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

• ClinicalTrials.gov Identifier: NCT05048797
• Recruitment Status: Recruiting
• First Posted: September 17, 2021
• Last Update Posted: May 16, 2024
• Sponsor: AstraZeneca
• Collaborator: Daiichi Sankyo
• Information provided by (Responsible Party): AstraZeneca

Tracking Information

• First Submitted Date: September 9, 2021
• First Posted Date: September 17, 2021
• Last Update Posted Date: May 16, 2024
• Actual Study Start Date: October 28, 2021
• Estimated Primary Completion Date: June 30, 2025 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: September 9, 2021)

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.

• Original Primary Outcome Measures: Same as current

Current Secondary Outcome Measures (submitted: September 9, 2021)

• 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.
• 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.
• 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
• 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.
• 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.
• 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.
• Landmark analysis of OS (OS24) [ Time Frame: Assessed up to approximately 24 months ]
  Defined as proportion of participants alive at 24 months
• 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 (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 [ Time Frame: Until progression or death, assessed up to approximately 28 months ]
  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 [ Time Frame: Up to cycle 4, approximately 12 weeks ]
  Serum concentration of T-DXd, total anti-HER2 antibody and DXd.
• Immunogenicity of T-DXd [ Time Frame: Until progression, assessed up to approximately 13 months ]
  Presence of anti-drug antibodies (ADAs) for T-DXd.
• Patient-reported pulmonary symptoms associated with Non-Small Cell Lung Cancer [ Time Frame: Until progression, assessed up to approximately 13 months ]
  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 [ Time Frame: Until progression, assessed up to approximately 13 months ]
  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 [ Time Frame: Until progression, assessed up to approximately 13 months ]
  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 [ Time Frame: Until progression, assessed up to approximately 13 months ]
  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.

• Original Secondary Outcome Measures: Same as current
• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• 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)
• 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.

• Study Type: Interventional
• Study Phase: Phase 3

Study Design

Allocation: Randomized
Intervention Model: Parallel Assignment
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)

Masking: None (Open Label)
Primary Purpose: Treatment

• Condition: Locally Advanced or Metastatic Non-Small Cell Lung Cancer

Intervention

• Drug: Trastuzumab Deruxtecan
  Trastuzumab Deruxtecan administered by intravenous infusion
  Other Name: DS-8201a; T-DXd
• 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

Study Arms

• Experimental: Arm 1
  Trastuzumab Deruxtecan (T-DXd)
  Intervention: Drug: Trastuzumab Deruxtecan
• Active Comparator: Arm 2
  Standard of Care Treatment (platinum, pemetrexed and pembrolizumab)
  Interventions:

  • Drug: Cisplatin
  • Drug: Carboplatin
  • Drug: Pembrolizumab
  • Drug: Pemetrexed

• Publications *: Not Provided

Recruitment Information

• Recruitment Status: Recruiting
• Estimated Enrollment (submitted: April 9, 2024): 450
• Original Estimated Enrollment (submitted: September 9, 2021): 264
• Estimated Study Completion Date: March 29, 2027
• Estimated Primary Completion Date: June 30, 2025 (Final data collection date for primary outcome measure)

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

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 18 Years to 123 Years (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Contacts

Contact: AstraZeneca Clinical Study Information Center; 1-877-240-9479; information.center@astrazeneca.com

• Listed Location Countries: Austria, Belgium, Brazil, Canada, China, Denmark, France, Germany, Hong Kong, India, Italy, Japan, Korea, Republic of, Mexico, Netherlands, Poland, Spain, Taiwan, Turkey, United States
• Removed Location Countries: Sweden

Administrative Information

• NCT Number: NCT05048797
• Other Study ID Numbers: D967SC00001; 2021-000634-33 ( EudraCT Number )
• Has Data Monitoring Committee: Yes

U.S. FDA-regulated Product

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No

IPD Sharing Statement

• Plan to Share IPD: Yes
• 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.
• Supporting Materials: Study Protocol
• Supporting Materials: Statistical Analysis Plan (SAP)
• 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.
• 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.
• URL: https://astrazenecagroup-dt.pharmacm.com/DT/Home

• Current Responsible Party: AstraZeneca
• Original Responsible Party: Same as current
• Current Study Sponsor: AstraZeneca
• Original Study Sponsor: Same as current
• Collaborators: Daiichi Sankyo
• Investigators: Not Provided
• PRS Account: AstraZeneca
• Verification Date: May 2024