A Single Arm Phase 2 Study to Evaluate Efficacy and Safety of Trastuzumab Deruxtecan for Patients With HER2 Mutant NSCLC

Study Overview
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Brief Summary
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The purpose of this study is to evaluate the efficacy and safety of T-DXd in participants with HER2 mutant metastatic non-squamous NSCLC.

Official Title
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An Open-label, Single-arm, Phase 2 Study to Evaluate the Efficacy and Safety of Trastuzumab Deruxtecan (T-DXd) for Patients With HER2-mutant Metastatic NSCLC Who Have Disease Progression on or After at Least One-line of Treatment (DESTINY-Lung05)

Conditions
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HER2-mutant Non-Small Cell Lung Cancer

Intervention / Treatment
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* Drug: Trastuzumab deruxtecan


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Pathologically documented metastatic non-squamous NSCLC. Has relapsed from or is refractory to at least one-line of anticancer treatment. Documented HER2 exon 19 or 20 mutation from central FFPE tumour tissue testing. WHO or ECOG performance status of 0 or 1. Presence of at least one measurable lesion assessed by the investigator based on RECIST 1.1. LVEF ≥ 50% within 28 days before enrolment. Exclusion Criteria: Mixed small cell lung cancer, squamous histology NSCLC, and sarcomatoid histology variant NSCLC. Corrected QT interval (QTcF) prolongation to > 470 ms (females) or > 450 ms (males), based on average of the screening triplicate 12-lead ECG. History of (non-infectious) ILD/pneumonitis that required steroids, has current ILD/pneumonitis, or where suspected ILD/pneumonitis cannot be ruled out by imaging at screening. Has unresolved toxicities from previous anticancer therapy, defined as toxicities (excluding alopecia) not yet resolved to Grade ≤1 or baseline. Participants with clinically stable chronic Grade 2 toxicity not reasonably expected to be exacerbated by study intervention may be included only after consultation with the AstraZeneca study physician or designee. Has been previously treated with HER2-targeted therapies, except for pan-HER class TKIs or has received prior treatment with an ADC which consists of an exatecan derivative that is a topoisomerase I inhibitor.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: T-DXd arm<br>Participants will receive T-DXd as an IV infusion Q3W, on Day 1 of each 3-week cycle. | Drug: Trastuzumab deruxtecan<br>* administered as an IV infusion<br>* Other names: T-DXd, DS-8201a;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| ICR-assessed ORR (objective response rate) | Confirmed ORR, defined as the proportion of participants with confirmed complete response or partial response, as assessed by independent central review(ICR) based on RECIST 1.1. | At an average of approximately 14 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Investigator-assessed ORR (objective response rate) | Confirmed ORR is defined as the proportion of participants who have a confirmed CR or confirmed PR, as determined by the investigator at local site per RECIST 1.1 | An average of approximately 14 months | 
| ICR-assessed and investigator-assessed DoR (duration of response) | DoR is time from the initial confirmed response (CR or PR) until documented tumour progression or death from any cause. | At an average of approximately 14 months | 
| ICR-assessed and investigator-assessed DCR (disease control rate) | DCR is the proportion of participants who achieved confirmed CR, PR, or SD during study intervention. | Approximately 6 weeks | 
| ICR-assessed and investigator-assessed PFS (progression-free survival) | PFS is the time from date of enrolment until first objective radiographic tumour progression or death from any cause. | An average of approximately 14 months | 
| OS (overall survival) | OS is the time from date of enrolment until death from any cause. | An average of approximately 22 months | 
| ICR-assessed CNS-PFS (central nervous system progression-free survival) | CNS-PFS is the time from date of enrolment until CNS tumour progression per RECIST 1.1 as assessed by ICR due to any cause in the absence of CNS progression. | An average of approximately 14 months | 
| Serum concentrations of T-DXd | Individual patient data and descriptive statistics will be provided for serum concentration data at each time point for T-DXd. | An average of approximately 14 months | 
| Serum concentrations of total anti-HER2 antibody | Individual patient data and descriptive statistics will be provided for serum concentration data at each time point for total anti-HER2 antibody. | An average of approximately 14 months | 
| Serum concentrations of DXd | Individual patient data and descriptive statistics will be provided for serum concentration data at each time point for DXd. | An average of approximately 14 months | 
| Immunogenicity | Presence of ADAs against T-DXd in serum during treatment and at follow-up. | An average of approximately 14 months | 
| Frequency of AEs, SAEs and AESIs | Occurrence of AEs and SAEs graded according to NCI CTCAE v5.0. | An average of approximately 16 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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DL05, T-DXd, HER2-mutant Non-Small Cell Lung Cancer, NSCLC, Trastuzumab deruxtecan, ERBB2