemotherapy for the Treatment of Adult Patients With Previously Untreated Triple-Negative or Hormone Receptor-low/HER2-negative Breast Cancer (D926QC00001; TROPION-Breast04)
Trial Snapshot
- Phase
- Phase 3
- Status
- Active, not recruiting
- Sponsor
- AstraZeneca
- Enrollment
- 1,902
- Locations
- 284
- Primary Endpoint
- Event-free survival (EFS) in the experimental vs control arms
Study Overview
Brief Summary
This is a Phase III, 2-arm, randomised, open-label, multicentre, global study assessing the efficacy and safety of neoadjuvant Dato-DXd plus durvalumab followed by adjuvant durvalumab with or without chemotherapy compared with neoadjuvant pembrolizumab plus chemotherapy followed by adjuvant pembrolizumab with or without chemotherapy in participants with previously untreated TNBC or hormone receptor-low/HER2-negative breast cancer.
Detailed Description
The primary objectives of the study are to demonstrate superiority of neoadjuvant Dato-DXd plus durvalumab followed by adjuvant durvalumab with or without chemotherapy relative to neoadjuvant pembrolizumab plus chemotherapy followed by adjuvant pembrolizumab with or without chemotherapy in participants with previously untreated TNBC or hormone receptor-low/HER2-negative breast cancer, by investigator assessment of EFS.
Study Design
- Study Type
- Interventional
- Allocation
- Randomized
- Intervention Model
- Parallel
- Primary Purpose
- Treatment
- Masking
- None
Eligibility Criteria
- Ages
- 18 Years to — (Adult, Older Adult)
- Sex
- All
- Accepts Healthy Volunteers
- No
Inclusion Criteria
- •Participant must be ≥ 18 years, at the time of signing the ICF.
- •Histologically confirmed Stage II or III unilateral or bilateral primary invasive TNBC or hormone receptor-low/HER2-negative breast cancer
- •ECOG PS of 0 or 1
- •Provision of acceptable tumor sample
- •Adequate bone marrow reserve and organ function
- •Contraceptive use by males or females should be consistent with local regulations regarding the methods of contraception for those participating in clinical studies and aligned with protocol requirements.
Exclusion Criteria
- •History of any prior invasive breast malignancy
- •History of another primary malignancy except for malignancy treated with curative intent with no known active disease within 5 years before randomization.
- •active or prior documented autoimmune or inflammatory disorders.
- •Evidence of distant disease.
- •Clinically significant corneal disease.
- •Has active or uncontrolled hepatitis B or C virus infection.
- •Known HIV infection that is not well controlled.
- •Uncontrolled infection requiring i.v. antibiotics, antivirals or antifungals; suspected infections; or inability to rule out infections.
- •Known to have active tuberculosis infection
- •Mean resting corrected QTcF interval > 470 ms obtained from ECG
- •Uncontrolled or significant cardiac disease.
- •History of non-infectious ILD/pneumonitis
- •Has severe pulmonary function compromise
- •Any prior or concurrent surgery, radiotherapy or systemic anticancer therapy for TNBC or hormone receptor-low/HER2-negative breast cancer
- •For females only: is pregnant (confirmed with positive serum pregnancy test) or breastfeeding, or planning to become pregnant.
- •Female participants should refrain from breastfeeding from enrolment throughout the study and for at least 7 months after last dose of study intervention, or as dictated by local PI for SoC if longer.
- •Concurrent use of systemic hormone replacement therapy or oral hormonal contraception
Arms & Interventions
Dato-DXd plus durvalumab
Participants receive durvalumab every 3 weeks (Q3W) + Dato-DXd Q3W as neoadjuvant therapy prior to surgery; followed by 9 cycles of durvaluamb Q3W as adjuvant therapy post-surgery. Adjuvant chemotherapy may be given in combination with durvalumab only if participants have residual disease.
