Clinical trial NCT05048797: 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
Official title: 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)
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: PHASE3
Conditions: Locally Advanced or Metastatic Non-Small Cell Lung Cancer
Keywords: 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
Non-small cell lung cancer
Lead sponsor: AstraZeneca
Sponsor class: INDUSTRY
Collaborators: name: Daiichi Sankyo
First posted: 2021-09-17
Enrollment: 450
Sex: ALL
Minimum age (years): 18
Maximum age (years): 123
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention model description: This study consists of two open-label treatment arms:

Arm 1: Trastuzumab Deruxtecan Arm 2: Standard of Care treatment (platinum, pemetrexed and pembrolizumab)
Primary purpose: TREATMENT

Brief summary: 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

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.

Eligibility 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-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

Primary outcomes:
measure: Progression Free Survival (PFS) by Blinded Independent Central Review (BICR)
timeFrame: Until progression or death, assessed up to approximately 12 months
Secondary outcomes:
measure: Overall Survival (OS)
timeFrame: Until death, assessed up to approximately 28 months.
measure: Progression Free Survival (PFS) by investigator assessment
timeFrame: Until progression, assessed up to approximately 12 months
measure: Objective Response Rate (ORR)
timeFrame: Until progression, assessed up to approximately 12 months
measure: Duration of Response (DoR)
timeFrame: Until progression, assessed up to approximately 12 months
measure: Time to second progression or death (PFS2)
timeFrame: Assessed up to approximately 20 months
measure: Landmark analysis of PFS (PFS12)
timeFrame: Assessed up to approximately 12 months
measure: Landmark analysis of OS (OS24)
timeFrame: Assessed up to approximately 24 months
measure: Central Nervous System (CNS) - Progression Free Survival (PFS)
timeFrame: Until CNS progression or death, assessed up to approximately 12 months
measure: Safety and tolerability of T-DXd versus Standard of Care treatment
timeFrame: Until progression or death, assessed up to approximately 28 months
measure: Pharmacokinetics (PK) of T-DXd, total anti-HER2 antibody and DXd in serum
timeFrame: Up to cycle 4, approximately 12 weeks
measure: Immunogenicity of T-DXd
timeFrame: Until progression, assessed up to approximately 13 months
measure: Patient-reported pulmonary symptoms associated with Non-Small Cell Lung Cancer
timeFrame: Until progression, assessed up to approximately 13 months
measure: Patient-reported tolerability of T-DXd described using symptomatic AEs
timeFrame: Until progression, assessed up to approximately 13 months
measure: Patient-reported tolerability of T-DXd described using overall side-effect bother
timeFrame: Until progression, assessed up to approximately 13 months
measure: Patient-reported tolerability of T-DXd described using physical function
timeFrame: Until progression, assessed up to approximately 13 months
Other outcomes:
Locations:
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city: Taipei
country: Taiwan
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city: Taipei
country: Taiwan
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city: Taipei
country: Taiwan
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city: Taoyuan
country: Taiwan
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city: Edirne
country: Turkey
facility: Research Site
city: Izmir
country: Turkey
facility: Research Site
city: Kadıkoy/Istanbul
country: Turkey
facility: Research Site
city: Çankaya
country: Turkey
facility: Research Site
Study officials:
References: