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A Study to Investigate the Efficacy and Safety of Dato-DXd With or Without Osimertinib Compared With Platinum Based Doublet Chemotherapy in Participants With EGFR-Mutated Locally Advanced or Metastatic Non-Small Cell Lung Cancer

PHASE3RECRUITING

This study will assess the effect of Dato-DXd in combination with osimertinib or Dato-DXd monotherapy versus platinum-based doublet chemotherapy in terms of progression-free survival (PFS).

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Study details:

This is a Phase III, open-label, 3-arm, multicenter study assessing the effects of Dato-DXd in combination with osimertinib or Dato-DXd monotherapy versus platinum-based doublet chemotherapy in participants with epidermal growth factor receptor gene mutation (EGFRm) locally advanced or metastatic non-small cell lung cancer (NSCLC) whose disease has progressed on prior osimertinib treatment. Participants will be randomized in a 1:1:1 ratio to one of the following intervention groups:. 1.

Dato-DXd + osimertinib combination therapy. 2. Dato-DXd monotherapy.

3. Platinum-based doublet chemotherapy. Participants will receive study intervention until Response Evaluation Criteria in Solid Tumors, Version 1.

1 (RECIST v1. 1) -defined radiological progression by the investigator, unacceptable toxicity, or other discontinuation criterion is met. After study intervention discontinuation, all participants will undergo an end of treatment (EoT) visit within 35 days of discontinuation and will be followed up for safety assessments 28 (+ 7) days after their last dose of study intervention.

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Eligibility criteria

Researchers look for people who fit a certain description, called eligibility criteria. See if you qualify.

Inclusion criteria

Histologically or cytologically confirmed non-squamous NSCLC.

Must have evidence of documented pre-existing EGFRm information (EGFRm known to be associated with (epidermal growth factor receptor [EGFR] tyrosine kinase inhibitor [TKis] sensitivity [Ex19del, L858R, G719X, S768I, or L861Q], either alone or in combination with other EGFR mutations, which may include T790M).

Documented extra-cranial radiologic progression on prior osimertinib monotherapy (as most recent line of treatment) in the adjuvant, locally advanced, or metastatic setting.

Less than or equal to (<=2) prior lines of EGFR TKIs (osimertinib is the only permitted prior third generation EGFR TKI).

At least one lesion, not previously irradiated, that qualifies as a RECIST v1.1 TL at baseline and can be accurately measured at baseline.

World Health Organization (WHO)/Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1.

Adequate bone marrow reserve and organ function within 7 days before randomization.

Exclusion criteria

Use of chemotherapy, vascular endothelial growth factor inhibitor, immunotherapy or any anti-cancer therapy in the metastatic setting. Platinum-based chemotherapy in non-metastatic setting within 12 months prior to randomization.

History of another primary malignancy except for malignancy treated with curative intent with no known active disease within 2 years before the first dose of study intervention.

Any evidence of severe or uncontrolled systemic diseases, including, but not limited to active bleeding diseases, active infection, active ILD/pneumonitis, cardiac disease.

Has significant third-space fluid retention (example [eg.], ascites or pleural effusion) as judged by the investigator and is not amenable for required repeated drainage.

History of non-infectious ILD/pneumonitis including radiation pneumonitis that required steroids or drug-induced ILD, has current ILD/pneumonitis, or has suspected ILD/pneumonitis that cannot be ruled out by imaging at screening.

Has severe pulmonary function compromise resulting from intercurrent pulmonary illnesses.

Unstable spinal cord compression and/or unstable brain metastases.

Participants with symptomatic brain metastases (including leptomeningeal involvement).

Clinically significant corneal disease.

Uncontrolled infection requiring IV antibiotics, antivirals, or antifungals, suspected infections or inability to rule out infections.

Has known human immunodeficiency virus (HIV) infection that is not well controlled.

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Eligibility

Age eligible for study : 18 and older

Healthy volunteers accepted : No

Gender eligible for study: All

Things to know

Study dates

Study start: 2024-10-04

Primary completion: 2026-06-30

Study completion finish: 2027-12-31

Study type

TREATMENT

Phase

PHASE3

Trial ID

NCT06417814

Intervention or treatment

DRUG: Dato-DXd

DRUG: Osimertinib

DRUG: Pemetrexed

DRUG: Carboplatin

DRUG: Cisplatin

Conditions

• Metastatic Non-small Cell Lung Cancer

Image related to Metastatic Non-small Cell Lung Cancer

Condition: Metastatic Non-small Cell Lung Cancer
DRUG: Dato-DXd and other drugs
Heidelberg, Not Specified, Australia and more
Sponsor: AstraZeneca

You may be eligible to participate in this trial based on your search. Check eligibility by answering some questions.

Are you running this trial? If you're a clinic or sponsor, you can claim this study. Claim or learn more.

