Study of Trastuzumab Deruxtecan, Pembrolizumab, and Platinum-based Chemotherapy in First-line HER2 Overexpressing Non-small Cell Lung Cancer

Phase 3

Not yet recruiting

• Conditions: Non-small Cell Lung Cancer
• Interventions: Drug: Trastuzumab Deruxtecan; Drug: pembrolizumab; Drug: Pemetrexed; Drug: Chemotherapy

• Registration Number: NCT06899126
• Lead Sponsor: Daiichi Sankyo

Brief Summary

This clinical trial is designed to assess the efficacy and safety of trastuzumab deruxtecan (T-DXd; Enhertu®) in combination with pembrolizumab versus platinum-based chemotherapy in combination with pembrolizumab in participants with no prior therapy for locally advanced unresectable or metastatic non-squamous NSCLC, whose tumors have HER2-overexpressing and PD-L1 TPS \<50% without known AGA that have locally available therapies targeting their AGAs in first-line advanced/metastatic setting.

Detailed Description

Not available

Study Timeline

• Study First Submitted: 2025-03-21
• Study First Submitted QC: 2025-03-21
• Study First Posted: 2025-03-27
• Status Verified: 2025-05
• Last Update Submitted: 2025-05-02
• Last Update Posted: 2025-05-06
• Study Start: 2025-09-07
• Primary Completion: 2030-03-05
• Study Completion: 2032-07-05

Recruitment & Eligibility

• Status: NOT_YET_RECRUITING
• Sex: All
• Target Recruitment: 686

Inclusion Criteria

1. Sign and date the Tissue Screening ICF, prior to any Tissue Screening procedure. Sign and date the Main ICF, prior to the start of any trial-specific qualification procedures.

   Sign and date the Optional PGx ICF (included in the Main Screening ICF) prior to any PGx procedure, and the Pregnant Partner ICF, if applicable.

2. Adults ≥18 years of age on the day of signing the ICF. Follow local regulatory requirements if the legal age of consent for trial participation is >18 years old.

3. Histologically documented non-squamous locally advanced unresectable or metastatic

   NSCLC and meets all of the following criteria:

   Has Stage IV NSCLC disease or Stage IIIB or IIIC disease but is not a candidate for surgical resection or definitive chemoradiation at the time of randomization (based on the American Joint Committee on Cancer, Eighth Edition). Has no known AGAs (based on existing test result of local test) that have locally available therapies targeting their AGAs in the first-line advanced/metastatic setting. Has no known HER2 mutation based on existing test results (if approved or validated local test is available). Note: Participants with mixed histology are eligible if adenocarcinoma is the predominant histology. Mixed tumors will be classified based on the predominant cell type.

4. Has not been treated with systemic anticancer therapy for advanced or metastatic non-squamous NSCLC. Participants who received adjuvant or neoadjuvant therapy other than those listed below, including ICI (ie, anti-PD-1/PD-L1) or a platinum-based regimen, are eligible if the last dose of adjuvant/neoadjuvant therapy was given at least 6 months before the date of the first trial dose and should not have progressed on or within 6 months of the last dose date of adjuvant/neoadjuvant therapy.

   1. Any agent, including an ADC, containing a chemotherapeutic agent targeting topoisomerase I.
   2. HER2-targeted antibody-based anticancer therapy.

5. Has adequate tumor tissue sample (not previously irradiated) available for assessment of HER2 and PD-L1 expression by central or Sponsor-specified laboratory. A new biopsy is required if the participant's most recent archival tumor tissue sample cannot be supplied.

Details pertaining to tumor tissue submission can be found in the Trial Laboratory Manual.

Exclusion Criteria

1. Has a medical history of MI within 6 months before randomization/enrollment or symptomatic CHF (NYHA Class II to Class IV). Participants with troponin levels above the ULN at Screening (as defined by the manufacturer) and without any MI-related symptoms should have a cardiologic consultation during the Screening Period to rule out MI.
2. Has a QTc prolongation to >480 ms based on the average of the Screening triplicate 12- lead ECG.
3. Has a 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.
4. Has lung-specific, intercurrent, clinically significant illnesses including, but not limited to, any underlying pulmonary disorder (eg, pulmonary emboli within 3 months of the trial randomization, severe asthma, severe COPD, restrictive lung disease, pleural effusion, etc.).
5. Had a prior complete pneumonectomy.

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Arm A: T-DXd	Trastuzumab Deruxtecan	Participants will receive T-DXd plus pembrolizumab
Arm A: T-DXd	pembrolizumab	Participants will receive T-DXd plus pembrolizumab
Arm B: Pemetrexed + Chemotherapy + Pembrolizumab	pembrolizumab	Participants will receive Pemetrexed plus platinum chemotherapy (cisplatin or carboplatin) plus pembrolizumab
Arm B: Pemetrexed + Chemotherapy + Pembrolizumab	Pemetrexed	Participants will receive Pemetrexed plus platinum chemotherapy (cisplatin or carboplatin) plus pembrolizumab
Arm B: Pemetrexed + Chemotherapy + Pembrolizumab	Chemotherapy	Participants will receive Pemetrexed plus platinum chemotherapy (cisplatin or carboplatin) plus pembrolizumab

Primary Outcome Measures

Name	Time	Method
Progression Free Survival by Blinded Independent Central Review	From date of randomization to the date of radiographic disease progression or death due to any cause, up to 54 months	PFS is defined as the time interval from the date of randomization to the date of radiographic disease progression or death due to any cause. Tumor response will be determined by BICR assessment of tumor scans using RECIST v1.1.

Secondary Outcome Measures

Name	Time	Method
Overall Survival	From date of randomization to the date of death due to any cause, up to 85 months	OS is defined as the time interval from the date of randomization to the date of death due to any cause.