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

Recruiting now · Phase 3

Conditions studied: Non-small Cell Lung Cancer

In brief

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.

Key facts

Study ID

NCT06899126

Run by

Daiichi Sankyo

People needed

686

Starts

2025-10-24

Expected to finish

2032-11-24

Last updated by the study team

2026-07-21

Who can join

Age: 18 and older. Sex: any. Healthy volunteers: not accepted.

You may qualify if…

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

You may not qualify if…

• 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.
• Has a QTc prolongation to >480 ms based on the average of the Screening triplicate 12- lead ECG.
• 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.
• Has clinically severe pulmonary compromise resulting from intercurrent, pulmonary 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).
• 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.
• Had a prior complete pneumonectomy.

Where it is running

• Alaska Oncology & Hematology, LLC — Anchorage, Alaska, United States (enrolling)
• California Research Institute — Los Angeles, California, United States (enrolling)
• Orange Coast Memorial Medical Center Fountain Valley — Fountain Valley, California, United States (enrolling)
• Providence Medical Foundation — Santa Rosa, California, United States (enrolling)
• Bay Pines VA Healthcare System — Bay Pines, Florida, United States (enrolling)
• Lynn Cancer Institute Center — Boca Raton, Florida, United States (enrolling)
• Holy Cross Hospital — Fort Lauderdale, Florida, United States (enrolling)
• Los Angeles Cancer Network (LACN) — Los Angeles, California, United States (enrolling)
• BRCR Global Plantation — Plantation, Florida, United States (enrolling)
• Cleveland Clinic Florida - Weston — Weston, Florida, United States (enrolling)
• Piedmont Cancer Institute OneOncology — Atlanta, Georgia, United States (enrolling)
• The Queens Medical Center — Honolulu, Hawaii, United States (enrolling)
• Hope and Healing Cancer Services — Hinsdale, Illinois, United States (enrolling)
• Dana-Farber Cancer Institute — Boston, Massachusetts, United States (enrolling)
• Mayo Clinic — Rochester, Minnesota, United States (enrolling)
• Logan Health Research — Kalispell, Montana, United States (enrolling)
• Renown Regional Medical Center — Reno, Nevada, United States (enrolling)
• Mid-Florida Hematology & Oncology Centers, P.A. — Orange City, Florida, United States (enrolling)
• FirstHealth Cancer Center — Pinehurst, North Carolina, United States (enrolling)
• Carolina Cancer Research Center — Wilson, North Carolina, United States (enrolling)
• Gabrail Cancer Center — Canton, Ohio, United States (enrolling)
• St. Charles Health System — Bend, Oregon, United States (enrolling)
• University of Texas M. D. Anderson Cancer Center — Houston, Texas, United States (enrolling)
• Lumi Research — Kingwood, Texas, United States (enrolling)
• Summit Cancer Treatment Center — Spokane, Washington, United States (enrolling)

Full record on ClinicalTrials.gov

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