Find a site

Closest Location:

Research Site

Research sites nearby

Select from list below to view details:

Research Site
Heidelberg, Not Specified, Australia
Research Site
Kogarah, Not Specified, Australia
Research Site
Liverpool, Not Specified, Australia
Research Site
Nedlands, Not Specified, Australia

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Participant Group/Arm	Intervention/Treatment
EXPERIMENTAL: Group 1: Dato-DXd + Osimertinib Combination Therapy Participants will receive Dato-DXd 6 mg/kg as IV infusion Q3W on Day 1 of every 21-day cycle, and osimertinib 80 milligrams (mg) once daily (QD) orally, until RECIST v1.1-defined radiological progression by investigator, unacceptable toxicity, or other discontinuation criterion is met.	DRUG: Dato-DXd Dato-DXd will be administered as IV infusion.
EXPERIMENTAL: Group 2: Dato-DXd Monotherapy Participants will receive Dato-DXd 6 milligrams per kilogram (mg/kg) as intravenous (IV) infusion every 3 weeks (Q3W) on Day 1 of every 21-day cycle, until RECIST v1.1-defined radiological progression by investigator, unacceptable toxicity, or other discontinuation criterion is met.	DRUG: Dato-DXd Dato-DXd will be administered as IV infusion.
EXPERIMENTAL: Group 3: Platinum-based Doublet Chemotherapy Participants will receive pemetrexed 500 milligrams per meter square (mg/m2) in combination with carboplatin (AUC5) or cisplatin 75 mg/m2 as IV infusion Q3W for 4 cycles followed by pemetrexed maintenance 500 mg/m2 as IV infusion Q3W, until RECIST v1.1-defined radiological progression by investigator, unacceptable toxicity, or another discontinuation criterion is met.	DRUG: Pemetrexed Pemetrexed will be administered as IV infusion.

What is the study measuring?

Primary outcome

Primary Outcome Measure	Primary Outcome Description	Primary Outcome Time Frame
Progression free Survival (PFS)	PFS is defined as the time from randomization to Blinded Independent Central Review (BICR)-assessed progression using RECIST v1.1 or death due to any cause, regardless of whether the participant withdraws from study therapy, receives other anti-cancer therapy, or clinical progression.	Up to 2.5 years

Secondary outcome

Secondary Outcome Measure	Secondary Outcome Description	Secondary Outcome Time Frame
Overall Survival (OS)	OS is defined as time from randomization until the date of death due to any cause.	Up to 3.5 years
Central Nervous System Progression-free Survival (CNS PFS)	CNS PFS is defined as the time from randomization to BICR confirmed progression in the CNS or death due to any cause, regardless of whether the participant withdraws from study therapy, receives other anti-cancer therapy, or clinically progresses prior to BICR confirmed CNS modified RECIST v1.1 progression.	Up to 2.5 years
Objective Response Rate (ORR)	ORR is defined as the percentage of participants who have a confirmed complete response (CR) or confirmed partial response (PR), as determined by BICR per RECIST v1.1.	Up to 2.5 years
Duration of Response (DoR)	DoR is defined as the time from the date of first documented response until date of documented progression per RECIST v1.1, as assessed by BICR or death due to any cause.	Up to 2.5 years
Progression-free Survival-2 (PFS-2)	PFS2 is defined as the time from randomization to the earliest of the progression event (following the initial investigator assessed progression), after first subsequent therapy, or death.	Up to 3.5 years
Objective Response Rate (ORR) Using CNS Modified RECIST v1.1	ORR is defined as the percentage of participants who have a confirmed CR or confirmed PR, using CNS modified RECIST v1.1.	Up to 2.5 years
Duration of Response (DoR) Using CNS Modified RECIST v1.1	DoR is defined as the time from the date of first documented response until date of documented progression or death due to any cause using CNS modified RECIST v1.1.	Up to 2.5 years
Time to Deterioration in Pulmonary Symptoms	Time to deterioration (in pulmonary symptoms \[dyspnea, cough, and chest pain\]) is defined as the time from randomization until the date of deterioration. Deterioration is defined as change from baseline that reaches a meaningful change threshold.	Up to 3.5 years
Time to Deterioration in Physical Functioning	Time to deterioration in physical functioning as measured by Patient-Reported Outcomes Measurement Information System (PROMIS) Physical Function short form 8c will be evaluated. Time to deterioration (in physical functionating) is defined as the time from randomization until the date of deterioration. Deterioration is defined as change from baseline that reaches a meaningful change threshold.	Up to 3.5 years
Time to Deterioration in Global Health Status (GHS)/Quality of Life (QoL)	Time to deterioration in GHS/QoL as measured by the GHS/QoL scale from EORTC IL172 will be reported. Time to deterioration (in GHS/QoL) is defined as the time from randomization until the date of deterioration. Deterioration is defined as change from baseline that reaches a meaningful change threshold.	Up to 3.5 years
Pharmacokinetics (PK) of Dato-DXd	Concentration of Dato-DXd, total anti-TROP2 antibody and DXd in plasma.	Up to 3.5 years
Immunogenicity of Dato-DXd	Presence of antidrug antibody (ADAs) for Dato-DXd (confirmatory results: positive or negative, titers).	Up to 3.5 years

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References

Clinical Trials Gov: A Study to Investigate the Efficacy and Safety of Dato-DXd With or Without Osimertinib Compared With Platinum Based Doublet Chemotherapy in Participants With EGFR-Mutated Locally Advanced or Metastatic Non-Small Cell Lung Cancer