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

Study 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.

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Key things to know

Main goalTreatment

This describes the study’s primary purpose.

What is being studiedDatopotamab Deruxtecan and Rilvegostomig

Plus 1 other study approaches.

Who it may be forNon-small cell lung cancer (NSCLC) · PD-L1 · Locally advanced

These are broad labels—not an eligibility decision.

Checked against the public recordLast updated Sep 23, 2026 · Source: ClinicalTrials.gov

Is enrollment open?Recruiting

The study is currently accepting participants.

What kind of study?Phase 3

Interventional

Where is it offered?289 U.S. locations

Locations may change over time.

Who runs it?AstraZeneca

Study sponsor

Study overview

What this study is about

Purpose: Treatment
Study type: Interventional
Phase: Phase 3
Sponsor: AstraZeneca
Interventions being studied: Drug: Datopotamab Deruxtecan; Drug: Rilvegostomig; Drug: Pembrolizumab

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How this study is categorized

These labels come from structured fields and exact terms in the public record.

Cancer type

Non-small cell lung cancer (NSCLC)→

Disease setting

Locally advanced→Metastatic or stage IV→

Biomarkers

PD-L1→

Treatment approach

Immunotherapy→

Public criteria

Who may be able to participate

The sponsor separates these requirements into two groups. You do not need to interpret them alone—use them to guide a conversation with the study team.

Requirements people may need to meetInclusion criteria

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

Reasons someone may not be able to joinExclusion criteria

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 disease that makes it undesirable for the participant to participate in the study or that would jeopardies compliance with the protocol.
Has clinically significant third-space fluid retention (for example pleural effusion) and is not amenable for repeated drainage.
History of any ILD/pneumonitis, including radiation pneumonitis (apart from radiation pneumonitis that did not require steroids), or drug-induced ILD/pneumonitis, has current or 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

Important: This is the sponsor’s public criteria, not a determination of eligibility. The study team must review your individual situation.

Study sites

U.S. locations

Research SiteAnchorage, Alaska
Research SiteTucson, Arizona
Research SiteLittle Rock, Arkansas
Research SiteSpringdale, Arkansas
Research SiteAnaheim, California
Research SiteBeverly Hills, California
Research SiteFountain Valley, California
Research SiteNewport Beach, California
Research SiteClermont, Florida
Research SiteGainesville, Florida
Research SiteMiami Beach, Florida
Research SiteOrange City, Florida

Source and freshness
Processed from ClinicalTrials.gov. Last public update: Sep 23, 2026. Always confirm current availability with the study team.

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