Olaparib may be given for participants with gBRCA-positive tumours and residual disease
Adjuvant chemotherapy may be one of these:
- Doxorubicin (Q3W) or epirubicin (Q3W) + cyclophosphamide (Q3W) for 4 cycles (12 weeks) followed by paclitaxel (weekly) and carboplatin (weekly or Q3W) for 4 cycles (12 weeks);
- Doxorubicin (Q3W) or epirubicin (Q3W) + cyclophosphamide (Q3W) for 4 cycles (12 weeks) followed by paclitaxel (weekly) for 4 cycles (12 weeks);
- Carboplatin (weekly or Q3W) + paclitaxel (weekly) for 4 cycles (12 weeks);
- Capecitabine (Q3W) for 8 cycles.
Intervention: Dato-DXd (Drug)
Dato-DXd plus durvalumab
Participants receive durvalumab every 3 weeks (Q3W) + Dato-DXd Q3W as neoadjuvant therapy prior to surgery; followed by 9 cycles of durvaluamb Q3W as adjuvant therapy post-surgery. Adjuvant chemotherapy may be given in combination with durvalumab only if participants have residual disease.
Olaparib may be given for participants with gBRCA-positive tumours and residual disease
Adjuvant chemotherapy may be one of these:
- Doxorubicin (Q3W) or epirubicin (Q3W) + cyclophosphamide (Q3W) for 4 cycles (12 weeks) followed by paclitaxel (weekly) and carboplatin (weekly or Q3W) for 4 cycles (12 weeks);
- Doxorubicin (Q3W) or epirubicin (Q3W) + cyclophosphamide (Q3W) for 4 cycles (12 weeks) followed by paclitaxel (weekly) for 4 cycles (12 weeks);
- Carboplatin (weekly or Q3W) + paclitaxel (weekly) for 4 cycles (12 weeks);
- Capecitabine (Q3W) for 8 cycles.
Intervention: Durvalumab (Drug)
Dato-DXd plus durvalumab
Participants receive durvalumab every 3 weeks (Q3W) + Dato-DXd Q3W as neoadjuvant therapy prior to surgery; followed by 9 cycles of durvaluamb Q3W as adjuvant therapy post-surgery. Adjuvant chemotherapy may be given in combination with durvalumab only if participants have residual disease.
Olaparib may be given for participants with gBRCA-positive tumours and residual disease
Adjuvant chemotherapy may be one of these:
- Doxorubicin (Q3W) or epirubicin (Q3W) + cyclophosphamide (Q3W) for 4 cycles (12 weeks) followed by paclitaxel (weekly) and carboplatin (weekly or Q3W) for 4 cycles (12 weeks);
- Doxorubicin (Q3W) or epirubicin (Q3W) + cyclophosphamide (Q3W) for 4 cycles (12 weeks) followed by paclitaxel (weekly) for 4 cycles (12 weeks);
- Carboplatin (weekly or Q3W) + paclitaxel (weekly) for 4 cycles (12 weeks);
- Capecitabine (Q3W) for 8 cycles.
Intervention: Doxorubicin (Drug)
Dato-DXd plus durvalumab
Participants receive durvalumab every 3 weeks (Q3W) + Dato-DXd Q3W as neoadjuvant therapy prior to surgery; followed by 9 cycles of durvaluamb Q3W as adjuvant therapy post-surgery. Adjuvant chemotherapy may be given in combination with durvalumab only if participants have residual disease.
Olaparib may be given for participants with gBRCA-positive tumours and residual disease
Adjuvant chemotherapy may be one of these:
- Doxorubicin (Q3W) or epirubicin (Q3W) + cyclophosphamide (Q3W) for 4 cycles (12 weeks) followed by paclitaxel (weekly) and carboplatin (weekly or Q3W) for 4 cycles (12 weeks);
- Doxorubicin (Q3W) or epirubicin (Q3W) + cyclophosphamide (Q3W) for 4 cycles (12 weeks) followed by paclitaxel (weekly) for 4 cycles (12 weeks);
- Carboplatin (weekly or Q3W) + paclitaxel (weekly) for 4 cycles (12 weeks);
- Capecitabine (Q3W) for 8 cycles.
