Study of Trastuzumab Deruxtecan, Pembrolizumab, and Platinum-based Chemotherapy in First-line HER2 Overexpressing Non-small Cell Lung Cancer (DESTINY-Lung06)

January 6, 2026 updated by: Daiichi Sankyo

A Phase 3, Multicenter, Randomized, Open-label Trial of Trastuzumab Deruxtecan in Combination With Pembrolizumab Versus Platinum-based Chemotherapy in Combination With Pembrolizumab, as First-line Therapy in Participants With Locally Advanced Unresectable or Metastatic HER2 Overexpressing and PD-L1 TPS <50% Non-squamous Non-small Cell Lung Cancer (DESTINY-Lung06)

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.

Study Overview

Status

Recruiting

Conditions

Intervention / Treatment

Study Type

Interventional

Enrollment (Estimated)

686

Phase

  • Phase 3

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Contact

Study Locations

  • Argentina
      • Buenos Aires, Argentina
        • Recruiting
        • CINME - Centro de Investigaciones Metabolicas
      • Buenos Aires, Argentina
        • Recruiting
        • Instituto Argentino de Diagnóstico y Tratamiento
      • Buenos Aires, Argentina
        • Recruiting
        • Instituto de Investigaciones Metabolicas (IDIM)
      • Rosario, Argentina
        • Recruiting
        • Instituto Medico de La Fundacion Estudios Clinicos
  • Belgium
      • Mons, Belgium
        • Recruiting
        • CHU Helora-Hospital de Mons
  • Brazil
      • Barretos, Brazil
        • Recruiting
        • Hospital de Cancer de Barretos - Fundacao Pio XII
      • Blumenau, Brazil
        • Recruiting
        • Centro de Pesquisas Clinica Reichow
      • Curitiba, Brazil
        • Recruiting
        • CIONC-Centro Integrado de Oncologia de Curitiba
      • Fortaleza, Brazil
        • Recruiting
        • Crio - Centro Regional Integrado de Oncologia
      • Natal, Brazil
        • Recruiting
        • Liga Norte-Rio-Grandense Contra O Câncer
      • Porto Alegre, Brazil
        • Recruiting
        • Hospital Ernesto Dornelles
      • Porto Alegre, Brazil
        • Recruiting
        • Hospital Sao Lucas da PUCRS
      • Ribeirão Preto, Brazil
        • Recruiting
        • Hospital das Clínicas FMRP-USP
      • Ribeirão Preto, Brazil
        • Recruiting
        • Centro de Tratamento Oncologico (CTO)
      • Salvador, Brazil
        • Recruiting
        • Obras Sociais Irmã Dulce - Hospital Santo Antônio
      • Santo André, Brazil
        • Recruiting
        • CEPHO - Centro de Estudos e Pesquisas de Hematologia e Oncologia
      • Sao Jose Rio Preto, Brazil
        • Recruiting
        • Fundacao Faculdade Regional de Medicina de Sao Jose Do Rio Preto
      • Vila Olímpia, Brazil
        • Recruiting
        • Centro Paulista de Oncologia S A
  • China
      • Beijing, China
        • Recruiting
        • China-Japan Friendship Hospital
      • Changchun, China
        • Recruiting
        • The First Hospital of Jilin University
      • Chengdu, China
        • Recruiting
        • West China Hospital, Sichuan University
      • Chengdu, China
        • Recruiting
        • Sichuan Cancer Hospital
      • Chongqing, China
        • Recruiting
        • Chongqing University Cancer Hospital
      • Guangzhou, China
        • Recruiting
        • Nanfang Hospital of Southern Medical University
      • Hangzhou, China
        • Recruiting
        • Sir Run Run Shaw Hospital of Zhejiang University School of Medicine
      • Harbin, China
        • Recruiting
        • Harbin medical university cancer hospital
      • Hefei, China
        • Recruiting
        • The second hospital of Anhui medical university
      • Hong Kong, China
        • Recruiting
        • Hong Kong Integrated Oncology Centre
      • Jinan, China
        • Recruiting
        • Cancer Hospital of Shandong First Medical University
      • Jordan, China
        • Recruiting
        • Hong Kong United Oncology Centre
      • Linyi, China
        • Recruiting
        • Linyi Cancer Hospital
      • Nanchang, China
        • Recruiting
        • The First Affiliated Hospital of NanChang University
      • Nanchang, China
        • Recruiting
        • The Second Affiliated Hospital of Nanchang University
      • Nanjing, China
        • Recruiting
        • Jiangsu Province Hospital
      • Neijiang, China
        • Recruiting
        • The Second People's Hospital of Neijiang
      • Shanghai, China
        • Recruiting
        • Shanghai East Hospital
      • Shenyang, China
        • Recruiting
        • Liaoning Cancer Hospital & Institute
      • Taiyuan, China
        • Recruiting
        • Shanxi Provincial Cancer hospital
      • Tianjin, China
        • Recruiting
        • Tianjin Medical University General Hospital
      • Wuhan, China
        • Recruiting
        • Union Hospital of Tongji Medical College, Huazhong University of Science and Technology
      • Xiangyang, China
        • Recruiting
        • Xiangyang Central Hospital
  • France
      • Lille, France
        • Recruiting
        • Hopital Albert Calmette - CHU Lille
  • Japan
      • Hidaka-shi, Japan
        • Recruiting
        • Saitama Medical University International Medical Center
      • Hirakata-shi, Japan
        • Recruiting
        • Kansai Medical University Hospital
      • Hirosaki-shi, Japan
        • Recruiting
        • Hirosaki University Hospital
      • Kawasaki-shi, Japan
        • Recruiting
        • St. Marianna University Hospital
      • Kitakyushu-shi, Japan
        • Recruiting
