A Study to Investigate the Efficacy and Safety of Trastuzumab Deruxtecan as the First Treatment Option for Unresectable, Locally Advanced/Metastatic Non-Small Cell Lung Cancer With HER2 Mutations

An Open-label, Randomized, Multicenter, Phase 3 Study to Assess the Efficacy and Safety of Trastuzumab Deruxtecan as First-line Treatment of Unresectable, Locally Advanced, or Metastatic NSCLC Harboring HER2 Exon 19 or 20 Mutations (DESTINY-Lung04)

DESTINY-Lung04 will investigate the efficacy and safety of Trastuzumab Deruxtecan (T-DXd) versus Standard of Care (SoC) as first-line treatment of Non-Small Cell Lung Cancer (NSCLC) with HER2 Exon 19 or 20 mutations

Study Overview

• Status: Active, not recruiting
• Conditions: Locally Advanced or Metastatic Non-Small Cell Lung Cancer
• Intervention / Treatment: Drug: Trastuzumab Deruxtecan; Drug: Cisplatin; Drug: Carboplatin; Drug: Pembrolizumab; Drug: Pemetrexed

Detailed Description

Eligible participants will be those diagnosed with unresectable, locally advanced or metastatic histologically documented non-squamous NSCLC with HER2 exons 19 or 20 mutations and who are treatment-naïve for palliative intent systemic therapy for locally advanced or metastatic disease.

The study aims to evaluate the efficacy, safety and tolerability of trastuzumab deruxtecan as first-line treatment of Non-Small Cell Lung Cancer (NSCLC) as compared with Standard of Care treatment (Investigator's choice of cisplatin or carboplatin + pembrolizumab + pemetrexed). This study aims to see if trastuzumab deruxtecan allows patients to live longer without the cancer getting worse or simply to live longer, compared to patients receiving standard of care treatment. This study is also looking to see how the treatment and the cancer affects patients' quality of life.

