Participants are eligible to be included in the study only if all of the following criteria apply:
Age.
Male or female participant must be ≥ 18 years of age at the time of signing the ICF.
HER2-positive (IHC 3+ or IHC 2+ ISH-positive) on a tumor biopsy as detected by prospective central test on the primary or metastatic tumor tissue sample. Note: If the participants’ HER2 status has already been assessed using same assay, testing platform, and scoring manual as part of the screening process from another AstraZeneca study using the prospective central test, this test result may be used for the determination of eligibility if the tumor sample age requirement is met for this study.
Central laboratory confirmed PD-L1 CPS ≥ 1 by PD‑L1 expression determined from the primary or metastatic tumor tissue sample. Note: If the participants’ PD-L1 expression has already been assessed using same assay, testing platform, and scoring manual as part of the screening process from another AstraZeneca study using the prospective central test, this test result may be used for the determination of eligibility if the tumor sample age requirement is met for this study.
Provision of tumor tissue sample from recent biopsy adequate for HER2 and PD-L1 testing. Additional details on sample requirements will be provided in the Laboratory Manual.
Previously untreated, unresectable, locally advanced or metastatic gastric or GEJ adenocarcinoma.
Prior treatment in the neo-adjuvant and/or adjuvant setting is permissible provided there is a > 6-month interval between the last administration of the prior regimen and the diagnosis of locally advanced or metastatic disease.
Prior use of approved immune CPIs (ie, anti-PD-1/PD-L1) in the neo-adjuvant and/or adjuvant setting is permissible provided there is > 6 months between the last administration of immune CPIs and the diagnosis of locally advanced or metastatic disease. However, patients with progression on neo-adjuvant or recurrence on adjuvant immune CPIs treatment should be excluded.
WHO or ECOG PS of 0 or 1 with no deterioration over the 2 weeks prior to the day of the first dosing.
Have measurable target disease assessed by the Investigator based on RECIST v1.1. Tumor lesions situated in a previously irradiated area are considered measurable if progression has been demonstrated in such lesions.
Have adequate organ and bone marrow function within 14 days before randomization as described in Table 6. All parameters must be the most recent results available. Note: Transfusion (red blood cell or platelet) or G-CSF administration is not allowed within 14 days prior to the day on which marrow function is assessed, or at any time after this day and prior to C1D1. See Protocol
Have a life expectancy of at least 6 months.
LVEF ≥ 55% within 28 days before randomization. Participants with ejection fraction of 50% to 54% may still be eligible with discussion with Sponsor AND after consultation with cardiology AND after being medically optimized.
Adequate treatment washout period before randomization, defined in Table 7. See Protocol
Participants must be ≥ 30 kg.
vidence of post-menopausal status or negative serum pregnancy test for FOCBP who are sexually active with a non-sterilized male partner. For FOCBP, a negative result for serum pregnancy test (test must have a sensitivity of at least 25 mIU/mL) must be available at the Screening Visit and urine β-HCG pregnancy test prior to each administration of study intervention. FOCBP are defined as those who are not surgically sterile (ie, underwent bilateral salpingectomy, bilateral oophorectomy, or complete hysterectomy) or post-menopausal (Appendix G). Women will be considered post-menopausal if they have been amenorrheic for 12 months without an alternative medical cause.
FOCBP who are sexually active with a non-sterilized male partner must use at least one highly effective method of contraception, presented in Table 27, from the time of screening and must agree to continue using such precautions for 7 months after the last dose of study intervention or as required by prescribing information for the Investigator’s choice of therapy received (following cisplatin USPI, this restriction period is 14 months), whichever is longer. Not all methods of contraception are highly effective. It is strongly recommended that non-sterilized male partners of FOCBP use a male condom plus spermicide while on study and for 7 months after the last dose of study intervention or as required by prescribing information for the Investigator’s choice of therapy received (following cisplatin USPI, this restriction period is 14 months), whichever is longer. (Note: Male condoms are not reliable as a sole contraception method). Complete heterosexual abstinence for the duration of the study and drug washout period is an acceptable contraceptive method if it is in line with the participant’s usual lifestyle (consideration must be made to the duration of the clinical study); however, periodic or occasional abstinence, the rhythm method, and the withdrawal method are not acceptable.
Female participants must not donate, or retrieve for their own use, ova from the time of screening and throughout the study treatment period, and for at least 7 months after the last dose of study intervention or as required by prescribing information for the Investigator’s choice of therapy received (following cisplatin USPI, this restriction period is 14 months), whichever is longer. They should refrain from breastfeeding throughout this time. Preservation of ova may be considered prior to enrollment in this study.
