A Phase III Study of Dato-DXd With or Without Durvalumab Compared With Investigator's Choice of Chemotherapy in Combination With Pembrolizumab in Patients With PD-L1 Positive Locally Recurrent Inoperable or Metastatic Triple-negative Breast Cancer

Study Overview
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Brief Summary
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This is a Phase III, randomised, open-label, 3-arm, multicentre, international study assessing the efficacy and safety of Dato-DXd with or without durvalumab compared with investigator's choice chemotherapy in combination with pembrolizumab in participants with PD-L1 positive locally recurrent inoperable or metastatic TNBC.

Detailed Description
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The primary objective of the study is to demonstrate superiority of Dato-DXd + durvalumab relative to ICC + pembrolizumab by assessment of PFS as assessed by BICR in participants with PD-L1 positive locally recurrent inoperable or metastatic TNBC. The study will be stratified based on geographic location (US/Canada/Europe vs. Dato-DXd monotherapy enrolling countries vs. rest of world), disease-free interval (DFI) history (de novo vs. prior DFI 6 to 12 months vs. prior DFI > 12 months), and prior PD-1/PD-L1 treatment for early stage TNBC (yes vs. no). This study aims to see if Dato-DXd with durvalumab allows patients to live longer without their breast cancer getting worse, or simply to live longer, compared to patients receiving standard of care chemotherapy and pembrolizumab. This study is also looking to see how the treatment and the breast cancer affects patients' quality of life.

Official Title
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A Phase III, Open-label, Randomised Study of Datopotamab Deruxtecan (Dato-DXd) With or Without Durvalumab Compared With Investigator's Choice of Chemotherapy (Paclitaxel, Nab-paclitaxel or Gemcitabine + Carboplatin) in Combination With Pembrolizumab in Patients With PD-L1 Positive Locally Recurrent Inoperable or Metastatic Triple-negative Breast Cancer (TROPION-Breast05)

Conditions
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Breast Cancer

Intervention / Treatment
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* Drug: Dato-DXd
* Drug: Durvalumab
* Drug: Paclitaxel
* Drug: Nab-paclitaxel
* Drug: Gemcitabine
* Drug: Carboplatin
* Drug: Pembrolizumab