• Study Type: Interventional
• Enrollment (Actual): 454
• Phase: Phase 3

Contacts and Locations

Study Locations

• Austria
  • Linz, Austria, 4020
    • Research Site
  • Vienna, Austria, 1210
    • Research Site
• Belgium
  • Ghent, Belgium, 9000
    • Research Site
  • Leuven, Belgium, 3000
    • Research Site
• Brazil
  • Barretos, Brazil, 14784-400
    • Research Site
  • Blumenau, Brazil, 89010-340
    • Research Site
  • Brasília, Brazil, 70200-730
    • Research Site
  • Natal, Brazil, 59075-740
    • Research Site
  • Salvador, Brazil, 40170-110
    • Research Site
  • São Paulo, Brazil, 01321-001
    • Research Site
  • São Paulo, Brazil, 01327-001
    • Research Site
  • Uberlândia, Brazil, 38408-150
    • Research Site
• Canada
  • British Columbia
    • Vancouver, British Columbia, Canada, V5Z 4E6
      • Research Site
  • Ontario
    • Brampton, Ontario, Canada, L6R 3J7
      • Research Site
    • Toronto, Ontario, Canada, M5G 1Z5
      • Research Site
  • Quebec
    • Montreal, Quebec, Canada, H4A 3J1
      • Research Site
• China
  • Beijing, China, 100142
    • Research Site
  • Beijing, China, 100730
    • Research Site
  • Changchun, China, 130021
    • Research Site
  • Changsha, China, 410013
    • Research Site
  • Changsha, China, 410008
    • Research Site
  • Chengdu, China, 610041
    • Research Site
  • Fuzhou, China, 350014
    • Research Site
  • Guangzhou, China, 510080
    • Research Site
  • Hangzhou, China, 310020
    • Research Site
  • Jinan, China, 250117
    • Research Site
  • Kunming, China, 650118
    • Research Site
  • Kunming, China, 650101
    • Research Site
  • Linhai, China, 317000
    • Research Site
  • Nanchang, China, 330006
    • Research Site
  • Nanjing, China, 210029
    • Research Site
  • Shanghai, China, 200032
    • Research Site
  • Shenyang, China, 110016
    • Research Site
  • Shenzhen, China, 518020
    • Research Site
  • Wenzhou, China, CN-325000
    • Research Site
  • Wuhan, China, 430022
    • Research Site
  • Xi'an, China, 710061
    • Research Site
  • Xiamen, China, 361003
    • Research Site
  • Yangzhou, China, 225001
    • Research Site
• Denmark
  • Vejle, Denmark, 7100
    • Research Site
• France
  • Bordeaux, France, 33000
    • Research Site
  • Dijon, France, 21079
    • Research Site
  • Le Mans, France, 72037
    • Research Site
  • Lyon, France, 69373
    • Research Site
  • Marseille, France, 13915
    • Research Site
  • Nantes, France, 44093
    • Research Site
  • Toulouse, France, 31059
    • Research Site
  • Villejuif, France, 94805
    • Research Site
• Germany
  • Cologne, Germany, 50937
    • Research Site
  • Dresden, Germany, 01307
    • Research Site
  • Mainz, Germany, 55131
    • Research Site
  • München, Germany, 81377
    • Research Site
  • Oldenburg, Germany, 26121
    • Research Site
• Hong Kong
  • Hong Kong, Hong Kong
    • Research Site
  • Hong Kong, Hong Kong, 999077
    • Research Site
  • Jordan, Hong Kong, 999077
    • Research Site
• India
  • Bangalore, India, 560027
    • Research Site
  • Delhi, India, 110085
    • Research Site
  • Hyderabad, India, 500032
    • Research Site
  • Mumbai, India, 400012
    • Research Site
  • Nashik, India, 422002
    • Research Site
• Italy
  • Milan, Italy, 20141
    • Research Site
  • Monza, Italy, 20090
    • Research Site
  • Orbassano, Italy, 10043
    • Research Site
  • Parma, Italy, 43100
    • Research Site
  • Roma, Italy, 00168
    • Research Site
  • Verona, Italy, 37126
    • Research Site
• Japan
  • Chūōku, Japan, 104-0045
    • Research Site
  • Fukuoka, Japan, 812-8582
    • Research Site
  • Kashiwa, Japan, 277-8577
    • Research Site
