NSCLC
Conditions
Keywords
Advanced or Metastatic Non-Small Cell Lung Cancer (NSCLC), Datopotamab deruxtecan (Dato-DXd, Datroway), Durvalumab (Imfinzi), Carboplatin, Chemotherapy, Antibody-Drug Conjugate (ADC), Trophoblast cell surface protein 2 (TROP2)
Brief summary
This is a Phase III, randomized, open-label, multicenter, global study to compare the efficacy and safety of Datopotamab Deruxtecan (Dato-DXd) in combination with durvalumab and carboplatin compared with pembrolizumab in combination with histology-specific platinum-based chemotherapy as first-line treatment of adults with stage IIIB, IIIC, or IV NSCLC without actionable genomic alterations (including sensitizing EGFR mutations, and ALK and ROS1 rearrangements).
Detailed description
Participants with locally advanced or metastatic NSCLC without actionable tumor tissue genomic alterations and confirmed to meet all eligibility criteria will be randomized in a 1:1 ratio to Dato-DXd in combination with durvalumab and carboplatin versus pembrolizumab in combination with histology-specific platinum-based chemotherapy as first-line treatment. The primary objectives of the study are to demonstrate superiority of Dato-DXd in combination with durvalumab and carboplatin relative to pembrolizumab in combination with platinum-based chemotherapy by assessment of the following: 1. PFS by BICR in first-line treatment of participants with non-squamous TROP2 biomarker positive locally-advanced or metastatic NSCLC 2. OS in first-line treatment of participants with non-squamous TROP2 biomarker positive locally-advanced or metastatic NSCLC 3. PFS by BICR in first-line treatment of participants with non-squamous locally-advanced or metastatic NSCLC 4. OS in first-line treatment of participants with non-squamous locally-advanced or metastatic NSCLC
Interventions
DRUGDatopotamab deruxtecan
Intravenous (IV) infusion every 3 weeks (Q3W) on Day 1 of each 21-day cycle.
DRUGDurvalumab
Intravenous (IV) infusion every 3 weeks (Q3W) on Day 1 of each 21-day cycle.
DRUGCarboplatin
Intravenous (IV) infusion every 3 weeks on Day 1 of each 21-day cycle for up to 4 cycles.
DRUGPembrolizumab
Intravenous (IV) infusion every 3 weeks (Q3W) on Day 1 of each 21-day cycle for a maximum of 35 cycles or 2 years (whichever occurs first).
DRUGCisplatin
Intravenous (IV) infusion every 3 weeks on Day 1 of each 21-day cycle for up to 4 cycles.
DRUGPemetrexed
Intravenous (IV) infusion every 3 weeks on Day 1 of each 21-day cycle.
DRUGPaclitaxel
Intravenous (IV) infusion every 3 weeks on Day 1 of each 21-day cycle for up to 4 cycles.
