Trial of Trastuzumab Deruxtecan (Enhertu®) Plus Chemotherapy Plus or Minus Pembrolizumab versus Chemotherapy Plus Trastuzumab Plus or Minus Pembrolizumab in First-line Metastatic HER2-positive Gastric or GEJ Cancer

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Daiichi Sankyo Inc.

Participant type

Patients

Age range

18-64 years, 65+ years

Gender

Male and Female

Therapeutic area

Diseases [C] - Digestive System Diseases [C06]

Trial duration

10 Jun 2025 → ongoing

Decision date (initial)

2025-05-06

Transition trial

No

Low-intervention

No

Rare-disease indication

No

Vulnerable population

Yes

Funding sources

Daiichi Sankyo, Inc

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Safety, Pharmacokinetic, Efficacy, Pharmacodynamic, Pharmacoeconomic, Pharmacogenetic

To compare the efficacy between arms within each cohort as measured by PFS based on BICR assessment.

Secondary objectives 12

1. To compare the efficacy between arms within each cohort as measured by OS
2. To assess safety and tolerability between arms within each cohort
3. To compare the efficacy between arms within each cohort as measured by confirmed ORR
4. To compare the efficacy between arms within each cohort as measured by PFS based on investigator assessment
5. To further evaluate the efficacy between arms within each cohort by DoR
6. To further evaluate the efficacy between arms within each cohort by TTR
7. To further evaluate the efficacy between arms within each cohort by PFS2
8. To evaluate the PK of T-DXd, total antiHER2-antibody, and DXd
9. To assess the immunogenicity of T-DXd
10. To evaluate patient reported symptoms between arms within each cohort
11. To evaluate patient reported functioning between arms within each cohort
12. To evaluate patient reported overall health status between arms within each cohort

Conditions and MedDRA coding

Unresectable, Locally Advanced or Metastatic HER2 positive Gastric or Gastroesophageal Junction Cancer

Study design 2 periods

Regulatory references

Scientific advice from competent authorities

European Medicines Agency

Plan to share IPD

Yes

IPD plan description

De-identified individual participant data (IPD) 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/

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 16

1. Sign and date the Tissue Prescreening ICF, prior to HER2 and PD-L1 CPS central testing. Sign and date the Main Screening 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.
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. Previously untreated, unresectable, locally advanced or metastatic gastric or GEJ adenocarcinoma histologically confirmed by pathology report. Prior treatment in the perioperative and/or adjuvant setting is permissible, provided there is >6 months between the end of perioperative or neoadjuvant treatment and the diagnosis of recurrent disease. Note: Prior use of IO (ie, anti-PD-1/PD-L1) therapy in the (neo)adjuvant setting is allowed as long as there is >6 months between the end of IO therapy and the diagnosis of recurrent disease.
4. Centrally determined HER2-positive (IHC 3+ or IHC 2+/ISH-positive) gastric or GEJ cancer as classified by the American Society of Clinical Oncology-College of American Pathologists for GC on a tumor biopsy as detected by prospective central test on new (core, incisional, excisional biopsy) or existing tumor tissue taken at the time of diagnosis of locally advanced or metastatic disease. Note: Archival samples taken from a previous diagnostic or surgical biopsy not previously irradiated can be accepted. Details pertaining to tumor tissue submission can be found in the Study Laboratory Manual.
5. Centrally determined tumor PD-L1 CPS using the PD-L1 22C3 PharmDx assay: • For the Main Cohort: PD-L1 CPS ≥1 • For the Exploratory Cohort: PD-L1 CPS <1.
6. All participants must provide a tumor sample for tissue-based IHC staining to centrally determine HER2 expression, PD-L1 CPS, and other correlatives. The mandatory FFPE tumor sample can be from either the primary tumor or metastatic biopsy. Specimens with limited tumor content (as centrally determined) and cytology samples are inadequate for defining tumor HER2 and PD-L1 status.
7. At least 1 target measurable lesion on CT or MRI, assessed by the investigator based on RECIST v1.1. Lesions situated in a previously irradiated area are considered measurif progression has been shown in such lesions.
8. LVEF ≥50% within 28 days before randomization.
9. ECOG performance status of 0 or 1 assessed 7 days before randomization
10. Adequate organ and bone marrow function within 14 days before randomization. Transfusion (red blood cell or platelet) or G-CSF administration is not allowed within 14 days prior to the day on which bone marrow function is assessed or at any time after this day and prior to Cycle 1 Day 1. Please refer to the protocol for further details..
11. Adequate treatment washout period before randomization. Please refer to the protocol for further details.
12. Male and female participants of reproductive/childbearing potential must agree to use a highly effective form of contraception, as detailed in Section 10.3.4, or avoid intercourse during trial intervention and for at least 7 months for females and 4 months for males after the last dose of trial intervention. Please refer to the protocol for further details.
13. Male participants must not freeze or donate sperm starting at randomization and throughout the trial period, and at least 4 months after the last dose of T-DXd. For participants receiving pembrolizumab, trastuzumab, 5-FU, capecitabine, cisplatin, or oxaliplatin, sites should follow local label or institutional guidelines. Preservation of sperm should be considered prior to randomization in this trial.
14. Female participants must not donate, or retrieve for their own use, ova from the time of randomization and throughout the trial intervention period, and for at least 7 months after the last dose of T-DXd. For participants receiving pembrolizumab, trastuzumab, 5-FU, capecitabine, cisplatin, or oxaliplatin, sites should follow local label or institutional guidelines. They should refrain from breastfeeding throughout this time. Preservation of ova may be considered prior to randomization in this trial.
15. Is willing and able to comply with scheduled visits, trial intervention plan, laboratory tests, other trial procedures, and trial restrictions.
16. Is willing and able to participate in the collection of PRO data. Note: If a participant is unable to read the questionnaire (ie, blind or illiterate) or if the linguistic version is not available for the participant’s native or preferred language, that participant will be exempted from completing PRO questionnaires but may still participate in the trial.

Exclusion criteria 25

1. Prior exposure to other HER2-targeting therapies (including ADCs).
2. Lack of physiological integrity of the upper gastrointestinal tract (ie, severe Crohn disease that results in malabsorption) or malabsorption syndrome that would preclude feasibility of oral chemotherapy (ie, capecitabine).
3. Known DPD enzyme deficiency. Note: Screening for DPD enzyme deficiency is required only in regions/countries where DPD testing is SoC and with unknown DPD status. For regions/countries where DPD testing is not SoC, local practice should be followed.
4. Contraindications to trastuzumab, 5-FU, capecitabine, cisplatin, or oxaliplatin treatment as per local label.
5. Medical history of myocardial infarction within 6 months before randomization or symptomatic CHF (New York Heart Association Class II to IV). Participants with troponin levels above ULN at Screening (as defined by the manufacturer) and without any myocardial infarction -related symptoms should have a cardiologic consultation during the Screening Period to rule out myocardial infarction.
6. Has a corrected QT interval (QTcF) prolongation to >470 ms (females) or >450 ms (males) based on the average of the screening triplicate 12-lead ECG.
7. 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.
8. 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 chronic obstructive pulmonary disease, restrictive lung disease, pleural effusion, etc).
9. Any autoimmune, connective tissue, or inflammatory disorders (eg, rheumatoid arthritis,Sjogren’s, sarcoidosis etc) where there is documented, or a suspicion of, pulmonary involvement at the time of screening. Full details of the disorder should be recorded in the eCRF for participants who are included in the trial.
10. Prior pneumonectomy (complete).
11. Has spinal cord compression, known clinically active central nervous system metastases (defined as untreated and symptomatic) and/or carcinomatous meningitis. Note: Participants with previously treated brain metastases may participate provided they a) are radiologically stable (ie, without evidence of progression) for at least 4 weeks as confirmed by repeat imaging performed during trial screening, b) are clinically stable (ie, asymptomatic and have not required steroid treatment or anticonvulsant for at least 14 days before the first dose of trial intervention), and c) have recovered from the acute toxic effect of radiotherapy. A minimum of 2 weeks must have elapsed between the end of whole brain radiotherapy and trial randomization.
12. Has known additional malignancy that is progressing or has required active treatment within the past 3 years. Note: Participants with basal cell carcinoma of the skin, squamous cell carcinoma of the skin, or carcinoma in situ, excluding carcinoma in situ of the bladder, who have undergone potentially curative therapy are not excluded.
13. Has a history of severe hypersensitivity reactions (≥Grade 3) to either the drug substances or inactive ingredients in the drug product.
14. Has an uncontrolled infection requiring systemic antibiotics, antivirals, or antifungals.
15. Has substance abuse, other medical conditions such as clinically significant cardiac or psychological conditions, or any other circumstance such that it is not in the best interest of the participant to participate, that may, in the opinion of the investigator, interfere with the participant’s participation in the clinical trial or evaluation of the clinical trial results.
16. Has an active primary immunodeficiency, known uncontrolled active HIV infection, including HIV-infected participants with a history of Kaposi’s sarcoma and/or Multicentric Castleman’s Disease. Note: HIV testing is required prior to randomization for all participants enrolled in the EU and Japan. For other regions, HIV testing should be performed if required by local regulations or IRB/EC.
17. Has active or uncontrolled hepatitis B virus infection. Participants are eligible if they meet the criteria below: a. HBsAg positive with chronic HBV infection (lasting 6 months or longer) and meet the additional conditions below: • HBV DNA viral load <2000 IU/mL • Start or maintain antiviral treatment if clinically indicated as per the investigator b. Normal transaminase values, or if liver metastases are present, has abnormal transaminase values with AST/ALT <3 × ULN that are not attributable to HBV infection.
18. Has active or uncontrolled hepatitis C virus infection. Participants are eligible if they meet the conditions below: a. History of hepatitis C infection with an HCV viral load that is below the level of detection in the absence of antiviral therapy during the previous 4 weeks. b. Normal transaminase values or, if liver metastases are present, abnormal transaminase values with AST/ALT <3 × ULN that are not attributable to HCV infection.
19. Has history of receiving live, attenuated vaccine (mRNA and replication deficient adenoviral vaccines are not considered attenuated live vaccines) within 30 days prior to the first dose of trial intervention.
20. Has unresolved toxicities from previous anticancer therapy, defined as toxicities (other than alopecia) not yet resolved to ≤Grade 1 or baseline.
21. Is pregnant or breastfeeding or planning to become pregnant.
22. Applicable for main cohort only: Has an active autoimmune disease that has required systemic treatment in past 2 years(ie, with use of disease modifying agents, corticosteroids or immunosuppressive drugs). Replacement therapy (eg, thyroxine, insulin, or physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency, etc) is not considered a form of systemic treatment and is allowed.
23. Applicable for main cohort only: Has a diagnosis of immunodeficiency or is receiving chronic systemic steroid therapy (in dosing exceeding 10 mg daily of prednisone equivalent) or any other form of immunosuppressive therapy within 7 days prior the first dose of trial intervention.
24. Applicable for main cohort only: Has a known history of active tuberculosis (Mycobacterium tuberculosis). No testing for tuberculosis is required unless mandated by local health authority.
25. Applicable for main cohort only: History of allogenic tissue/solid organ transplant.