  • Matsuyama, Japan, 791-0280
    • Research Site
  • Niigata, Japan, 951-8566
    • Research Site
  • Okayama, Japan, 700-8558
    • Research Site
  • Osaka, Japan, 541-8567
    • Research Site
  • Osakasayama-shi, Japan, 589-8511
    • Research Site
  • Sapporo, Japan, 060-8638
    • Research Site
  • Sendai, Japan, 980-0873
    • Research Site
  • Sunto-gun, Japan, 411-8777
    • Research Site
  • Yokohama, Japan, 241-8515
    • Research Site
  • Yonago-shi, Japan, 683-8504
    • Research Site
• Mexico
  • Mexico City, Mexico, '14080
    • Research Site
  • Mexico City, Mexico, 03810
    • Research Site
• Netherlands
  • Amsterdam, Netherlands, 1081 HV
    • Research Site
  • Groningen, Netherlands, 9700 RB
    • Research Site
  • Nijmegen, Netherlands, 6525 GA
    • Research Site
• Poland
  • Gdansk, Poland, 80-952
    • Research Site
  • Olsztyn, Poland, 10-357
    • Research Site
  • Przemyśl, Poland, 37-700
    • Research Site
  • Warsaw, Poland, 02-781
    • Research Site
• South Korea
  • Cheongju-si, South Korea, 28644
    • Research Site
  • Goyang-si, South Korea, 10408
    • Research Site
  • Gyeonggi-do, South Korea, 13620
    • Research Site
  • Seoul, South Korea, 03080
    • Research Site
  • Seoul, South Korea, 05505
    • Research Site
  • Seoul, South Korea, 06351
    • Research Site
• Spain
  • L'Hospitalet de Llobregat, Spain, 08908
    • Research Site
  • Madrid, Spain, 28041
    • Research Site
  • Málaga, Spain, 29730
    • Research Site
  • Valencia, Spain, 46026
    • Research Site
• Taiwan
  • Kaohsiung City, Taiwan, 833
    • Research Site
  • Taichung, Taiwan, 40705
    • Research Site
  • Taichung, Taiwan, 40201
    • Research Site
  • Tainan, Taiwan, 70403
    • Research Site
  • Taipei, Taiwan, 235
    • Research Site
  • Taipei, Taiwan, TAIWAN
    • Research Site
  • Taipei, Taiwan, 10048
    • Research Site
  • Taoyuan District, Taiwan, 333
    • Research Site
• Turkey (Türkiye)
  • Edirne, Turkey (Türkiye), 22030
    • Research Site
  • Izmir, Turkey (Türkiye), 35040
    • Research Site
  • Kadıkoy/Istanbul, Turkey (Türkiye), 34722
    • Research Site
  • Çankaya, Turkey (Türkiye), 06680
    • Research Site
• United States
  • Alaska
    • Anchorage, Alaska, United States, 99508
      • Research Site
  • California
    • Los Alamitos, California, United States, 90720
      • Research Site
    • Los Angeles, California, United States, 90048
      • Research Site
    • Orange, California, United States, 92868
      • Research Site
    • San Francisco, California, United States, 94143
      • Research Site
    • Santa Monica, California, United States, 90404
      • Research Site
  • Maryland
    • Silver Spring, Maryland, United States, 20910
      • Research Site
  • Massachusetts
    • Boston, Massachusetts, United States, 02215
      • Research Site
  • Michigan
    • Ann Arbor, Michigan, United States, 48109
      • Research Site
  • New Jersey
    • Basking Ridge, New Jersey, United States, 07920
      • Research Site
    • Middletown, New Jersey, United States, 07748
      • Research Site
    • Montvale, New Jersey, United States, 07645
      • Research Site
    • New Brunswick, New Jersey, United States, 08901
      • Research Site
  • New York
    • Commack, New York, United States, 11725
      • Research Site
    • Harrison, New York, United States, 10604
      • Research Site
    • New York, New York, United States, 10065
      • Research Site
    • Uniondale, New York, United States, 11553
      • Research Site
  • Pennsylvania
    • Pittsburgh, Pennsylvania, United States, 15232
      • Research Site
  • Texas
    • Dallas, Texas, United States, 75246
      • Research Site