Sponsors
AstraZeneca
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Masking description
None (Open Label)
Eligibility
Sex/Gender
ALL
Age
18 Years to 130 Years
Healthy volunteers
No
Inclusion criteria
Inclusion: * Participants ≥ 18 years at screening * Histologically or cytologically documented NSCLC that at the time of randomisation is Stage IIIB or IIIC disease not amenable to surgical resection or definitive chemoradiation or Stage IV metastatic disease * Lacks sensitising EGFR tumour tissue mutation and ALK and ROS1 rearrangements and has no documented tumour genomic alterations in NTRK, BRAF, RET, MET or other actionable driver oncogenes with approved and available therapies (actionable genomic alterations). Testing is not required for tumors with squamous histology, with exceptions. * ECOG PS of 0 or 1 * Archival tumour tissue * Has adequate bone marrow reserve and organ function within 7 days before randomization Exclusion: * Mixed small-cell lung cancer and NSCLC histology; sarcomatoid variant of NSCLC * History of another primary malignancy with exceptions * Persistent toxicities caused by previous anti-cancer therapy not yet improved to Grade ≤ 1 or baseline, with exceptions. * Spinal cord compression or clinically or radiologically active brain metastases * History of leptomeningeal carcinomatosis. * Known active or uncontrolled hepatitis B or C virus infection. * Uncontrolled or suspected infection requiring IV antibiotics, antivirals, or antifungals. * Clinically significant corneal disease * History of non-infectious ILD/pneumonitis that required steroids, has current ILD/pneumonitis, or has suspected ILD/pneumonitis that cannot be ruled out by imaging at screening.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Progression-Free Survival (PFS) by blinded independent central review (BICR) in the non-squamous TROP2 biomarker positive population | Approximately 3 years | PFS is defined as time from randomisation until progression per Response Evaluation Criteria in Solid Tumors, Version 1.1 (RECIST 1.1) as assessed by BICR, or death due to any cause. |
| Overall Survival (OS) in the non-squamous TROP2 biomarker positive population | Approximately 5 years | OS is defined as the time from randomisation until the date of death due to any cause. |
| PFS by BICR in the non-squamous population | Approximately 3 years | PFS is defined as time from randomisation until progression per RECIST 1.1 as assessed by BICR, or death due to any cause. |
| OS in the non-squamous population | Approximately 5 years | OS is defined as the time from randomisation until the date of death due to any cause. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| PFS by BICR in ITT and TROP2 biomarker-defined populations | Approximately 3 years | PFS is defined as time from randomisation until progression per RECIST 1.1 as assessed by BICR, or death due to any cause. |
| OS in ITT and TROP2 biomarker-defined populations | Approximately 5 years | OS is defined as the time from randomisation until the date of death due to any cause. |
| Objective Response Rate (ORR) in ITT, non-squamous and TROP2 biomarker-defined populations | Approximately 5 years | ORR is defined as the proportion of participants who have a confirmed Complete Response (CR) or confirmed Partial Response (PR), as determined by BICR per RECIST 1.1. |
| Duration of Response (DoR) in ITT, non-squamous and TROP2 biomarker-defined populations | Approximately 5 years | DoR is defined as the time from the date of first documented confirmed response until date of documented progression per RECIST 1.1, as assessed by BICR and investigator clinical assessment or death due to any cause. |
| PFS by investigator in ITT, non-squamous and TROP2 biomarker-defined populations | Approximately 3 years | PFS is defined as time from randomisation until progression per RECIST 1.1 as assessed by investigator clinical assessment, or death due to any cause. |
| Pharmacokinetics of Dato-DXd when combined with durvalumab and carboplatin. | Approximately 5 years | Concentration of Dato-DXd, total anti-TROP2 antibody, and DXd (payload deruxtecan) in plasma and pharmacokinetic (PK) parameters (such as peak and trough concentrations, as data allow; sparse sampling). |
| Anti-Drug Antibody (ADA) for Dato-DXd | Approximately 5 years | The immunogenicity of Dato-DXd when combined with durvalumab and carboplatin. |
| Time to Second Progression or Death (PFS2) in ITT, non-squamous and TROP2 biomarker-defined populations | Approximately 5 years | PFS2 is defined as the time from randomisation to the earliest of the progression events (following the initial progression), subsequent to first subsequent therapy, or death. |
| Clinical Outcome Assessments in ITT, non-squamous and TROP2 biomarker-defined populations | Approximately 5 years | Clinical Outcome Assessments, such as TTD in pulmonary symptoms (dyspnoea, cough and chest pain) as measured by the NSCLC-SAQ, and TTD in physical functioning as measured by PROMIS Physical Function short form 8c |
Countries
Austria, Brazil, Bulgaria, Canada, China, France, Germany, Greece, Hungary, India, Italy, Japan, Mexico, Peru, Poland, South Korea, Spain, Sweden, Taiwan, Turkey (Türkiye), United Kingdom, United States, Vietnam
Contacts
STUDY_CHAIRCharu Aggarwal
Perelman Center for Advanced Medicine
Outcome results
None listed