        • Hospital of the University of Occupational and Environmental Health
      • Kumamoto, Japan
        • Recruiting
        • Saiseikai Kumamoto Hospital
      • Kurume-shi, Japan
        • Recruiting
        • Kurume University Hospital
      • Matsusaka-shi, Japan
        • Recruiting
        • Matsusaka Municipal Hospital
      • Okayama, Japan
        • Recruiting
        • NHO Okayama Medical Center
      • Osaka, Japan
        • Recruiting
        • Osaka International Cancer Institute
      • Osaka, Japan
        • Recruiting
        • Osaka City General Hospital
      • Sakaishi, Japan
        • Recruiting
        • NHO Kinki-Chuo Chest Medical Center
      • Sapporo, Japan
        • Recruiting
        • Keijinkai Teine Keijinkai Hospital
      • Shinjuku-ku, Japan
        • Recruiting
        • Tokyo Medical University Hospital
      • Sunto-gun, Japan
        • Recruiting
        • Shizuoka Cancer Center
      • Toyoake-shi, Japan
        • Recruiting
        • Fujita Health University Hospital
      • Wakayama, Japan
        • Recruiting
        • Wakayama Medical University Hospital
      • Yokohama, Japan
        • Recruiting
        • Kanagawa Cancer Center
      • Yonago-shi, Japan
        • Recruiting
        • Tottori University Hospital
  • Malaysia
      • Kuala Lumpur, Malaysia
        • Recruiting
        • Hospital Kuala Lumpur
      • Kuantan, Malaysia
        • Recruiting
        • Hospital Tengku Ampuan Afzan
      • Petaling Jaya, Malaysia
        • Recruiting
        • Beacon Hospital Sdn Bhd
  • Portugal
      • Lisbon, Portugal
        • Recruiting
        • Unidade Local de Saude de Santa Maria, E.P.E. - Hospital Pulido Valente
  • South Korea
      • Goyang-si, South Korea
        • Recruiting
        • National Cancer Center
      • Jinju, South Korea
        • Recruiting
        • Gyeongsang National University Hospital
      • Seongnam, South Korea
        • Recruiting
        • Seoul National University Bundang Hospital
      • Seongnam, South Korea
        • Recruiting
        • CHA Bundang Medical Center, CHA University
      • Seoul, South Korea
        • Recruiting
        • Samsung Medical Center
      • Seoul, South Korea
        • Recruiting
        • Asan Medical Center
      • Seoul, South Korea
        • Recruiting
        • Severance Hospital, Yonsei University Health System
      • Suwon, South Korea
        • Recruiting
        • The Catholic university of Korea, St. Vincent's Hospital
  • Taiwan
      • Kaohsiung City, Taiwan
        • Recruiting
        • Kaohsiung Medical University Chung-Ho Memorial Hospital
      • Taichung, Taiwan
        • Recruiting
        • Taichung Veterans General Hospital
      • Tainan, Taiwan
        • Recruiting
        • National Cheng Kung University Hospital
      • Tainan, Taiwan
        • Recruiting
        • Chi Mei Hospital, Liouying
      • Taipei, Taiwan
        • Recruiting
        • Taipei Veterans General Hospital
      • Taipei, Taiwan
        • Recruiting
        • Tri-Service General Hospital
      • Taipei, Taiwan
        • Recruiting
        • Koo Foundation Sun Yat-Sen Cancer Center
      • Taoyuan, Taiwan
        • Recruiting
        • Chang Gung Memorial Hospital,Linkou
  • United Kingdom
      • London, United Kingdom
        • Recruiting
        • Charing Cross Hospital
  • United States
    • Alaska
      • Anchorage, Alaska, United States, 99508
        • Recruiting
        • Alaska Oncology & Hematology, LLC
    • California
      • Fountain Valley, California, United States, 97208
        • Recruiting
        • Orange Coast Memorial Medical Center Fountain Valley
      • Los Angeles, California, United States, 90027
        • Recruiting
        • California Research Institute
      • Los Angeles, California, United States, 91204
        • Recruiting
        • Los Angeles Cancer Network (LACN)
      • Santa Rosa, California, United States, 95403
        • Recruiting
        • Providence Medical Foundation
    • Florida
      • Bay Pines, Florida, United States, 33744
        • Recruiting
        • Bay Pines VA Healthcare System
      • Fort Lauderdale, Florida, United States, 33308
        • Recruiting
        • Holy Cross Hospital
      • Orange City, Florida, United States, 33763
        • Recruiting
        • Mid-Florida Hematology & Oncology Centers, P.A.
      • Plantation, Florida, United States, 33321
        • Recruiting
        • BRCR Global Plantation
    • Illinois
      • Hinsdale, Illinois, United States, 60521
        • Recruiting
        • Hope and Healing Cancer Services
    • Montana
      • Kalispell, Montana, United States, 59901
        • Recruiting
        • Logan Health Research
    • New York
      • Westbury, New York, United States, 11590
        • Active, not recruiting
        • Clinical Research Alliance
    • North Carolina
      • Pinehurst, North Carolina, United States, 28374
        • Recruiting
        • FirstHealth Cancer Center
    • Ohio
      • Canton, Ohio, United States, 44718
        • Recruiting
        • Gabrail Cancer Center
    • Oregon
      • Bend, Oregon, United States, 97701
        • Recruiting
        • St. Charles Health System
    • Texas
      • Houston, Texas, United States, 77030
        • Recruiting
        • University of Texas M. D. Anderson Cancer Center
      • Kingwood, Texas, United States, 77339
        • Recruiting
        • Lumi Research
    • Washington
      • Spokane, Washington, United States, 99208
        • Recruiting
        • Summit Cancer Treatment Center

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

  • Adult
  • Older Adult

Accepts Healthy Volunteers

No

Description

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 Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: Treatment
  • Allocation: Randomized
  • Interventional Model: Parallel Assignment
  • Masking: None (Open Label)

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
Experimental: Arm A: T-DXd
Participants will receive T-DXd plus pembrolizumab
Drug: Trastuzumab Deruxtecan
T-DXd will be administered at a dose of 5.4 mg/kg intravenously (IV) every 3 weeks (Q3W)
Other Names:
  • DS-8201a
  • T-DXd
  • ENHERTU®
Drug: pembrolizumab
pembrolizumab will be administered at a dose of 200 mg IV Q3W
Other Names:
  • KEYTRUDA®
Active Comparator: Arm B: Pemetrexed + Chemotherapy + Pembrolizumab
Participants will receive Pemetrexed plus platinum chemotherapy (cisplatin or carboplatin) plus pembrolizumab
Drug: pembrolizumab
pembrolizumab will be administered at a dose of 200 mg IV Q3W
Other Names:
  • KEYTRUDA®
Drug: Pemetrexed
Pemetrexed will be administered at a dose of 500 mg/m2 IV Q3W
Drug: Chemotherapy

One of the following two will be administered in Arm B:

Cisplatin at a dose of 75 mg/m2 IV or carboplatin AUC at a dose of 5 mg/mL/min IV

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Progression Free Survival by Blinded Independent Central Review
Time Frame: 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.
From date of randomization to the date of radiographic disease progression or death due to any cause, up to 54 months

Secondary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Overall Survival
Time Frame: 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.
From date of randomization to the date of death due to any cause, up to 85 months

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

Daiichi Sankyo

Collaborators

Merck Sharp & Dohme LLC

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (Actual)

October 24, 2025

Primary Completion (Estimated)

March 5, 2030

Study Completion (Estimated)

July 5, 2032

Study Registration Dates

First Submitted

March 21, 2025

First Submitted That Met QC Criteria

March 21, 2025

First Posted (Actual)

March 27, 2025

Study Record Updates

Last Update Posted (Actual)

January 8, 2026

Last Update Submitted That Met QC Criteria

January 6, 2026

Last Verified

January 1, 2026

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • DS8201-793
  • 2024-515658-26-00 (Ctis)
  • KEYNOTE-G23 (Other Identifier: Merck Sharp & Dohme LLC)
  • MK-3475-G23 (Other Identifier: Merck Sharp & Dohme LLC)

Plan for Individual participant data (IPD)

Plan to Share Individual Participant Data (IPD)?

YES

IPD Plan Description

De-identified individual participant data (IPD) on completed studies and applicable supporting clinical trial documents may be available upon request at https://vivli.org/. In cases where clinical trial data and supporting documents are provided pursuant to our company policies and procedures, Daiichi Sankyo will continue to protect the privacy of our clinical trial participants. Details on data sharing criteria and the procedure for requesting access can be found at this web address: https://vivli.org/ourmember/daiichi-sankyo/

IPD Sharing Time Frame

Completed studies that has reached a global end or completion with all data set collected and analyzed, and for which the medicine and indication have received European Union (EU) and United States (US), and/or Japan (JP) marketing approval on or after 01 January 2014 or by the US or EU or JP Health Authorities when regulatory submissions in all regions are not planned and after the primary study results have been accepted for publication.

IPD Sharing Access Criteria

Formal request from qualified scientific and medical researchers on IPD and clinical study documents on completed clinical trials supporting products submitted and licensed in the United States, the European Union and/or Japan from 01 January 2014 and beyond for the purpose of conducting legitimate research. This must be consistent with the principle of safeguarding study participants' privacy and consistent with provision of informed consent.

IPD Sharing Supporting Information Type

  • STUDY_PROTOCOL
  • SAP
  • ICF

Drug and device information, study documents

Studies a U.S. FDA-regulated drug product

Yes

Studies a U.S. FDA-regulated device product

No

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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