Phase III, Open-label, Study of First-line Dato-DXd in Combination With Rilvegostomig for Advanced Non-squamous NSCLC With High PD-L1 Expression (TC ≥ 50%) and Without Actionable Genomic Alterations
- Conditions
- Non-Small Cell Lung Cancer
- Interventions
- Registration Number
- NCT06357533
- Lead Sponsor
- AstraZeneca
- Brief Summary
The purpose of this study is to evaluate efficacy and safety of Dato-DXd in combination with rilvegostomig or rilvegostomig monotherapy compared with pembrolizumab monotherapy as a first line therapy in participants with locally advanced or metastatic non-squamous NSCLC with high PD-L1 expression (TC ≥ 50%) and without actionable genomic alterations.
- Detailed Description
This is a Phase III, randomized, open-label, Global Study of Datopotamab Deruxtecan (Dato-DXd) in Combination With Rilvegostomig or Rilvegostomig monotherapy versus Pembrolizumab monotherapy for the first-line treatment of participants with locally-advanced or metastatic non-squamous NSCLC with high PD-L1 expression (TC ≥ 50%) and without actionable genomic alterations.
Recruitment & Eligibility
- Status
- RECRUITING
- Sex
- All
- Target Recruitment
- 675
- Histologically or cytologically documented non-squamous NSCLC.
- Stage IIIB or IIIC or Stage IV metastatic NSCLC (according to Edition 8 of the AJCC staging manual) not amenable to curative surgery or definitive chemoradiation.
- Absence of sensitising EGFR mutations, and ALK and ROS1 rearrangements, and absence of documented local test result for any other known genomic alteration for which there are locally approved and available targeted first-line therapies.
- Must provide tumor sample to determine PD-L1 status, TROP2 status and other biomarkers.
- Known tumour PD-L1 expression status defined as TC ≥ 50%
- At least one lesion, not previously irradiated that qualifies as a RECIST 1.1 target lesion at baseline
- ECOG performance status of 0 or 1
- Adequate bone marrow reserve and organ function within 7 days before the first dose of study intervention
- Prior systemic therapy for advanced/metastatic NSCLC.
- Squamous cell histology, or predominantly squamous cell histology NSCLC; mixed small cell lung cancer; NSCLC histology, sarcomatoid variant.
- History of another primary malignancy within 3 years
- Active or prior documented autoimmune or inflammatory disorders (with exceptions)
- Any evidence of severe or uncontrolled systemic diseases, including, but not limited to active bleeding diseases, active infection, active ILD/pneumonitis, cardiac disease.
- Has clinically significant third-space fluid retention (for example pleural effusion) and is not amenable for repeated drainage.
- 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
- Has significant pulmonary function compromise, as determined by the investigator
- Spinal cord compression, or brain metastases unless participant treated and no longer symptomatic, radiologically stable, and who require no treatment with corticosteroids or anticonvulsants.
- History of leptomeningeal carcinomatosis
- Known clinically significant corneal disease
- Active infection with TB, HBV, HCV, Hepatitis A, or known HIV infection that is not well controlled
- History of active primary immunodeficiency
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- PARALLEL
- Arm && Interventions
Group Intervention Description Arm 1: Datopotamab Deruxtecan in Combination With Rilvegostomig Rilvegostomig Participants in the Datopotamab Deruxtecan (Dato-DXd) in combination with Rilvegostomig group will receive Dato-DXd plus rilvegostomig as intravenous (IV) infusion every 3 weeks (Q3W) on Day 1 of each 21-day cycle. Arm 2: Rilvegostomig Monotherapy Rilvegostomig Participants in the rilvegostomig monotherapy group will receive rilvegostomig as intravenous (IV) infusion every 3 weeks (Q3W) on Day 1 of each 21-day cycle. Arm 3: Pembrolizumab Monotherapy Pembrolizumab Participants in the pembrolizumab group will receive pembrolizumab as intravenous (IV) infusion every 3 weeks (Q3W) on Day 1 of each 21-day cycle. Arm 1: Datopotamab Deruxtecan in Combination With Rilvegostomig Datopotamab Deruxtecan Participants in the Datopotamab Deruxtecan (Dato-DXd) in combination with Rilvegostomig group will receive Dato-DXd plus rilvegostomig as intravenous (IV) infusion every 3 weeks (Q3W) on Day 1 of each 21-day cycle.
- Primary Outcome Measures
Name Time Method Progression-Free Survival (PFS) in TROP2 biomarker positive participants. Approximately 4 years PFS is defined as time from randomisation until progression per RECIST 1.1 as assessed by BICR, or death due to any cause.
The analysis will include all randomised participants, as randomised, regardless of whether the participant withdraws from randomised therapy, receives another anti-cancer therapy or clinically progresses prior to RECIST 1.1 progression, in the following population:
• TROP2 biomarker positive population
The measure of interest is the HR of PFS. PFS by investigator will be reported as a sensitivity analysis.Overall Survival (OS) in TROP2 biomarker positive participants. Approximately 6 years OS is defined as the time from randomisation until the date of death due to any cause.
The analysis will include all randomised participants, as randomised, regardless of whether the participant withdraws from randomised therapy or receives another anti-cancer therapy, in the following population:
• TROP2 biomarker positive population The measure of interest is the HR of OS.
- Secondary Outcome Measures
Name Time Method Progression-Free Survival (PFS) in the FAS population. Approximately 4 years PFS is defined as time from randomisation until progression per RECIST 1.1 as assessed by BICR, or death due to any cause.
The analysis will include all randomised participants, as randomised, regardless of whether the participant withdraws from randomised therapy, receives another anti cancer therapy or clinically progresses prior to RECIST 1.1 progression, in the following population:
• FAS population
The measure of interest is the HR of PFS. PFS by investigator will be reported as a sensitivity analysis.Overall Survival (OS) in the FAS population. Approximately 6 years OS is defined as the time from randomisation until the date of death due to any cause.
The analysis will include all randomised participants, as randomised, regardless of whether the participant withdraws from randomised therapy or receives another anti-cancer therapy, in the following population:
• FAS population The measure of interest is the HR of OS.Assessment of Objective Response Rate (ORR) by BICR in TROP2 biomarker positive and FAS populations Approximately 4 years ORR is defined as the proportion of participants who have a CR or PR, as determined by BICR per RECIST 1.1.
The analyses will include all randomised participants, as randomised, with measurable disease at baseline, in the following populations:
* TROP2 biomarker positive population
* FAS population Data obtained from randomisation up until progression, or the last evaluable assessment in the absence of progression, will be included in the assessment of ORR, regardless of whether the participant withdraws from therapy. Participants who go off treatment without a response or progression, receive a subsequent therapy, and then respond will not be included as responders in the ORR.
The measure of interest is the OR of the ORR. ORR by investigator will be reported as a sensitivity analysis.Assessment of Duration of Response (DoR) by BICR in TROP2 biomarker positive and FAS populations Approximately 4 years 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 and investigator assessment or death due to any cause.
The analyses will include all randomised participants who have a response, as randomised, regardless of whether the participant withdraws from randomised therapy, receives another anti cancer therapy or clinically progresses prior to RECIST 1.1 progression, in the following populations:
* TROP2 biomarker positive population
* FAS population The measure of interest is the median of DoR. DoR by investigator will be reported as a sensitivity analysis.Participant-reported lung cancer symptoms of NSCLC and participant-reported GHS/QOL in participants treated with Dato-DXd in combination with rilvegostomig relative to pembrolizumab. Approximately 6 years Time to deterioration in: pulmonary symptoms (dyspnoea, cough, and chest pain) as measured by the NSCLC-SAQ, in overall lung cancer symptoms as measured by the NSCLC-SAQ, and in GHS/QoL as measured by the GHS/QoL scale from EORTC IL172.
Time to deterioration is defined as the time from randomisation until the date of deterioration. Deterioration is defined as change from baseline that reaches a clinically meaningful deterioration threshold. The analyses will include all randomised participants, in the following populations:
* TROP2 biomarker positive population
* FAS population The measure of interest is the HR of time to deterioration in pulmonary symptoms, HR of time to deterioration in overall lung cancer symptoms, and HR of time to deterioration in GHS/QoL.Participant-reported physical functioning in participants treated with Dato DXd in combination with rilvegostomig relative to pembrolizumab. Approximately 6 years Time to deterioration in physical functioning as measured by PROMIS Physical Function short form 8c.
Time to deterioration is defined as the time from randomisation until the date of deterioration. Deterioration is defined as change from baseline that reaches a clinically meaningful deterioration threshold. The analyses will include all randomised participants, in the following populations:
* TROP2 biomarker positive population
* FAS population The measure of interest is the HR of time to deterioration in physical functioning.Pharmacokinetics (PK) Approximately 6 years Concentration of rilvegostomig, Dato-DXd, total anti TROP2 antibody, and MAAA 1181a (payload deruxtecan) in plasma or serum and PK parameters (peak and trough concentrations).
Immunogenicity Approximately 6 years Presence of ADA for Dato-DXd and rilvegostomig (confirmatory results, titres and neutralising antibodies for confirmed positive samples).
Second Progression-Free Survival (PFS2). Approximately 6 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. Progression event includes radiological (RECIST 1.1) or clinical disease progression.
The date of second progression will be recorded by the investigator in the eCRF and defined according to local standard practice.
The analyses will include all randomised participants, as randomised, regardless of whether the participant withdraws from subsequent therapy and regardless of missed visits, in the following populations:
* TROP2 biomarker positive population
* FAS population The measure of interest is the HR of PFS2.
Trial Locations
- Locations (1)
Research Site
🇬🇧Truro, United Kingdom