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 123 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• Participants at least 18 years of age
• Locally advanced and unresectable NSCLC, not amenable to curative therapy, or metastatic disease
• Histologically documented non-squamous NSCLC with HER2 mutation in exons 19 or 20 by tissue NGS or ctDNA
• Treatment-naïve for palliative intent systemic therapy for locally advanced or metastatic disease
• Left ventricular ejection fraction (LVEF) ≥ 50%
• Measurable disease assessed by Investigator based on RECIST 1.1
• Protocol-defined adequate organ function including cardiac, renal, hepatic function
• ECOG 0-1
• Having tumour tissue available for central testing

Exclusion Criteria:

• Tumors with targetable alterations to EGFR (or other targetable mutations including but not limited to ALK, if routinely tested as a targetable alteration with approved available therapy)
• Any untreated brain metastases, including asymptomatic or clinically inactive brain metastases
• Active autoimmune or inflammatory disorders
• Medical history of myocardial infarction within 6 months prior to randomization
• History of non-infectious pneumonitis/ILD, current or suspected ILD
• Lung-specific intercurrent clinical significant severe illness
• Contraindication to platinum-based doublet chemotherapy or pembrolizumab

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Arm 1; Trastuzumab Deruxtecan (T-DXd)	Drug: Trastuzumab Deruxtecan; Trastuzumab Deruxtecan administered by intravenous infusion; Other Names: DS-8201a; T-DXd
Active Comparator: Arm 2; Standard of Care Treatment (platinum, pemetrexed and pembrolizumab)	Drug: Cisplatin; Investigator's choice of platinum chemotherapy (cisplatin) administered by intravenous infusion; Drug: Carboplatin; Investigator's choice of platinum chemotherapy (carboplatin) administered by intravenous infusion; Drug: Pembrolizumab; Pembrolizumab administered by intravenous infusion; Drug: Pemetrexed; Pemetrexed administered by intravenous infusion

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Progression Free Survival (PFS) by Blinded Independent Central Review (BICR)	Defined as time from randomization until progression per RECIST 1.1 as assessed by Blinded Independent Central Review (BICR), or death due to any cause.	Until progression or death, assessed up to approximately 12 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Overall Survival (OS)	Defined as time from randomization until the date of death due to any cause.	Until death, assessed up to approximately 28 months.
Progression Free Survival (PFS) by investigator assessment	Defined as time from randomization until progression per RECIST 1.1 as assessed by the investigator, or death due to any cause.	Until progression, assessed up to approximately 12 months
Objective Response Rate (ORR)	Defined as the proportion of participants who have a complete response (CR) or partial response (PR) as assessed by Blinded Independent Central Review (BICR) and investigator according to RECIST 1.1	Until progression, assessed up to approximately 12 months
Duration of Response (DoR)	Defined as the time from the date of first documented response until date of documented progression as assessed by Blinded Independent Central Review (BICR) and investigator assessment according to RECIST 1.1.	Until progression, assessed up to approximately 12 months
Time to second progression or death (PFS2)	Defined as the time from randomization until second progression on next-line of treatment as assessed by investigator at the local site using assessments conducted per local standard clinical practice, or death due to any cause.	Assessed up to approximately 20 months
Landmark analysis of PFS (PFS12)	Defined as proportion of participants alive and progression-free at 12 months, as assessed by Blinded Independent Central Review (BICR) and investigator.	Assessed up to approximately 12 months
Landmark analysis of OS (OS24)	Defined as proportion of participants alive at 24 months	Assessed up to approximately 24 months
Central Nervous System (CNS) - Progression Free Survival (PFS)	Defined as time from randomization until Central Nervous System (CNS) progression per RECIST 1.1 as assessed by Blinded Independent Central Review (BICR) or death due to any cause in the absence of CNS progression.	Until CNS progression or death, assessed up to approximately 12 months
Safety and tolerability of T-DXd versus Standard of Care treatment	Assessed by the occurrence of AEs, SAEs, and changes from baseline in laboratory parameters, vital signs, ECG, and ECHO/MUGA scan results.	Until progression or death, assessed up to approximately 28 months
Pharmacokinetics (PK) of T-DXd, total anti-HER2 antibody and DXd in serum	Serum concentration of T-DXd, total anti-HER2 antibody and DXd.	Up to cycle 4, approximately 12 weeks
Immunogenicity of T-DXd	Presence of anti-drug antibodies (ADAs) for T-DXd.	Until progression, assessed up to approximately 13 months
Patient-reported pulmonary symptoms associated with Non-Small Cell Lung Cancer	Time to sustained deterioration in pulmonary symptoms (cough, dyspnea, chest pain) while on treatment using the Non-Small Cell Lung Cancer-Symptom Assessment Questionnaire (NSCLC-SAQ).	Until progression, assessed up to approximately 13 months
Patient-reported tolerability of T-DXd described using symptomatic AEs	Symptomatic AEs: Descriptive summary of the proportion of participants reporting symptomatic AEs while on treatment, as assessed by the Patient-reported outcomes version of the Common Terminology Criteria for Adverse Events (PRO-CTCAE) and items from the European Organisation for Research and Treatment of Cancer (EORTC) Item Library.	Until progression, assessed up to approximately 13 months
Patient-reported tolerability of T-DXd described using overall side-effect bother	Overall side-effect bother: Descriptive summary of the proportion of participants reporting overall side-effect bother on the Patient's Global Impression of Treatment Tolerability (PGI-TT) while on treatment.	Until progression, assessed up to approximately 13 months
Patient-reported tolerability of T-DXd described using physical function	Physical Function: The proportion of participants with maintained or improved physical function while on treatment, based on the European Organisation for Research and Treatment of Cancer 30-item core quality of life questionnaire (EORTC-QLQ-C30) physical functioning scale.	Until progression, assessed up to approximately 13 months