Non-sterilized male participants who are sexually active with a female partner of childbearing potential must use a condom with spermicide from screening to 6 months after the last dose of study intervention or as required by prescribing information for the Investigator’s choice of therapy received (following cisplatin USPI, this restriction period is 11 months), whichever is longer. Complete heterosexual abstinence for the duration of the study and drug washout period is an acceptable contraceptive method if it is in line with the participant’s usual lifestyle (consideration must be made to the duration of the clinical study); however, periodic or occasional abstinence, the rhythm method, and the withdrawal method are not acceptable. It is strongly recommended for the female partners of a male participant to also use at least one highly effective method of contraception throughout this period, as described in Table 27. In addition, male participants should refrain from fathering a child throughout the study treatment period and for 6 months after the last dose of study intervention or as required by prescribing information for the Investigator’s choice of therapy received (following cisplatin USPI, this restriction period is 11 months), whichever is longer. Male participants should refrain from freezing or donating sperm from the time of screening until 6 months after the last dose of the study intervention or as required by prescribing information for the Investigator’s choice of therapy received (following cisplatin USPI, this restriction period is 11 months), whichever is longer. Preservation of sperm may be considered prior to enrollment in this study.
Capable of giving signed informed consent as described in Appendix A which includes compliance with the requirements and restrictions listed in the ICF and in this CSP.
Provision of signed and dated written ICF prior to any mandatory study specific procedures, sampling, and analyses.
Lack of physiological integrity of the upper gastrointestinal tract.
Known partial or total DPD enzyme deficiency based on local or central laboratory testing, with testing required only in regions where it is SoC. Central testing will be available for participants where testing is SoC and with unknown DPD status. For regions where DPD testing is not SoC, local practice should be followed.
Contraindication to pembrolizumab or trastuzumab, contraindications to fluoropyrimidine (5-FU and capecitabine) or platinum (cisplatin and oxaliplatin) treatment as per local label.
History of another primary malignancy except for malignancy treated with curative intent with no known active disease within 3 years before the first dose of study intervention and of low potential risk for recurrence. Exceptions also include adequately resected basal cell carcinoma or squamous cell carcinoma of the skin, lentigo maligna that has undergone potentially curative therapy or adequately treated in situ disease without evidence of disease.
Persistent toxicities caused by previous anti-cancer therapy excluding alopecia, not yet improved to Grade ≤ 1 or baseline. Note: Participants may be enrolled with the following chronic, stable Grade 2 toxicities (defined as no worsening to > Grade 2 for at least 3 months prior to the first dose of study intervention and managed with SoC treatment) which the Investigator deems related to previous anti-cancer therapy:
Chemotherapy-induced neuropathy
Fatigue
Vitiligo
Endocrine disorders, that are controlled with replacement hormone therapy. Residual Grade 1 or Grade 2 endocrinopathies from prior immune CPIs may be allowed (eg, hypothyroidism/hyperthyroidism, type I diabetes, hyperglycemia, adrenal insufficiency, adrenalitis).
Participants with irreversible toxicity that is not reasonably expected to be exacerbated by study intervention in the opinion of the Investigator may be included (eg, hearing loss).
Spinal cord compression or brain metastases unless asymptomatic, treated and stable and not requiring corticosteroid or anticonvulsant may be included in the study if they have recovered from the acute toxic effect of radiotherapy. A minimum of 2 weeks must have elapsed between the end of whole brain radiotherapy or spinal cord compression and study randomization.
Uncontrolled infection including TB (clinical evaluation that includes clinical history, physical examination, radiographic findings, and TB testing in line with local practice) and active hepatitis A infection.
Uncontrolled infection requiring IV antibiotics, anti-virals, or antifungals.
Receipt of live, attenuated vaccine (mRNA and replication deficient adenoviral vaccines are not considered attenuated live vaccines) within 30 days prior to the first dose of study intervention. Note: Participants, if enrolled, should not receive live vaccine during the study and up to 30 days after the last dose of study intervention.
Has a known history of active primary immunodeficiency, uncontrolled active HIV infection with serologic evidence of viral infection within 28 days of C1D1. Participants should be tested for HIV prior to randomization if required by local regulations or IRB/IEC.
Has chronic or active hepatitis B; however, participants who have chronic hepatitis B are eligible only if they meet all of the following criteria:
Controlled HBV load: HBV DNA < 100 U/mL by PCR or undetectable.
ALT is normal.
Remain on anti-viral therapy, per institutional practice, during the study intervention and follow-up periods to ensure adequate viral suppression.
Absence of cirrhosis or fibrosis on prior imaging or biopsy.
Absence of HCV co-infection or history of HCV co-infection.
Access to a local hepatitis B expert during and after the study.