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 1

1. 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.

Secondary endpoints 12

1. OS is defined as the time interval from the date of randomization to the date of death due to any cause.
2. Incidence of TEAEs, SAEs, AESIs, deaths, ECOG performance status, vital signs, clinical laboratory results, ECGs, and ECHO/MUGA results.
3. ORR is defined as the proportion of participants with a BOR of confirmed CR or confirmed PR according to RECIST v1.1.
4. PFS is defined as the time interval from the date of randomization to the date of disease progression or death due to any cause. Disease progression will be determined by investigators’ assessment of tumor scans according to RECIST v1.1.
5. DoR is defined as the time from the date of first documentation of objective tumor response (CR or PR) for responding participants (CR or PR) only to the first documentation of objective tumor progression or death due to any cause.
6. TTR is defined as the time from the date of randomization to the date of the first documentation of objective response (CR or PR). Time to response will be measured for responding participants (CR or PR) only.
7. PFS2 is defined as the time from the date of randomization to the first documented progression on next-line therapy or death due to any cause.
8. Serum concentrations of T-DXd, total anti-HER2-antibody, and DXd.
9. The proportion of participants having treatment-emergent ADA. Titer and neutralizing antibodies will be determined when ADA is positive.
10. Time to confirmed deterioration and change from baseline in the following measure: • FACT-GA subscale
11. Time to confirmed deterioration and change from baseline in the following measure: • FACT-GA Physical Well-being subscale
12. Time to confirmed deterioration and change from baseline in the following measure: • EQ-5D-5L VAS

Investigational products

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

Test 1

Comparator 7

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Daiichi Sankyo Inc.

Sponsor organisation

Daiichi Sankyo Inc.

Address

211 Mount Airy Road

City

Basking Ridge

Postcode

07920-2311

Country

United States

Scientific contact point

Organisation

Daiichi Sankyo Inc.

Contact name

Clinical Trial office

Public contact point

Organisation

Daiichi Sankyo Inc.

Contact name

Clinical Trial office

Third parties 12

Locations

12 EU/EEA countries · 100 investigational sites

By country

Investigational sites

Country notifications

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

Results and documents

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

Documents 133 files

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

Application history

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