Phase Ib Study of the Safety of T-DXd and Immunotherapy Agents With and Without Chemotherapy in Advanced or Metastatic HER2+, Non-squamous NSCLC

Study summary

DESTINY-Lung03 will investigate the safety and tolerability of trastuzumab deruxtecan in combination with Immunotherapy Agents with and without chemotherapy in patients with HER2 over-expressing non-small cell lung cancer. The efficacy will be also analyzed as a secondary endpoint.

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Key things to know

Main goalTreatment

This describes the study’s primary purpose.

What is being studiedT-DXd and Durvalumab

Plus 5 other study approaches.

Who it may be forNon-small cell lung cancer (NSCLC) · Locally advanced · Metastatic or stage IV

These are broad labels—not an eligibility decision.

Checked against the public recordLast updated Apr 13, 2026 · Source: ClinicalTrials.gov

Is enrollment open?Recruiting

The study is currently accepting participants.

What kind of study?Phase 1

Interventional

Where is it offered?91 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 1
Sponsor: AstraZeneca
Interventions being studied: Drug: T-DXd; Biological: Durvalumab; Drug: Cisplatin; Drug: Carboplatin; Drug: Pemetrexed; Drug: Volrustomig; Drug: Rilvegostomig

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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→

Treatment approach

Immunotherapy→Chemotherapy→

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 documented unresectable locally advanced/metastatic non-squamous NSCLC
Part 1: Progression after 1 or 2 lines of systemic therapy for recurrent or metastatic setting.
Part 3, Part 4 and Part 5: Patients must have tumors that do not harbor known genomic alterations or actionable driver kinases, for which approved therapies are available are allowed.
Part 3, Part 4 and Part 5: Patient must be treatment-naïve for advanced or metastatic NSCLC. Patients who have received prior adjuvant, or neoadjuvant chemotherapy, or definitive chemoradiation for advanced disease are eligible, provided that progression has occurred \> 6 months from end of last therapy
HER2overexpression status as determined by central review of tumor tissue
WHO / ECOG performance status of 0 or 1
Measurable target disease assessed by the investigator using RECIST 1.1
Has protocol defined adequate organ and bone marrow function
Part 3, Part 4 and Part 5: Minimum body weight of 35 kg.

Reasons someone may not be able to joinExclusion criteria

HER2 mutation if previously known
Has a history of (non-infectious) ILD/pneumonitis that required steroids, has current ILD/pneumonitis, or where suspected ILD/pneumonitis cannot be ruled out by imaging at screening
Lung-specific intercurrent clinically significant illnesses including, but not limited to, any underlying pulmonary disorder and prior pneumonectomy
Active primary immunodeficiency known HIV infection, or active chronic and resolved hepatitis B (positive hepatitis B virus surface antigen \[HBsAg+ve\] or hepatitis B virus core antibody (anti-HBc +ve) regardless of HBV DNA level)) or hepatitis C infection. Patients positive for HCV antibody are eligible only if polymerase chain reaction is negative for HCV RNA. Patients should be tested for HIV prior to treatment assignment if required by local regulations or IRB/EC
Active infection including tuberculosis and uncontrolled infection requiring IV antibiotics, antivirals, or antifungals
Spinal cord compression or clinically active central nervous system metastases, defined as untreated and symptomatic, or requiring therapy with corticosteroids or anticonvulsants to control associated symptoms
Medical history of myocardial infarction within 6 months before treatment assignment, symptomatic CHF (New York Heart Association Class II to IV), clinically important cardiac arrhythmias, or a recent (\< 6 months) cardiovascular event including stroke
For Part 3, Part 4 and Part 5: Cardiomyopathy of any etiology, symptomatic CHF (as defined by New York Heart Association Class \> II), unstable angina pectoris, history of MI within the past 12 months, or cardiac arrhythmia are to be excluded. Patients with troponin levels above ULN at screening (as defined by the manufacturer), and without any myocardial related symptoms, should have a cardiologic consultation before treatment assignment to rule out acute cardiopulmonary events.
Ascites or pericardial effusion that requires drainage, peritoneal shunt, Pleuroperitoneal shunt or CART (Concentrated Ascites Reinfusion Therapy)
For Part 3, Part 4 and Part 5: Active non-infectious skin disease (including any grade rash, urticarial, dermatitis, ulceration, or psoriasis) requiring systemic treatment, active or prior documented autoimmune or inflammatory disorders requiring chronic treatment with steroids or other immunosuppressive treatment.
Unresolved toxicities not yet resolved to Grade ≤ 1 or baseline from previous anticancer therapy OR prior discontinuation of any planned study therapy due to toxicity.
must not have any medical contraindication to platinum-based chemotherapy.
Part 3, Part 4 and Part 5 patients must not have had prior exposure to anti-PD-1, anti-PD-L1, anti-CTLA-4, anti-TIGIT or any other experimental immunotherapy in any setting.
For Part 3, Part 4 and Part 5: History of substance abuse or any other medical or psychological conditions that may, in the opinion of the Investigator, interfere with the subject's participation in the clinical study or evaluation of the clinical study results
For Part 3, Part 4 and Part 5: History of thromboembolic events within 3 months before the first dose of IP (limited to pulmonary embolism, deep vein thrombosis, or cerebral venous sinus thrombosis).

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 SiteDuarte, California
Research SiteNewport Beach, California
Research SiteOrange, California
Research SiteSanta Rosa, California
Research SiteWestwood, Kansas
Research SiteBaltimore, Maryland
Research SiteDetroit, Michigan
Research SiteBuffalo, New York
Research SiteNew York, New York
Research SiteThe Bronx, New York
Research SiteHouston, Texas
Research SiteFairfax, Virginia

Source and freshness
Processed from ClinicalTrials.gov. Last public update: Apr 13, 2026. Always confirm current availability with the study team.

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