Intervention: Epirubicin (Drug)
Dato-DXd plus durvalumab
Participants receive durvalumab every 3 weeks (Q3W) + Dato-DXd Q3W as neoadjuvant therapy prior to surgery; followed by 9 cycles of durvaluamb Q3W as adjuvant therapy post-surgery. Adjuvant chemotherapy may be given in combination with durvalumab only if participants have residual disease.
Olaparib may be given for participants with gBRCA-positive tumours and residual disease
Adjuvant chemotherapy may be one of these:
- Doxorubicin (Q3W) or epirubicin (Q3W) + cyclophosphamide (Q3W) for 4 cycles (12 weeks) followed by paclitaxel (weekly) and carboplatin (weekly or Q3W) for 4 cycles (12 weeks);
- Doxorubicin (Q3W) or epirubicin (Q3W) + cyclophosphamide (Q3W) for 4 cycles (12 weeks) followed by paclitaxel (weekly) for 4 cycles (12 weeks);
- Carboplatin (weekly or Q3W) + paclitaxel (weekly) for 4 cycles (12 weeks);
- Capecitabine (Q3W) for 8 cycles.
Intervention: Paclitaxel (Drug)
Dato-DXd plus durvalumab
Participants receive durvalumab every 3 weeks (Q3W) + Dato-DXd Q3W as neoadjuvant therapy prior to surgery; followed by 9 cycles of durvaluamb Q3W as adjuvant therapy post-surgery. Adjuvant chemotherapy may be given in combination with durvalumab only if participants have residual disease.
Olaparib may be given for participants with gBRCA-positive tumours and residual disease
Adjuvant chemotherapy may be one of these:
- Doxorubicin (Q3W) or epirubicin (Q3W) + cyclophosphamide (Q3W) for 4 cycles (12 weeks) followed by paclitaxel (weekly) and carboplatin (weekly or Q3W) for 4 cycles (12 weeks);
- Doxorubicin (Q3W) or epirubicin (Q3W) + cyclophosphamide (Q3W) for 4 cycles (12 weeks) followed by paclitaxel (weekly) for 4 cycles (12 weeks);
- Carboplatin (weekly or Q3W) + paclitaxel (weekly) for 4 cycles (12 weeks);
- Capecitabine (Q3W) for 8 cycles.
Intervention: Carboplatin (Drug)
Dato-DXd plus durvalumab
Participants receive durvalumab every 3 weeks (Q3W) + Dato-DXd Q3W as neoadjuvant therapy prior to surgery; followed by 9 cycles of durvaluamb Q3W as adjuvant therapy post-surgery. Adjuvant chemotherapy may be given in combination with durvalumab only if participants have residual disease.
Olaparib may be given for participants with gBRCA-positive tumours and residual disease
Adjuvant chemotherapy may be one of these:
- Doxorubicin (Q3W) or epirubicin (Q3W) + cyclophosphamide (Q3W) for 4 cycles (12 weeks) followed by paclitaxel (weekly) and carboplatin (weekly or Q3W) for 4 cycles (12 weeks);
- Doxorubicin (Q3W) or epirubicin (Q3W) + cyclophosphamide (Q3W) for 4 cycles (12 weeks) followed by paclitaxel (weekly) for 4 cycles (12 weeks);
- Carboplatin (weekly or Q3W) + paclitaxel (weekly) for 4 cycles (12 weeks);
- Capecitabine (Q3W) for 8 cycles.
Intervention: Capecitabine (Drug)
Pembrolizumab plus chemotherapy
Participants receive pembrolizumab every 3 weeks (Q3W) + paclitaxel weekly + carboplatin (weekly or Q3W) x 4 cycles, followed by pembrolizumab Q3W + (doxorubicin OR epirubicin) + cyclophosphamide Q3W x 4 cycles as neoadjuvant therapy prior to surgery; followed by 9 cycles of pembrolizumab Q3W as adjuvant therapy post-surgery. Adjuvant capecitabine (Q3W) for 8 cycles may be given in combination with pembrolizumab only if participants have residual disease. Olaparib may be given for participants with gBRCA-positive tumours and residual disease.
Intervention: Pembrolizumab (Drug)
Pembrolizumab plus chemotherapy
Participants receive pembrolizumab every 3 weeks (Q3W) + paclitaxel weekly + carboplatin (weekly or Q3W) x 4 cycles, followed by pembrolizumab Q3W + (doxorubicin OR epirubicin) + cyclophosphamide Q3W x 4 cycles as neoadjuvant therapy prior to surgery; followed by 9 cycles of pembrolizumab Q3W as adjuvant therapy post-surgery. Adjuvant capecitabine (Q3W) for 8 cycles may be given in combination with pembrolizumab only if participants have residual disease. Olaparib may be given for participants with gBRCA-positive tumours and residual disease.
Intervention: Doxorubicin (Drug)
Pembrolizumab plus chemotherapy
Participants receive pembrolizumab every 3 weeks (Q3W) + paclitaxel weekly + carboplatin (weekly or Q3W) x 4 cycles, followed by pembrolizumab Q3W + (doxorubicin OR epirubicin) + cyclophosphamide Q3W x 4 cycles as neoadjuvant therapy prior to surgery; followed by 9 cycles of pembrolizumab Q3W as adjuvant therapy post-surgery. Adjuvant capecitabine (Q3W) for 8 cycles may be given in combination with pembrolizumab only if participants have residual disease. Olaparib may be given for participants with gBRCA-positive tumours and residual disease.
Intervention: Cyclophosphamide (Drug)
Dato-DXd plus durvalumab
Participants receive durvalumab every 3 weeks (Q3W) + Dato-DXd Q3W as neoadjuvant therapy prior to surgery; followed by 9 cycles of durvaluamb Q3W as adjuvant therapy post-surgery. Adjuvant chemotherapy may be given in combination with durvalumab only if participants have residual disease.
Olaparib may be given for participants with gBRCA-positive tumours and residual disease
Adjuvant chemotherapy may be one of these:
- Doxorubicin (Q3W) or epirubicin (Q3W) + cyclophosphamide (Q3W) for 4 cycles (12 weeks) followed by paclitaxel (weekly) and carboplatin (weekly or Q3W) for 4 cycles (12 weeks);
- Doxorubicin (Q3W) or epirubicin (Q3W) + cyclophosphamide (Q3W) for 4 cycles (12 weeks) followed by paclitaxel (weekly) for 4 cycles (12 weeks);
- Carboplatin (weekly or Q3W) + paclitaxel (weekly) for 4 cycles (12 weeks);
- Capecitabine (Q3W) for 8 cycles.
Intervention: Olaparib (Drug)
Pembrolizumab plus chemotherapy
Participants receive pembrolizumab every 3 weeks (Q3W) + paclitaxel weekly + carboplatin (weekly or Q3W) x 4 cycles, followed by pembrolizumab Q3W + (doxorubicin OR epirubicin) + cyclophosphamide Q3W x 4 cycles as neoadjuvant therapy prior to surgery; followed by 9 cycles of pembrolizumab Q3W as adjuvant therapy post-surgery. Adjuvant capecitabine (Q3W) for 8 cycles may be given in combination with pembrolizumab only if participants have residual disease. Olaparib may be given for participants with gBRCA-positive tumours and residual disease.
Intervention: Olaparib (Drug)
Dato-DXd plus durvalumab
Participants receive durvalumab every 3 weeks (Q3W) + Dato-DXd Q3W as neoadjuvant therapy prior to surgery; followed by 9 cycles of durvaluamb Q3W as adjuvant therapy post-surgery. Adjuvant chemotherapy may be given in combination with durvalumab only if participants have residual disease.
