Phase III, Open-label, First-line Study of Dato-DXd in Combination With Durvalumab and Carboplatin for Advanced NSCLC Without Actionable Genomic Alterations

Phase 3Active Not RecruitingNCT05687266

AstraZeneca1,350 enrolled

Overview

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).

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

Study Type

INTERVENTIONAL

Allocation

RANDOMIZED

Purpose

TREATMENT

Masking

NONE

Enrollment

1,350

Conditions

Interventions

Datopotamab deruxtecanDRUG

Intravenous (IV) infusion every 3 weeks (Q3W) on Day 1 of each 21-day cycle.

DurvalumabDRUG

Intravenous (IV) infusion every 3 weeks (Q3W) on Day 1 of each 21-day cycle.

CarboplatinDRUG

Intravenous (IV) infusion every 3 weeks on Day 1 of each 21-day cycle for up to 4 cycles.

PembrolizumabDRUG

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).

CisplatinDRUG

Intravenous (IV) infusion every 3 weeks on Day 1 of each 21-day cycle for up to 4 cycles.

PemetrexedDRUG

Intravenous (IV) infusion every 3 weeks on Day 1 of each 21-day cycle.

PaclitaxelDRUG

Intravenous (IV) infusion every 3 weeks on Day 1 of each 21-day cycle for up to 4 cycles.

Eligibility

Sex: ALLMin age: 18 YearsMax age: 130 Years

Medical Language ↔ Plain English

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.

Outcomes

Primary Outcomes

Progression-Free Survival (PFS) by blinded independent central review (BICR) in the non-squamous 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 BICR, or death due to any cause.

Time frame: Approximately 3 years

Overall Survival (OS) in the non-squamous TROP2 biomarker positive population

OS is defined as the time from randomisation until the date of death due to any cause.

Time frame: Approximately 5 years

PFS by BICR in the non-squamous population

PFS is deﬁned as time from randomisation until progression per RECIST 1.1 as assessed by BICR, or death due to any cause.

Time frame: Approximately 3 years

OS in the non-squamous population

OS is deﬁned as the time from randomisation until the date of death due to any cause.

Time frame: Approximately 5 years

Secondary Outcomes

PFS by BICR in ITT and TROP2 biomarker-defined populations

PFS is defined as time from randomisation until progression per RECIST 1.1 as assessed by BICR, or death due to any cause.

Time frame: Approximately 3 years

OS in ITT and TROP2 biomarker-defined populations

OS is defined as the time from randomisation until the date of death due to any cause.

Time frame: Approximately 5 years

Objective Response Rate (ORR) in ITT, non-squamous and TROP2 biomarker-defined 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 per RECIST 1.1.

Time frame: Approximately 5 years

Duration of Response (DoR) in ITT, non-squamous and TROP2 biomarker-defined 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 clinical assessment or death due to any cause.

Time frame: Approximately 5 years

PFS by investigator in ITT, non-squamous and TROP2 biomarker-defined populations

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.

Time frame: Approximately 3 years

Pharmacokinetics of Dato-DXd when combined with durvalumab and carboplatin.

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).

Time frame: Approximately 5 years

Anti-Drug Antibody (ADA) for Dato-DXd

The immunogenicity of Dato-DXd when combined with durvalumab and carboplatin.

Time frame: Approximately 5 years

Time to Second Progression or Death (PFS2) in ITT, non-squamous and TROP2 biomarker-defined 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.

Time frame: Approximately 5 years

Clinical Outcome Assessments in ITT, non-squamous and TROP2 biomarker-defined populations

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

Time frame: Approximately 5 years

Phase III, Open-label, First-line Study of Dato-DXd in Combination With Durvalumab and Carboplatin for Advanced NSCLC Without Actionable Genomic Alterations

Overview

Conditions

Interventions

Eligibility

Locations (254)

Outcomes

Primary Outcomes

Secondary Outcomes