A study to investigate the efficacy and safety of trastuzumab deruxtecan as the first treatment option for locally advanced/metastatic Non-Small Cell Lung Cancer with HER2 mutations

Overview

Sponsor-declared trial summary

Key facts

Sponsor

AstraZeneca AB

Participant type

Patients

Age range

18-64 years, 65+ years

Gender

Male and Female

Therapeutic area

Diseases [C] - Neoplasms [C04]

Trial duration

17 Dec 2021 → ongoing

Decision date (initial)

2024-07-17

Transition trial

Yes

Low-intervention

No

Rare-disease indication

Yes

Vulnerable population

Yes

Funding sources

AstraZeneca AB, Sweden

External identifiers

EU CT number

2023-503674-20-00

EudraCT number

2021-000634-33

ClinicalTrials.gov

NCT05048797

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Efficacy

To assess the efficacy of T-DXd relative to platinum with pemetrexed plus pembrolizumab by assessment of Progression-Free Survival (PFS) by Blinded Independent Central Review (BICR) in participants with unresectable, locally advanced, or metastatic NSCLC harboring HER2 exon 19 or 20 mutations.

Secondary objectives 8

1. To assess efficacy of T-DXd relative to platinum with pemetrexed plus pembrolizumab by assessment of Overall Survival (OS).
2. To assess efficacy of T-DXd relative to platinum with pemetrexed plus pembrolizumab in terms of PFS by investigator assessment, Objective Response Rate (ORR), Duration of Response (DoR), time to second progression or death (PFS2), & landmark analysis of PFS12 and OS24
3. To assess efficacy of T-DXd relative to platinum with pemetrexed plus pembrolizumab by assessment of CNS-PFS (per RECIST 1.1).
4. To assess safety and tolerability of T-DXd compared to platinum with pemetrexed plus pembrolizumab.
5. To assess PK of T-DXd, total anti-HER2 antibody and DXd in serum.
6. To investigate immunogenicity of T-DXd.
7. To assess benefit of T-DXd relative to platinum with pemetrexed plus pembrolizumab with patient-reported pulmonary symptoms associated with NSCLC.
8. To describe patient-reported tolerability of T-DXd as compared to platinum with pemetrexed plus pembrolizumab.

Conditions and MedDRA coding

Unresectable, locally advanced, or metastatic Non-Small Cell Lung Cancer with HER2 exon 19 or 20 mutations

Study design 3 periods

Regulatory references

Scientific advice from competent authorities

Food And Drug Administration, European Medicines Agency

EMA paediatric investigation plan (PIP)

EMEA-002978-PIP01-21

Plan to share IPD

Yes

IPD 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 Vivli.org. All requests will be evaluated as per the AZ disclosure commitment: https://astrazenecagrouptrials.pharmacm.com/ST/Submission/Disclosure. Yes, indicates that AZ are accepting requests for IPD, but this does not mean all requests will be shared. AstraZeneca will meet or exceed data availability as per the commitments made to the EFPIA PhRMA Data Sharing Principles. When a request has been approved AstraZeneca will provide access to the anonymized individual patient-level data via secure research environment https://vivli.org/. Signed Data Usage Agreement (non-negotiable contract for data accessors) must be in place before accessing requested information.

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 9

1. Male and female participants at least 18 years of age
2. Locally advanced not amenable to curative therapy, or metastatic disease
3. Histologically documented non-squamous NSCLC with HER2 mutation in exons 19 or 20 by tissue NGS or ctDNA (locally or centrally tested)
4. Treatment-naïve for palliative intent systemic therapy for locally advanced or metastatic disease
5. Left ventricular ejection fraction (LVEF) ≥ 50%
6. Measurable disease assessed by Investigator based on RECIST v1.1
7. Protocol-defined adequate organ function including cardiac, renal, hepatic function
8. ECOG 0-1
9. Having tumour tissue available for central testing

Exclusion criteria 7

1. 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)
2. Clinically active brain metastases, defined as untreated AND/OR symptomatic, or requiring therapy to control associated symptoms. All participants with brain metastases must have previously completed local therapy.
3. Active autoimmune or inflammatory disorders
4. Medical history of myocardial infarction within 6 months prior to randomization
5. History of non-infectious pneumonitis/ILD, current or suspected ILD
6. Lung-specific intercurrent clinical significant severe illness
7. Contraindication to platinum-based doublet chemotherapy or pembrolizumab

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 1

1. Progression Free Survival (PFS) 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 endpoints 10

1. 1. Overall Survival (OS) defined as time from randomization until date of death due to any cause.
2. 2-1: PFS by investigator assessment defined as time from randomization until progression as assessed by investigator (per RECIST 1.1) or death due to any cause. Objective Response Rate (ORR) and Duration of Response (DoR) by BICR and Investigator assessment per RECIST 1.1. ORR is defined as proportion of participants who have a complete response (CR) or partial response (PR).
3. 2-2: DoR is defined as time from date of first documented response until date of documented progression. PFS2 is defined as time from randomization to second progression on next-line of treatment as assessed by investigator or death due to any cause.
4. 2-3: PFS12 is the landmark of PFS which is defined as proportion of participants alive and progression-free at 12 months as assessed by BICR and investigator. OS24 is the landmark of OS defined as proportion of patients alive at 24 months
5. 3. CNS-PFS defined as time from randomization until CNS-progression (RECIST 1.1) as assessed by BICR or death due to any cause in absence of CNS progression.
6. 4. AEs, SAEs, changes from baseline in laboratory parameters, vital signs, ECG, ECHO/MUGA results.
7. 5. Pharmacokinetics (PK) of T-DXd and serum concentration of T-DXd, total anti-HER2 antibody and DXd
8. 6. Presence of ADAs for T-DXd
9. 7. Time to sustained deterioration in pulmonary symptoms while on treatment using NSCLC-Symptom Assessment Questionnaire (SAQ)
10. 8. Patient Reported Tolerability will be described among participants using the following outcomes: Symptomatic AEs (assessed by PROCTCAE and EORTC Item Library), Overall Side Effect Bother (reported on Patient's Global Impression of Treatment Tolerability (PGI-TT)), Physical Function (based on EORTC-QLQ-30)

Investigational products

Investigational medicinal products (IMPs), comparators, placebo, auxiliary

Test 1

Comparator 5

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

AstraZeneca AB

Sponsor organisation

AstraZeneca AB

Address

Astraallen Gartuna, Karlebyhus Byggnad 674 Karlebyhus Byggnad 674

City

Sodertalje

Postcode

151 85

Country

Sweden

Scientific contact point

Organisation

AstraZeneca AB

Contact name

AstraZeneca Clinical Study Information Center

Public contact point

Organisation

AstraZeneca AB

Contact name

AstraZeneca Clinical Study Information Center

Third parties 1

Locations

9 EU/EEA countries · 38 investigational sites

By country

Investigational sites

Country notifications

Trial-start, recruitment-start, end and early-termination notifications submitted per Member State

Oversight and notifications

Regulatory notifications under CTR Articles 38, 52, 53, 54 and 77

Serious breaches 1 · Art. 52 CTR

Results and documents

Annex IV summary of results, Annex V layperson summary, and all documents registered in CTIS for this trial

Documents 96 files

Public protocol annexes, IB summaries, regulatory submissions and post-authorisation documents registered in CTIS.

Application history

4 submissions — initial application plus substantial / non-substantial modifications