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)

JRCT ID: jRCT2011210058

Registered date:23/12/2021

Basic Information

• Recruitment status: Recruiting
• Health condition(s) or Problem(s) studied: NSCLC Harboring HER2 Exon 19 or 20 Mutations
• Date of first enrollment: 07/01/2022
• Target sample size: 264
• Countries of recruitment: Austria,Japan,Belgium,Japan,Brazil,Japan,Canada,Japan,China,Japan,Denmark,Japan,France,Japan,Germany,Japan,India,Japan,Italy,Japan,Netherlands,Japan,Poland,Japan,Korea,Japan,Spain,Japan,Taiwan,Japan,Turkey,Japan,United States,Japan,Mexico,Japan,Hong Kong,Japan
• Study type: Interventional

Intervention(s)

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

Outcome(s)

Primary Outcome

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 Outcome

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 (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.

9. 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.

10. 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.

11. Immunogenicity of T-DXd [ Time Frame: Until progression, assessed up to approximately 13 months ]
Presence of anti-drug antibodies (ADAs) for T-DXd.

12. 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).

13. 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.

14. 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.

15. 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.

Key inclusion & exclusion criteria

• Age minimum: >= 18age old
• Age maximum: Not applicable
• Gender: Both

Include 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-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

Exclude 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

Related Information

• Primary Sponsor: Inoguchi Akihiro
• Secondary Sponsor: AstraZeneca
• Secondary ID(s): NCT05048797