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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

Primary Purpose

Locally Advanced or Metastatic Non-Small Cell Lung Cancer

Status

Recruiting

Phase

Phase 3

Locations

International

Study Type

Interventional

Intervention

Trastuzumab Deruxtecan

Cisplatin

Carboplatin

Pembrolizumab

Pemetrexed

About this trial

This is an interventional treatment trial for Locally Advanced or Metastatic Non-Small Cell Lung Cancer focused on measuring 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

Eligibility Criteria

18 Years - 123 Years (Adult, Older Adult)All SexesDoes not accept healthy volunteers

Inclusion Criteria:

Participants at least 18 years of age
Locally advanced 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 clinically active brain metastases; previously treated brain metastases allowed
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

Arms of the Study

Arm 1

Arm 2

Arm Type

Experimental

Active Comparator

Arm Label

Arm 1

Arm 2

Arm Description

Trastuzumab Deruxtecan (T-DXd)

Standard of Care Treatment (platinum, pemetrexed and pembrolizumab)

Outcomes

Primary Outcome Measures

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.

Secondary Outcome Measures

Overall Survival (OS)

Defined as time from randomization until the date of death due to any cause.

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.

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

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.

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.

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.

Landmark analysis of OS (OS24)

Defined as proportion of participants alive at 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.

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.

Pharmacokinetics (PK) of T-DXd, total anti-HER2 antibody and DXd in serum

Serum concentration of T-DXd, total anti-HER2 antibody and DXd.

Immunogenicity of T-DXd

Presence of anti-drug antibodies (ADAs) for T-DXd.

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).

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.

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.

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.

Full Information

NCT ID

NCT05048797

First Posted

September 9, 2021

Last Updated

October 12, 2023

Sponsor

AstraZeneca

Collaborators

Daiichi Sankyo, Inc.

1. Study Identification

Unique Protocol Identification Number

NCT05048797

Brief Title

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

2. Study Status

Record Verification Date

October 2023

Overall Recruitment Status

Recruiting

Study Start Date

October 28, 2021 (Actual)

Primary Completion Date

January 17, 2025 (Anticipated)

Study Completion Date

March 1, 2027 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title

Sponsor

Name of the Sponsor

AstraZeneca

Collaborators

Daiichi Sankyo, Inc.

4. Oversight

Studies a U.S. FDA-regulated Drug Product

Yes

Studies a U.S. FDA-regulated Device Product

Data Monitoring Committee

Yes

5. Study Description

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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study

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

7. Study Design

Primary Purpose

Treatment

Study Phase

Phase 3

Interventional Study Model

Parallel Assignment

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)

Masking

None (Open Label)

Allocation

Randomized

Enrollment

264 (Anticipated)

8. Arms, Groups, and Interventions

Arm Title

Arm 1

Arm Type

Experimental

Arm Description

Trastuzumab Deruxtecan (T-DXd)

Arm Title

Arm 2

Arm Type

Active Comparator

Arm Description

Standard of Care Treatment (platinum, pemetrexed and pembrolizumab)

Intervention Type

Drug

Intervention Name(s)

Trastuzumab Deruxtecan

Other Intervention Name(s)

DS-8201a; T-DXd

Intervention Description

Trastuzumab Deruxtecan administered by intravenous infusion

Intervention Type

Drug

Intervention Name(s)

Cisplatin

Intervention Description

Investigator's choice of platinum chemotherapy (cisplatin) administered by intravenous infusion

Intervention Type

Drug

Intervention Name(s)

Carboplatin

Intervention Description

Investigator's choice of platinum chemotherapy (carboplatin) administered by intravenous infusion

Intervention Type

Drug

Intervention Name(s)

Pembrolizumab

Intervention Description

Pembrolizumab administered by intravenous infusion

Intervention Type

Drug

Intervention Name(s)

Pemetrexed

Intervention Description

Pemetrexed administered by intravenous infusion

Primary Outcome Measure Information:

Title

Progression Free Survival (PFS) by Blinded Independent Central Review (BICR)

Description

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.

Time Frame

Until progression or death, assessed up to approximately 12 months

Secondary Outcome Measure Information:

Title

Overall Survival (OS)

Description

Defined as time from randomization until the date of death due to any cause.

Time Frame

Until death, assessed up to approximately 28 months.

Title

Progression Free Survival (PFS) by investigator assessment

Description

Defined as time from randomization until progression per RECIST 1.1 as assessed by the investigator, or death due to any cause.

Time Frame

Until progression, assessed up to approximately 12 months

Title

Objective Response Rate (ORR)

Description

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

Time Frame

Until progression, assessed up to approximately 12 months

Title

Duration of Response (DoR)

Description

Time Frame

Until progression, assessed up to approximately 12 months

Title

Time to second progression or death (PFS2)

Description

Time Frame

Assessed up to approximately 20 months

Title

Landmark analysis of PFS (PFS12)

Description

Defined as proportion of participants alive and progression-free at 12 months, as assessed by Blinded Independent Central Review (BICR) and investigator.

Time Frame

Assessed up to approximately 12 months

Title

Landmark analysis of OS (OS24)

Description

Defined as proportion of participants alive at 24 months

Time Frame

Assessed up to approximately 24 months

Title

Central Nervous System (CNS) - Progression Free Survival (PFS)

Description

Time Frame

Until CNS progression or death, assessed up to approximately 12 months

Title

Safety and tolerability of T-DXd versus Standard of Care treatment

Description

Assessed by the occurrence of AEs, SAEs, and changes from baseline in laboratory parameters, vital signs, ECG, and ECHO/MUGA scan results.

Time Frame

Until progression or death, assessed up to approximately 28 months

Title

Pharmacokinetics (PK) of T-DXd, total anti-HER2 antibody and DXd in serum

Description

Serum concentration of T-DXd, total anti-HER2 antibody and DXd.

Time Frame

Up to cycle 4, approximately 12 weeks

Title

Immunogenicity of T-DXd

Description

Presence of anti-drug antibodies (ADAs) for T-DXd.

Time Frame