Participation Criteria
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Eligibility Criteria
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Key Inclusion Criteria Histologically or cytologically documented locally recurrent inoperable, which cannot be treated with curative intent, or metastatic TNBC, as defined by the ASCO-CAP guidelines. ECOG PS 0 or 1. All participants must provide a FFPE metastatic or locally recurrent inoperable tumour sample. PD-L1 positive TNBC based on results from an appropriately validated investigational PD-L1 (22C3) assay (CPS ≥ 10) from a sponsor designated central laboratory. No prior chemotherapy or targeted systemic anti-cancer therapy for metastatic or locally recurrent inoperable breast cancer. - Patients with recurrent disease will be eligible if they have completed treatment for Stage I-III breast cancer, if indicated, and ≥6 months have elapsed between completion of treatment with curative intent and the first documented recurrence. Eligible for one of the chemotherapy options listed as ICC (paclitaxel, nab-paclitaxel, or gemcitabine + carboplatin). Measurable disease as per RECIST 1.1. Adequate bone marrow reserve and organ function. Male and female participants of childbearing potential must agree to use protocol-specified method(s) of contraception. Key Exclusion Criteria As judged by investigator, severe or uncontrolled medical conditions including systemic diseases, history of allogeneic organ transplant and active bleeding diseases, ongoing or active infection, significant cardiac or psychological conditions. History of another primary malignancy except for malignancy treated with curative intent with no known active disease within 3 years before Cycle 1 Day 1 and of low potential risk for recurrence. Neoplastic spinal cord compression or active brain metastases, leptomeningeal carcinomatosis or history of leptomeningeal carcinomatosis. - Participants with treated clinically inactive brain metastases that are no longer symptomatic, who require no treatment with corticosteroids or anticonvulsants, may be included in the study if they have recovered from acute toxic effects of radiotherapy. Uncontrolled infection requiring IV antibiotics, antivirals or antifungals. Active or uncontrolled hepatitis B or C virus infection. Known HIV infection that is not well controlled. Uncontrolled or significant cardiac disease. History of non-infectious ILD/pneumonitis (including radiation pneumonitis) that required steroids, current ILD/pneumonitis, or suspected ILD/pneumonitis that cannot be ruled out by imaging at screening. Severe pulmonary function compromise. Clinically significant corneal disease. Active or prior documented autoimmune or inflammatory disorders. Prior exposure to any treatment including ADC containing a chemotherapeutic agent targeting topoisomerase I and TROP2-targeted therapy. Any concurrent anti-cancer treatment. Participants with a known severe hypersensitivity to PD-1/PD-L1 inhibitors or Dato-DXd. Currently pregnant (confirmed with positive pregnancy test), breastfeeding or planning to become pregnant.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: Participants will be randomised either 1:1 to Arm 1 (Dato-DXd + durvalumab) and Arm 2 (ICC + pembrolizumab), or in selected countries, 1:1:1 to Arms 1, 2 and 3 (Dato-DXd monotherapy). Once approximately 75 participants are randomised to Arm 3, this cohort will close, and all countries will continue with a 1:1 randomisation strategy for Arms 1 and 2.
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Dato-DXd + durvalumab<br>Arm 1: Dato-DXd + durvalumab | Drug: Dato-DXd<br>* Provided in 100mg vials. IV infusion. Experimental drug.<br>* Other names: Datopotamab deruxtecan (Dato-DXd, DS-1062a);Drug: Durvalumab<br>* Provided in 500mg vials. IV infusion. Experimental drug.<br>* Other names: MEDI4736;|
| Active Comparator: Investigator's Choice of Chemotherapy (ICC) in combination with pembrolizumab<br>Arm 2: Investigator's Choice of Chemotherapy (ICC) in combination with pembrolizumab (paclitaxel, nab-paclitaxel, or gemcitabine + carboplatin) | Drug: Paclitaxel<br>* IV infusion. Active comparator.<br>Drug: Nab-paclitaxel<br>* IV infusion. Active comparator.<br>Drug: Gemcitabine<br>* IV infusion. Active comparator.<br>Drug: Carboplatin<br>* IV infusion. Active comparator.<br>Drug: Pembrolizumab<br>* IV infusion. Active comparator.<br>|
| Experimental: Dato-DXd<br>Arm 3: Dato-DXd | Drug: Dato-DXd<br>* Provided in 100mg vials. IV infusion. Experimental drug.<br>* Other names: Datopotamab deruxtecan (Dato-DXd, DS-1062a);|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Progression Free Survival (PFS) | PFS is defined as time from randomisation until progression per RECIST 1.1 as assessed by BICR, or death due to any cause. The comparison will include all randomised participants, as randomised, regardless of whether the participant withdraws from randomised therapy, receives another anticancer therapy or clinically progresses prior to RECIST 1.1 progression. However, if the participant progresses or dies immediately after 2 or more consecutive missed visits, the participant will be censored at the time of the latest evaluable assessment prior to the 2 missed visits. The measure of interest is the HR of PFS. | From randomisation until progression per RECIST 1.1 as assessed by BICR, or death due to any cause (anticipated to be up to 33 months). | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall Survival (OS) | OS is defined as the time from randomisation until the date of death due to any cause. | From randomisation until the date of death due to any cause (anticipated to be up to 64 months). | 
