Study of Datopotamab Deruxtecan (Dato-DXd) in Combination With Durvalumab and Carboplatin for First-Line Treatment of Patients With Advanced NSCLC Without Actionable Genomic Alterations

Study Overview
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Brief Summary
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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
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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 Progression Free Survival (PFS) by BICR and Overall Survival (OS) in first-line treatment of TROP2 biomarker positive participants.

Official Title
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A Phase III, Randomised, Open-label, Multicentre, Global Study of Datopotamab Deruxtecan (Dato-DXd) in Combination With Durvalumab and Carboplatin Versus Pembrolizumab in Combination With Platinum-based Chemotherapy for the First-line Treatment of Patients With Locally Advanced or Metastatic NSCLC Without Actionable Genomic Alterations (D926NC00001; AVANZAR)

Conditions
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NSCLC

Intervention / Treatment
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* Drug: Datopotamab deruxtecan
* Drug: Durvalumab
* Drug: Carboplatin
* Drug: Pembrolizumab
* Drug: Cisplatin
* Drug: Pemetrexed
* Drug: Paclitaxel


Participation Criteria
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Eligibility Criteria
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Inclusion: Participants ≥ 18 years at screening Participants with histologically or cytologically documented NSCLC that is Stage IIIB or IIIC disease not amenable for surgical resection or definitive chemoradiation or Stage IV metastatic NSCLC disease at the time of randomisation, who have not received prior chemotherapy or other systemic therapy for first-line Stage IIIB, IIIC or IV 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 therapies (actionable genomic alterations). ECOG PS of 0 or 1 Archival tumour tissue collected prior to signing of ICF Has adequate bone marrow reserve and organ function within 7 days before randomisation Exclusion: History of another primary malignancy except for malignancy treated with curative intent with no known active disease within 3 years before the first dose of study intervention and of low potential risk for recurrence Mixed small-cell lung cancer and NSCLC histology; sarcomatoid variant of NSCLC Persistent toxicities caused by previous anti-cancer therapy not yet improved to Grade ≤ 1 or baseline (with exceptions) Active or prior documented autoimmune, connective tissue or inflammatory disorders (with exceptions) Spinal cord compression or brain metastases unless asymptomatic, stable, not requiring steroids for at least 7 days prior to randomisation, and a minimum of 2 weeks have elapsed between the end of radiotherapy and study enrollment History of leptomeningeal carcinomatosis Clinically significant corneal disease Known active or uncontrolled hepatitis B or C virus infection Known HIV infection that is not well controlled 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

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 130 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
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Dato-DXd + Durvalumab + Carboplatin<br>Participants will be randomized to receive 6.0mg/kg Dato-DXd plus 1120 mg durvalumab plus carboplatin area under the curve [AUC] 5 mg/mL/minute. | Drug: Datopotamab deruxtecan<br>* Intravenous (IV) infusion every 3 weeks (Q3W) on Day 1 of each 21-day cycle.<br>* Other names: Dato-DXd;Drug: Durvalumab<br>* Intravenous (IV) infusion every 3 weeks (Q3W) on Day 1 of each 21-day cycle.<br>* Other names: MEDI4736, Imfinzi;Drug: Carboplatin<br>* Intravenous (IV) infusion every 3 weeks on Day 1 of each 21-day cycle for up to 4 cycles.<br>|
| Active Comparator: Histologic-specific therapy<br>Non-squamous NSCLC participants will be randomized to receive 200 mg pembrolizumab plus 500 mg/m2 pemetrexed plus either AUC 5 mg/mL/minute carboplatin or 75 mg/m2 cisplatin. Squamous NSCLC participants will be randomized to receive 200 mg of pembrolizumab plus 200 mg/m2 paclitaxel plus AUC 5 or 6 mg/mL/minute carboplatin. | Drug: Carboplatin<br>* Intravenous (IV) infusion every 3 weeks on Day 1 of each 21-day cycle for up to 4 cycles.<br>Drug: Pembrolizumab<br>* 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).<br>* Other names: Keytruda;Drug: Cisplatin<br>* Intravenous (IV) infusion every 3 weeks on Day 1 of each 21-day cycle for up to 4 cycles.<br>Drug: Pemetrexed<br>* Intravenous (IV) infusion every 3 weeks on Day 1 of each 21-day cycle.<br>* Other names: Alimta, Pemfexy;Drug: Paclitaxel<br>* Intravenous (IV) infusion every 3 weeks on Day 1 of each 21-day cycle for up to 4 cycles.<br>* Other names: Taxol;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Progression-Free Survival (PFS) in the TROP2 biomarker positive population | 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 blinded independent central review (BICR), or death due to any cause. | Approximately 3 Years | 
| Overall Survival (OS) in the TROP2 biomarker positive population | OS is defined as the time from randomisation until the date of death due to any cause. | Approximately 4 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| PFS in the Intent-to-Treat (ITT) population | PFS is defined as time from randomisation until progression per RECIST 1.1 as assessed by BICR, or death due to any cause. | Approximately 3 years | 
| OS in the ITT population | OS is defined as the time from randomisation until the date of death due to any cause. | Approximately 4 years | 
| PFS in the TROP2 biomarker negative population | PFS is defined as time from randomisation until progression per RECIST 1.1 as assessed by BICR, or death due to any cause. | Approximately 3 years | 
| OS in the TROP2 biomarker negative population | OS is defined as the time from randomisation until the date of death due to any cause. | Approximately 4 years | 
| Objective Response Rate (ORR) in the TROP2 biomarker positive and ITT populations | ORR is defined as the proportion of participants who have a confirmed Complete Response (CR) or confirmed Partial Response (PR), as determined by BICR and investigator per RECIST 1.1. | Approximately 4 years | 
| Duration of Response (DoR) in the TROP2 biomarker positive and ITT populations | 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 assessment or death due to any cause. | Approximately 4 years | 
| PFS in the TROP2 biomarker positive and ITT populations | PFS is defined as time from randomisation until progression per RECIST 1.1 as assessed by investigator assessment, or death due to any cause. | Approximately 3 years | 
| Pharmacokinetics of Dato-DXd when combined with durvalumab and carboplatin. | Concentration of Dato-DXd, total anti-TROP2 antibody, and MAAA-1181a in plasma and pharmacokinetic (PK) parameters (such as peak and trough concentrations, as data allow; sparse sampling). | Approximately 4 years | 
| Anti-Drug Antibody (ADA) for Dato-DXd | The immunogenicity of Dato-DXd when combined with durvalumab and carboplatin. | Approximately 4 years | 
| Time to Second Progression or Death (PFS2) in the TROP2 biomarker positive and ITT populations | 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. | Approximately 4 years | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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TROP2, Advanced or Metastatic Non-Small Cell Lung Cancer (NSCLC), Datopotamab deruxtecan (Dato-DXd), Durvalumab, Carboplatin, Chemotherapy, Antibody-Drug Conjugate (ADC)