Olaparib may be given for participants with gBRCA-positive tumours and residual disease
Adjuvant chemotherapy may be one of these:
- Doxorubicin (Q3W) or epirubicin (Q3W) + cyclophosphamide (Q3W) for 4 cycles (12 weeks) followed by paclitaxel (weekly) and carboplatin (weekly or Q3W) for 4 cycles (12 weeks);
- Doxorubicin (Q3W) or epirubicin (Q3W) + cyclophosphamide (Q3W) for 4 cycles (12 weeks) followed by paclitaxel (weekly) for 4 cycles (12 weeks);
- Carboplatin (weekly or Q3W) + paclitaxel (weekly) for 4 cycles (12 weeks);
- Capecitabine (Q3W) for 8 cycles.
Intervention: Cyclophosphamide (Drug)
Pembrolizumab plus chemotherapy
Participants receive pembrolizumab every 3 weeks (Q3W) + paclitaxel weekly + carboplatin (weekly or Q3W) x 4 cycles, followed by pembrolizumab Q3W + (doxorubicin OR epirubicin) + cyclophosphamide Q3W x 4 cycles as neoadjuvant therapy prior to surgery; followed by 9 cycles of pembrolizumab Q3W as adjuvant therapy post-surgery. Adjuvant capecitabine (Q3W) for 8 cycles may be given in combination with pembrolizumab only if participants have residual disease. Olaparib may be given for participants with gBRCA-positive tumours and residual disease.
Intervention: Epirubicin (Drug)
Pembrolizumab plus chemotherapy
Participants receive pembrolizumab every 3 weeks (Q3W) + paclitaxel weekly + carboplatin (weekly or Q3W) x 4 cycles, followed by pembrolizumab Q3W + (doxorubicin OR epirubicin) + cyclophosphamide Q3W x 4 cycles as neoadjuvant therapy prior to surgery; followed by 9 cycles of pembrolizumab Q3W as adjuvant therapy post-surgery. Adjuvant capecitabine (Q3W) for 8 cycles may be given in combination with pembrolizumab only if participants have residual disease. Olaparib may be given for participants with gBRCA-positive tumours and residual disease.
Intervention: Paclitaxel (Drug)
Pembrolizumab plus chemotherapy
Participants receive pembrolizumab every 3 weeks (Q3W) + paclitaxel weekly + carboplatin (weekly or Q3W) x 4 cycles, followed by pembrolizumab Q3W + (doxorubicin OR epirubicin) + cyclophosphamide Q3W x 4 cycles as neoadjuvant therapy prior to surgery; followed by 9 cycles of pembrolizumab Q3W as adjuvant therapy post-surgery. Adjuvant capecitabine (Q3W) for 8 cycles may be given in combination with pembrolizumab only if participants have residual disease. Olaparib may be given for participants with gBRCA-positive tumours and residual disease.
Intervention: Carboplatin (Drug)
Pembrolizumab plus chemotherapy
Participants receive pembrolizumab every 3 weeks (Q3W) + paclitaxel weekly + carboplatin (weekly or Q3W) x 4 cycles, followed by pembrolizumab Q3W + (doxorubicin OR epirubicin) + cyclophosphamide Q3W x 4 cycles as neoadjuvant therapy prior to surgery; followed by 9 cycles of pembrolizumab Q3W as adjuvant therapy post-surgery. Adjuvant capecitabine (Q3W) for 8 cycles may be given in combination with pembrolizumab only if participants have residual disease. Olaparib may be given for participants with gBRCA-positive tumours and residual disease.
Intervention: Capecitabine (Drug)
Outcomes
Primary Outcomes
Event-free survival (EFS) in the experimental vs control arms
Time Frame: Date of randomization to date of the EFS event, up to 93 months after the first subject randomized
EFS is defined as the time from the date of randomisation until the date of the first occurrence of any of the following events: disease progression precluding surgery, disease recurrence (local, regional, distant, or contralateral), second primary invasive cancer (other than squamous or basal cell skin cancer), or relapse from prior malignancy, or death by any cause (in the absence of recurrence). Non-invasive breast cancers and positive margins in the surgical sample do not count as an event for EFS. EFS will be determined by the investigator based on all available clinical assessments. The analysis will include all randomised participants, as randomised, regardless of whether the participant withdraws from randomised therapy or receives another anticancer therapy. The measure of interest will be the Hazard Ratio of EFS.
