Phase 3 Study of Trastuzumab Deruxtecan as First-line Treatment of Unresectable, Locally Advanced, or Metastatic NSCLC Harboring HER2 Exon 19 or 20 Mutations (DESTINY-Lung04)

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

Status

Active, not recruiting

Phases

Phase 3

Study type

Interventional

Source

JPRN

Registry ID

JPRN-jRCT2011210058

Enrollment

450

Registered

2021-12-23

Start date

2022-01-07

Completion date

Unknown

Last updated

2026-06-29

For informational purposes only — not medical advice. Sourced from public registries and may not reflect the latest updates. Terms

Conditions

NSCLC Harboring HER2 Exon 19 or 20 Mutations

Interventions

Arm1: T-DXd Arm2: Cisplatin or carboplatin with pemetrexed + pembrolizumab Note: Investigator choice of cisplatin or carboplatin.

Eligibility

Sex/Gender

All

Inclusion criteria

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-naive 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

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

Design outcomes

Primary

Measure	Time frame
Progression Free Survival (PFS) by Blinded Independent Central Review (BICR) [ Time Frame: Until progression or death, assessed up to approximately 12 months ] 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.	—

Secondary

Measure	Time frame
1. Overall Survival (OS) [ Time Frame: Until death, assessed up to approximately 28 months ] Defined as time from randomization until the date of death due to any cause. 2. Progression Free Survival (PFS) by investigator assessment [ Time Frame: Until progression, assessed up to approximately 12 months ] Defined as time from randomization until progression per RECIST 1.1 as assessed by the investigator, or death due to any cause. 3. Objective Response Rate (ORR) [ Time Frame: Until progression, assessed up to approximately 12 months ] 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 4. Duration of Response (DoR) [ Time Frame: Until progression, assessed up to approximately 12 months ] 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. 5. Time to second progression or death (PFS2) [ Time Frame: Assessed up to approximately 20 months ] 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. 6. Landmark analysis of PFS (PFS12) [ Time Frame: Assessed up to approximately 12 months ] Defined as proportion of participants alive and progression-free at 12 months, as assessed by Blinded Independent Central Review (BICR) and investigator. 7. Landmark analysis of OS (OS24) [ Time Frame: Assessed up to approximately 24 months ] Defined as proportion of participants alive at 24 months 8. Central Nervous System (CNS) - Progression Free Survival (PFS) [ Time Frame: Until CNS progression or death, assessed up to approximately 12 months ] Defined as time from randomization until Central Nervous System (	—

Measure

Time frame

1. Overall Survival (OS) [ Time Frame: Until death, assessed up to approximately 28 months ] Defined as time from randomization until the date of death due to any cause. 2. Progression Free Survival (PFS) by investigator assessment [ Time Frame: Until progression, assessed up to approximately 12 months ] Defined as time from randomization until progression per RECIST 1.1 as assessed by the investigator, or death due to any cause. 3. Objective Response Rate (ORR) [ Time Frame: Until progression, assessed up to approximately 12 months ] 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 4. Duration of Response (DoR) [ Time Frame: Until progression, assessed up to approximately 12 months ] 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. 5. Time to second progression or death (PFS2) [ Time Frame: Assessed up to approximately 20 months ] 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. 6. Landmark analysis of PFS (PFS12) [ Time Frame: Assessed up to approximately 12 months ] Defined as proportion of participants alive and progression-free at 12 months, as assessed by Blinded Independent Central Review (BICR) and investigator. 7. Landmark analysis of OS (OS24) [ Time Frame: Assessed up to approximately 24 months ] Defined as proportion of participants alive at 24 months 8. Central Nervous System (CNS) - Progression Free Survival (PFS) [ Time Frame: Until CNS progression or death, assessed up to approximately 12 months ] Defined as time from randomization until Central Nervous System (

—

Countries

Austria, Belgium, Brazil, Canada, China, Denmark, France, Germany, Hong Kong, India, Italy, Japan, Korea, Mexico, Netherlands, Poland, Spain, Taiwan, Turkey, United States

Contacts

Public ContactContact for Clinical Trial Information

DAIICHI SANKYO Co.,Ltd.

dsclinicaltrial_jp@daiichisankyo.com+81-3-6225-1111

Outcome results

None listed

Source: JPRN (via WHO ICTRP) · Data processed: Jul 3, 2026