Collaborators and Investigators

• Sponsor: AstraZeneca
• Collaborators: Daiichi Sankyo

Publications and helpful links

Helpful Links

• Lung Cancer Study Locator details (for US)

Study record dates

Study Major Dates

• Study Start (Actual): October 28, 2021
• Primary Completion (Estimated): April 30, 2026
• Study Completion (Estimated): July 30, 2027

Study Registration Dates

• First Submitted: September 9, 2021
• First Submitted That Met QC Criteria: September 9, 2021
• First Posted (Actual): September 17, 2021

Study Record Updates

• Last Update Posted (Actual): April 3, 2026
• Last Update Submitted That Met QC Criteria: April 2, 2026
• Last Verified: March 1, 2026

More Information

Terms related to this study

• Keywords: Non-small cell lung cancer; DS-8201a; HER2 exon 19 or 20 mutations; ERBB2 gene (coding for the HER2 protein); T-DXd; Trastuzumab Deruxtecan; Locally advanced and unresectable non-squamous NSCLC; Metastatic non-squamous NSCLC
• Additional Relevant MeSH Terms: Neoplasms by Site; Neoplasms; Respiratory Tract Diseases; Lung Diseases; Respiratory Tract Neoplasms; Thoracic Neoplasms; Lung Neoplasms; Carcinoma, Bronchogenic; Bronchial Neoplasms; Carcinoma, Non-Small-Cell Lung; Amino Acids, Peptides, and Proteins; Organic Chemicals; Heterocyclic Compounds; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Inorganic Chemicals; Chlorine Compounds; Nitrogen Compounds; Coordination Complexes; Guanine; Hypoxanthines; Purinones; Purines; Glutamates; Amino Acids, Acidic; Amino Acids; Amino Acids, Dicarboxylic; Platinum Compounds; Pemetrexed; Carboplatin; Cisplatin; pembrolizumab; trastuzumab deruxtecan
• Other Study ID Numbers: D967SC00001; 2021-000634-33 (EudraCT Number); 2023-503674-20-00 (Registry Identifier: CTIS)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: Qualified researchers can request access to anonymized individual patient-level data from AstraZeneca group of companies sponsored clinical trials via the request portal. All request will be evaluated as per the AZ disclosure commitment: https://astrazenecagrouptrials.pharmacm.com/ST/Submission/Disclosure.
• IPD Sharing Time Frame: AstraZeneca will meet or exceed data availability as per the commitments made to the EFPIA Pharma Data Sharing Principles. For details of our timelines, please rerefer to our disclosure commitment at https://astrazenecagrouptrials.pharmacm.com/ST/Submission/Disclosure.
• IPD Sharing Access Criteria: When a request has been approved AstraZeneca will provide access to the de-identified individual patient-level data in an approved sponsored tool . Signed Data Sharing Agreement (non-negotiable contract for data accessors) must be in place before accessing requested information. Additionally, all users will need to accept the terms and conditions of the SAS MSE to gain access. For additional details, please review the Disclosure Statements at https://astrazenecagrouptrials.pharmacm.com/ST/Submission/Disclosure.
• IPD Sharing Supporting Information Type: STUDY_PROTOCOL; SAP

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No