| Objective Response Rate (ORR) | ORR is defined as the proportion of participants who have a CR or PR, as determined by the BICR/investigator assessment, per RECIST 1.1. | From randomisation up until progression (anticipated to be up to 33 months). | 
| Duration of Response (DoR) | DoR is defined as the time from the date of first documented response until date of documented progression per RECIST 1.1, as assessed by BICR/investigator assessment or death due to any cause. | From the date of first documented response until date of documented progression per RECIST 1.1, as assessed by BICR/investigator assessment or death due to any cause (anticipated to be up to 33 months). | 
| Progression-Free Survival (PFS) by Investigator assessment | PFS is defined as time from randomisation until progression per RECIST 1.1 as assessed by investigator, or death due to any cause. | From randomisation until progression per RECIST 1.1 as assessed by the investigator, or death due to any cause (anticipated to be up to 33 months). | 
| Clinical Benefit Rate (CBR) at 24 weeks | CBR at 24 weeks is defined as the percentage of participants who have a CR or PR or who have SD, per RECIST 1.1, as assessed by BICR/per investigator assessment and derived from the raw tumour data for at least 23 weeks after randomisation. | From randomisation up until progression, or the last evaluable assessment in the absence of progression (anticipated to be up to 33 months). | 
| Time to deterioration (TTD) in breast and arm symptoms in participants treated with Dato-DXd + durvalumab compared with ICC + pembrolizumab | TTD in breast symptoms and arm symptoms as measured by the arm symptoms scale from EORTC IL116 TTD is defined as time from the date of randomisation to the date of deterioration. Deterioration is defined as change from baseline that reaches a clinically meaningful deterioration threshold. | From the date of randomisation to the date of deterioration (from randomization to 18 weeks post-progression). | 
| Time to deterioration (TTD) in pain in participants treated with Dato-DXd + durvalumab compared with ICC + pembrolizumab | TTD in pain as measured by the EORTC IL199. | Time from the date of randomisation to the date of deterioration (from randomization to 18 weeks post-progression). | 
| Time to deterioration (TTD) in physical functioning in participants treated with Dato-DXd + durvalumab compared with ICC + pembrolizumab | TTD in physical function as measured by the PROMIS Short Form v2.0 - Physical Function 8c. | From the date of randomisation to the date of deterioration (from randomization to 18 weeks post-progression). | 
| Time to deterioration (TTD) in GHS/QoL in participants treated with Dato-DXd + durvalumab compared with ICC + pembrolizumab | TTD in GHS/QoL as measured by the GHS/QoL scale from EORTC IL172. | From the date of randomisation to the date of deterioration (from randomization to 18 weeks post-progression). | 
| Time to First Subsequent Therapy (TFST) | TFST is defined as the time from randomisation until the start date of the first subsequent anticancer therapy after discontinuation of randomised treatment, or death due to any cause. | From randomisation until the start date of the first subsequent anticancer therapy after discontinuation of randomised treatment, or death due to any cause (anticipated to be up to 64 months). | 
| Time to Second Subsequent Therapy (TSST) | TSST is defined as the time from randomisation until the start date of the second subsequent anticancer therapy after discontinuation of first subsequent treatment, or death due to any cause. | From randomisation until the start date of the second subsequent anti cancer therapy after discontinuation of first subsequent treatment, or death due to any cause (anticipated to be up to 64 months). | 
| Progression Free Survival 2 (PFS2) | PFS2 will be defined as the time from the randomisation to the earliest progression event (following the initial progression), subsequent to first subsequent therapy, or death. The date of second progression will be recorded by the investigator in the eCRF and defined according to local standard clinical practice based on radiological or clinical progression. | From the randomisation to the earliest of the progression event (following the initial progression), subsequent to first subsequent therapy, or death (anticipated to be up to 64 months). | 
| Pharmacokinetics of Dato-DXd in combination with durvalumab | Concentration of Dato-DXd, total anti-TROP2 antibody, and DXd (payload) in plasma. | From first dose to end of treatment (anticipated to be up to 33 months). | 
| Immunogenicity of Dato-DXd in combination with durvalumab | Presence of antidrug antibodies for Dato-DXd (confirmatory results: positive or negative, titres). | From first dose to end of treatment safety follow-up (anticipated to be up to 33 months). | 
| Safety and tolerability of Dato-DXd + durvalumab as compared with ICC + pembrolizumab | Safety and tolerability will be evaluated in the safety population in terms of AEs. | From first dose to end of treatment safety follow-up (anticipated to be up to 33 months). | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Breast Cancer, Triple-negative, Metastatic, Inoperable, Datopotamab deruxtecan, Dato-DXd, DS1062a, DS1062, Durvalumab, Paclitaxel, Nab-paclitaxel, Gemcitabine, Carboplatin, Pembrolizumab, PD-1/PD-L1 Therapy, TROP2, Antibody Drug Conjugate (ADC), Immune Checkpoint Inhibitor (ICI)