Secondary Outcomes
- Participant-reported physical function in the experimental vs. control arms(From Cycle 1 Day 1 of neoadjuvant treatment until pre-surgery safety FU visit (for approximately 24 weeks) or EOT - whichever occurs first, and then from Cycle 1 Day 1 of adjuvant treatment until EOT (for approximately 27 weeks).)
- Participant-reported fatigue in the experimental vs. control arms(From Cycle 1 Day 1 of neoadjuvant treatment until pre-surgery safety FU visit (for approximately 24 weeks) or EOT - whichever occurs first, and then from Cycle 1 Day 1 of adjuvant treatment until EOT (for approximately 27 weeks).)
- Participant-reported Global health status/Quality of life (GHS/QoL)in the experimental vs. control arms(From Cycle 1 Day 1 of neoadjuvant treatment until pre-surgery safety FU visit (for approximately 24 weeks) or EOT - whichever occurs first, and then from Cycle 1 Day 1 of adjuvant treatment until EOT (for approximately 27 weeks).)
- Pharmacokinetics of Dato-DXd (in combination with durvalumab)(Day 1 of cycles 1,2,4,8 (Each cycle is 21 days) and at pre-surgery safety follow up visit)
- Immunogenicity of Dato-DXd (in combination with durvalumab)(Day 1 of cycles 1,2,4,8 (Each cycle is 21 days) and at pre-surgery safety follow up visit)
- Safety of Dato-DXd (in combination with durvalumab)(Randomization to final safety follow-up visit, either 90 days after last dose of study intervention for those who complete planned study intervention or 90 days after date of discontinuation for those who discontinue study intervention prematurely)
- Pathologic Complete Response (pCR) in the experimental vs control arms(At the time of definitive surgery)
- Overall Survival (OS) in the experimental vs control arms(Date of randomization to date of death due to any cause, up to 108 months after the first subject randomized)
- Distant disease-free survival (DDFS) in the experimental vs control arms(Date of randomization to date of the DDFS event, up to 93 months after the first subject randomized)
- Participant-reported breast and arm symptoms in the experimental vs. control arms(From Cycle 1 Day 1 of neoadjuvant treatment until pre-surgery safety FU visit (for approximately 24 weeks) or EOT - whichever occurs first.)
- Participant-reported physical function in the experimental vs. control arms(From Cycle 1 Day 1 of neoadjuvant treatment until pre-surgery safety FU visit (for approximately 24 weeks) or EOT - whichever occurs first, and then from Cycle 1 Day 1 of adjuvant treatment until EOT (for approximately 27 weeks).)
- Participant-reported fatigue in the experimental vs. control arms(From Cycle 1 Day 1 of neoadjuvant treatment until pre-surgery safety FU visit (for approximately 24 weeks) or EOT - whichever occurs first, and then from Cycle 1 Day 1 of adjuvant treatment until EOT (for approximately 27 weeks).)
- Participant-reported Global health status/Quality of life (GHS/QoL)in the experimental vs. control arms(From Cycle 1 Day 1 of neoadjuvant treatment until pre-surgery safety FU visit (for approximately 24 weeks) or EOT - whichever occurs first, and then from Cycle 1 Day 1 of adjuvant treatment until EOT (for approximately 27 weeks).)
- Pharmacokinetics of Dato-DXd (in combination with durvalumab)(Day 1 of cycles 1,2,4,8 (Each cycle is 21 days) and at pre-surgery safety follow up visit)
- Immunogenicity of Dato-DXd (in combination with durvalumab)(Day 1 of cycles 1,2,4,8 (Each cycle is 21 days) and at pre-surgery safety follow up visit)
- Safety of Dato-DXd (in combination with durvalumab)(Randomization to final safety follow-up visit, either 90 days after last dose of study intervention for those who complete planned study intervention or 90 days after date of discontinuation for those who discontinue study intervention prematurely)