Recruiting
Phase 1

Trastuzumab Deruxtecan & Immunotherapy

Sponsor:

AstraZeneca

Code:

NCT04686305

Conditions

Locally Advanced or Metastatic Non-Small Cell Lung Cancer

Eligibility Criteria

Sex: All

Age: 18+

Healthy Volunteers: Not accepted

Interventions

T-DXd

Durvalumab

Cisplatin

Carboplatin

Pemetrexed

Study Details

Brief 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.

Conditions

Locally Advanced or Metastatic Non-Small Cell Lung Cancer

Study ID

NCT04686305

Start date

Mar 9, 2021

Status verified date

Feb, 2026

Completion date

Jun 30, 2027

Anticipated

Primary completion date

Jun 30, 2027

Anticipated

Eligibility Criteria

Eligibility Criteria

Sex: All

Age: 18+

Healthy Volunteers: Not accepted

Inclusion 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.

Exclusion 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).

Study Design

Enrollment

304 participants

Anticipated

Allocation

Randomized

Intervention Model

Parallel Assignment

Primary purpose

Treatment

Interventions and Outcome Measures

Arms

experimental: Arm 1A: T-DXd, Durvalumab and Cisplatin

T-DXd, Durvalumab and Cisplatin

experimental: Arm 1B: T-DXd, Durvalumab and Carboplatin

T-DXd, Durvalumab and Carboplatin

experimental: Arm 1C: T-DXd, Durvalumab and Pemetrexed

T-DXd, Durvalumab and Pemetrexed (Arm not initiated)

experimental: Arm 1D: T-DXd

T-DXd

experimental: Arm 3A: T-DXd and Volrustomig

Drug: T-DXd and Volrustomig T-DXd: administered as an IV infusion Other Name: DS-8201a, Trastuzumab deruxtecan Biological/Vaccine: Volrustomig Volrustomig: administered as an IV infusion Other Name: Volrustomig

experimental: Arm 3B: T-DXd, Volrustomig and Carboplatin

Drug: T-DXd, Volrustomig and Carboplatin T-DXd: administered as an IV infusion Other Name: DS-8201a, Trastuzumab deruxtecan Biological/Vaccine: Volrustomig Volrustomig: administered as an IV infusion Other Name: Volrustomig Drug: Carboplatin Carboplatin: administered as an IV infusion

experimental: Arm 4A: T-DXd and Rilvegostomig

T-DXd and Rilvegostomig Drug: T-DXd, Rilvegostomig T-DXd: administered as an IV infusion Other Name: DS-8201a, Trastuzumab deruxtecan Biological/Vaccine: Rilvegostomig Rilvegostomig: administered as an IV infusion Other Name: Rilvegostomig, AZD2936

experimental: Arm 4B T-DXd and Rilvegostomig with Carboplatin

Drug: T-DXd, Rilvegostomig and Carboplatin T-DXd: administered as an IV infusion Other Name: DS-8201a, Trastuzumab deruxtecan Biological/Vaccine: Rilvegostomig Rilvegostomig: administered as an IV infusion Other Name: Rilvegostomig, AZD2936 Drug: Carboplatin Carboplatin: administered as an IV infusion

experimental: Arm 5A: T-DXd and Volrustomig

Drug: T-DXd and volrustomig T-DXd: administered as an IV infusion Other Name: DS-8201a, trastuzumab deruxtecan Biological/Vaccine: Volrustomig Volrustomig: administered as an IV infusion (priming dose in first cycle, fixed dose in subsequent cycles) Other Name: volrustomig

experimental: Arm 5B: T-DXd and Volrustomig

Drug: T-DXd and volrustomig T-DXd: administered as an IV infusion Other Name: DS-8201a, trastuzumab deruxtecan Biological/Vaccine: Volrustomig Volrustomig: administered as an IV infusion (fixed dose from first cycle onward) Other Name: volrustomig

Interventions

T-DXd

T-DXd: administered as an IV infusion

Durvalumab

Durvalumab: administered as an IV infusion

Cisplatin

Cisplatin: administered as an IV infusion

Carboplatin

Carboplatin: administered as an IV infusion

Pemetrexed

Pemetrexed: administered as an IV infusion (drug not used)

Volrustomig

Volrustomig: administered as an IV infusion

Rilvegostomig

Rilvegostomig: administered as an IV infusion

Primary outcome measure

  • Frequency of AEs and SAEs [ Time Frame: Safety and tolerability (and to determine RP2D) will be assessed for approximately 20 months from informed consent ]

Central Contacts and Locations

Central contacts

AstraZeneca Clinical Study Information Center

1-877-240-9479information.center@astrazeneca.com

AstraZeneca Lung Cancer Study Locator Service

1-884-432-3892az-lcsl@careboxhealth.com

Locations

Research Site

Recruiting

Orange, California, United States, 92868

Research Site

Recruiting

Baltimore, Maryland, United States, 21287

Research Site

Recruiting

Houston, Texas, United States, 77030

Research Site

Recruiting

Fairfax, Virginia, United States, 22031

Research Site

Recruiting

Montreal, Quebec, Canada, H3T 1E2

More Information

Sponsor

AstraZeneca

Last update posted

Apr 13, 2026

Last verified

Feb, 2026

Keywords

  • HER2+
  • HER2 expression
  • DS-8201a
  • T-DXd
  • Trastuzumab Deruxtecan
  • Volrustomig (MEDI5752)
  • Antibody - drug conjugate
  • bispecific antibody
  • Volrustomig
  • Rilvegostomig
  • Carboplatin
  • First line
  • Locally advanced and unresectable non-squamous NSCLC
  • Metastatic non-squamous NSCLC
  • Non-small cell lung cancer

Trial information was received from ClinicalTrials.gov and was last updated on 2026-09-10. This information was provided to ClinicalTrials.gov by AstraZeneca on 2026-04-13.