Trastuzumab deruxtecan plus pembrolizumab versus platinum chemotherapy plus pembrolizumab for first-line HER2‑overexpressing non‑squamous NSCLC

Is this trial a fit for you?

A plain-English reading of the study's rules. Only the study team can confirm whether you qualify.

What this trial studies

This is a phase 3 randomized comparison of trastuzumab deruxtecan (T‑DXd) plus pembrolizumab versus pemetrexed‑containing platinum chemotherapy plus pembrolizumab in patients with treatment‑naive, locally advanced unresectable or metastatic non‑squamous NSCLC that overexpresses HER2 and has PD‑L1 TPS <50% without known actionable genomic alterations with available local therapies. Eligible participants undergo tissue screening to confirm HER2 overexpression and other entry criteria before randomization. The trial measures clinical efficacy endpoints such as progression‑free survival and overall survival along with safety and tolerability of the combinations. Patients receive regular imaging and clinical monitoring during and after treatment per protocol.

Why it matters

Who can join: the full rules

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 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 the local test results obtained using validated or approved tests as required per local regulation) 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 non-squamous NSCLC 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 if their disease has progressed at least 6 months after 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 must be ruled out for MI. It is highly recommended that the investigator refer such participants for a cardiologic consultation during the Screening Period.
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 clinically severe pulmonary compromise resulting from intercurrent, pulmonary illnesses including, but not limited to:

   1. Any underlying pulmonary disorder (eg, pulmonary emboli within 3 months of the trial randomization, severe asthma, severe COPD, restrictive lung disease, pleural effusion).
   2. Any auto immune, connective tissue, or inflammatory disorders with potential pulmonary involvement (eg, rheumatoid arthritis, Sjogren's syndrome, sarcoidosis).

   Severe conditions are those defined as impacting daily activities and/or requiring use of supplemental oxygen.
5. Had a prior complete pneumonectomy.

Where it's running

• Alaska Oncology & Hematology, LLC
  Anchorage, Alaska, United States Recruiting
• Orange Coast Memorial Medical Center Fountain Valley
  Fountain Valley, California, United States Recruiting
• California Research Institute
  Los Angeles, California, United States Recruiting
• Los Angeles Cancer Network (LACN)
  Los Angeles, California, United States Recruiting
• Providence Medical Foundation
  Santa Rosa, California, United States Recruiting
• Bay Pines VA Healthcare System
  Bay Pines, Florida, United States Recruiting

+196 more sites. See ClinicalTrials.gov for the full list.

Study contacts

• Study coordinator: Contact for Trial Information
• Email: CTRinfo_us@daiichisankyo.com
• Phone: 908-992-6400

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How to take part

1. Review the eligibility criteria above with your treating physician.
2. Check the official listing on ClinicalTrials.gov for the latest contact details and recruitment status.
3. Contact the study coordinator or principal investigator to ask for pre-screening. Pre-screening is free and never obligates you to enroll.