Has chronic or active hepatitis C; however, participants who have chronic hepatitis C are eligible if ALT is normal (NA for participants with liver metastases) and HCV RNA is undetectable by PCR, either spontaneously or in response to a successful prior course of anti-hepatitis C therapy. Controlled hepatitis C viral load is defined as undetectable hepatitis C RNA by PCR either spontaneously or in response to a successful prior course of anti-hepatitis C therapy.
Has substance abuse or any other medical conditions such as clinically significant cardiac or psychological conditions, that may, in the opinion of the Investigator, interfere with the participant’s participation in the clinical study or evaluation of the clinical study results.
Participants with a medical history of MI within 6 months before enrollment, symptomatic CHF (NYHA Class II to IV), or clinically significant arrhythmia. Participants with troponin levels above ULN at screening (as defined by the manufacturer), and without any myocardial related symptoms, should have a cardiologic consultation before enrollment to rule out MI.
QTcF prolongation to > 470 ms (females) or > 450 ms (males), based on average of the screening triplicate 12-lead ECG.
Participants with congenital long QT syndrome and those with a history of QT prolongation associated with other medications that required discontinuation of that medication.
Active or prior documented autoimmune or inflammatory disorders requiring chronic treatment with steroids or other immunosuppressive treatment.
Lung criteria:
History of (non-infectious) ILD/pneumonitis, has current ILD/pneumonitis, or where suspected ILD/pneumonitis cannot be ruled out by imaging at screening.
Lung-specific intercurrent clinically significant illnesses including, but not limited to, any underlying pulmonary disorder (eg, pulmonary emboli within 3 months of the study enrollment, severe asthma, severe COPD, restrictive lung disease, pleural effusion, etc.)
Prior pneumonectomy (complete).
As judged by the Investigator, any evidence of diseases (such as hearing loss, severe or uncontrolled systemic diseases, including ongoing or active infection, uncontrolled hypertension, and active bleeding diseases, serious chronic gastrointestinal conditions associated with diarrhea), which, in the Investigator’s opinion, makes it undesirable for the participant to participate in the study or that would jeopardize compliance with the protocol.
Any active non-infectious skin disease (including any grade rash, urticaria, dermatitis, ulceration, or psoriasis) requiring systemic treatment.
A pleural effusion, ascites or pericardial effusion that requires drainage, peritoneal shunt, or CART.
Previous severe toxicity, which is clinically significant as judged by the Investigator, observed during the participant’s previous exposure to any of the medications to be used in combination in the study.
History of any of the following: drug-induced severe cutaneous adverse reaction (including, but not limited to Stevens-Johnson syndrome/toxic epidermal necrolysis, or drug reaction with eosinophilia and systemic symptoms).
Participants with a known allergy or hypersensitivity to any of the drugs used as study intervention, or any of the excipients of the product, or a history of severe hypersensitivity reactions to other monoclonal antibodies.
Prior exposure, without adequate treatment washout period before randomization, defined in Table 7. See Protocol
Prior exposure to other HER2 targeting therapies, ADCs, or therapeutic anti-cancer vaccines.
Any concurrent anti-cancer treatment with the exception of receptor activator of nuclear factor kappa-B ligand inhibitors (eg, denosumab for the treatment of complications resulting from bone metastases). Concurrent use of hormonal therapy for non-cancerrelated conditions (eg, HRT therapy) is allowed.
Herbal and natural remedies which are used with immune-modulating intent.
EGFR TKIs must not be given concomitantly and should be used with caution in the 90 days after the last dose of rilvegostomig.
Have had major surgical procedure (excluding placement of vascular access) or significant traumatic injury within 4 weeks prior to the first dose of study intervention or an anticipated need for major surgery during the study.
Current or prior use of immunosuppressive medication within 14 days before the first dose of study intervention. The following are exceptions to this criterion:
Intranasal, inhaled, topical steroids or local steroid injections (eg, intra-articular injection).
Systemic corticosteroids at physiologic doses not to exceed 10 mg/day of prednisone or its equivalent.
Steroids as premedication for hypersensitivity reactions or as an anti-emetic (eg, CT scan premedication).
History of allogenic tissue/solid organ transplant
Previous randomization in the present study or a prior T-DXd or rilvegostomig study regardless of intervention arm assignment.
Participation in another clinical study with a study intervention or investigational medicinal device administered in the last 6 months prior to randomization, or concurrent enrollment in another clinical study, unless it is an observational (non-interventional) clinical study or during the follow-up period of an interventional study.
Involvement in the planning and/or conduct of the study (applies to both AstraZeneca staff and/or staff at the study site).
Judgment by the Investigator that the participant should not participate in the study if the participant is unlikely to comply with study procedures, restrictions, and requirements.
For females only: Currently pregnant (confirmed with positive pregnancy test) or breastfeeding female participants, or participants who are planning to become pregnant.
The following restrictions apply while the participant is receiving study intervention and for the specified times before and after: