Inclusion Criteria:

1. Written informed consent

2. At least 18 years old at the time of signing Informed Consent Form (ICF).

3. Histologically or cytologically confirmed Head and Neck Squamous Cell Carcinoma
(HNSCC) with evidence of metastatic or locally recurrent/advanced disease not
amenable to curative local therapy (surgery or radiation). Eligible primary tumor
locations include oral cavity, oropharynx (p16 positive or negative), hypopharynx
and larynx. Patients with unknown primary HNSCC, SCC of nasopharynx or paranasal
sinuses are excluded.

4. For oropharyngeal cancer, documented Human Papillomavirus (HPV) status (p16
Immunohistochemistry (IHC) or HPV DNA/RNA) is required.

5. At least one measurable lesion per RECIST v1.1

6. ECOG performance status of 0 or 1.

7. Life expectancy greater than 12 weeks.

8. Cohort-Specific Criteria:

- Cohort A: R/M HNSCC in the second- or third-line setting, pretreated with an
Immune Checkpoint Inhibitor (ICI) and progressed on platinum-based therapy in
the R/M setting.

- Cohort B: R/M HNSCC in the first-line setting, systemic therapy-naïve in the
R/M setting.

9. Willingness and ability to undergo both a newly obtained, image-guided or surgical
tumor biopsy during the screening period and a mandatory on-treatment tumor biopsy.

10. No evidence of past or active hepatitis B infection, w/exception

11. No evidence of active hepatitis C infection. Patients with undetectable Hepatitis C
Virus (HCV) Ribonucleic Acid (RNA) test are eligible.

12. Participants must have no known history of HIV infection. HIV-1/2 testing is only
required for patients with known risk factors.

13. Willingness and ability to comply with scheduled visits, treatment plans, laboratory
tests, and other protocol requirements.

14. Patients with feeding tubes (e.g. gastrostomy tubes) are eligible.

15. Patients must have adequate organ function, as defined in protocol

16. A female participant is eligible to participate if she meets all the criteria listed
in protocol

17. Male participants are eligible to participate if they agree to criteria listed in
protocol during the study intervention period and for at least 5 months after the
last dose of GSK5764227.

Exclusion Criteria:

1. Participants with non-squamous histologies (e.g., adenocarcinoma, salivary gland
carcinomas, and sarcomas) or HNSCC arising from the nasopharynx or paranasal sinuses
are excluded. Participants with unknown primary tumors (even if squamous histology
is confirmed) are also excluded.

2. Has ongoing adverse reaction(s) from prior therapy that have not recovered to ≤Grade
1 or to the baseline status preceding prior therapy (excluding, for example,
alopecia, hearing loss, vitiligo, endocrinopathy managed with replacement therapy,
and Grade 2 neuropathy), or that the Investigator, with the agreement of the Study
PI, considers to be not clinically relevant for the tolerability of study
intervention in the current clinical study.

3. Any participation in another investigational study within 4 weeks prior to
screening.

4. Prior treatment with orlotamab, enoblituzumab, I-Dxd, or other B7-H3 targeted
agents.

5. Has a history of autoimmune disease that has required systemic treatments in the 2
years prior to screening.

- For dostarlimab: Patients requiring chronic systemic immunosuppressive therapy
within 30 days prior to first dose are excluded, except for those receiving low-dose
corticosteroids (≤10 mg/day prednisone equivalent), inhaled/topical steroids, or
physiological replacement therapy.

6. Serious arteriovenous thromboembolic events (such as deep vein thrombosis, pulmonary
embolism, etc.) within 3 months prior to the first dose (w/exceptions)

7. Evidence of brain metastasis unless all the following criteria are met:

- Asymptomatic.

- Medically stable for at least 4 weeks prior to initial dosing.

- No steroid treatment required for at least 2 weeks prior to initial dosing.

- No imaging evidence of severe edema located around the tumor lesion.

- Also excluded are untreated progression due to brain metastasis during or after
the last treatment prior to screening, evidence of meningeal/brainstem
metastasis, or evidence of spinal cord compression (detected by radiographic
examination, symptomatic or not).

8. History of another primary solid tumor except for the following:

- Solid tumors that have been cured and inactive for ≥2 years before enrollment
and at very low risk of recurrence.

- Prior HNSCC primary that has been curatively treated with no evidence of
disease at enrollment.

- Adequately treated non-melanoma skin cancer or lentigo maligant without
evidence of relapse.

- Adequately treated carcinoma in situ (e.g., cervix carcinoma in situ) without
evidence of relapse.

- Definitively treated non-metastatic prostate cancer.

9. Has had any major surgery (such as craniotomy, thoracotomy, or laparotomy) within 4
weeks prior to first dose of study intervention.

10. History of prior allogeneic or autologous bone marrow transplant or solid organ
transplant.

11. Any of the cardiac examination abnormalities as listed in protocol.

12. Serious or poorly controlled hypertension, including history of hypertensive crisis,
hypertensive encephalopathy, adjustment of antihypertensive medications due to poor
blood pressure control within 2 weeks prior to the first dose, or recurrent systolic
blood pressure ≥160 mmHg or diastolic blood pressure ≥100 mmHg during the screening
period.

13. Clinically significant bleeding symptoms or significant bleeding tendency within 1
month prior to the first dose, and:

- Receipt of any transfusion of blood products (including platelets or red blood
cells) or administration of colony-stimulating factors (including G-CSF,
granulocyte-macrophage colony-stimulating factor, or recombinant
erythropoietin) within 14 days before enrollment, and

- Donation of blood or blood products more than 500 mL (approximately 1 pint)
within 1 month prior to the first dose of study intervention.

14. Serious infections within 4 weeks prior to the first dose, including but not limited
to the list in protocol.

15. Any history or current evidence of pulmonary disease

16. History of severe neurological or psychiatric disorder (including, but not limited
to, epilepsy, dementia, or major depression) or any serious and/or unstable medical,
psychiatric, or other condition (including laboratory abnormalities) that, in the
Investigator's judgment, could interfere with the participant's safety, ability to
provide informed consent, protocol compliance, or the assessment of study outcomes.

17. Has any active renal condition (e.g., requirement for dialysis, or any other
significant renal condition that could affect the participant's safety).

18. Allergy or hypersensitivity to any component of GSK5764227 (ADC, antibody, toxin
GSK5757810); history of severe allergies (e.g., anaphylactic shock) or severe
infusion-related reactions; or idiosyncrasy to recombinant humanized or mouse
proteins. For Cohort B, this also includes allergy or hypersensitivity to
dostarlimab or any of its components.

19. Receipt of live vaccine within 30 days of the start of study intervention.

20. Has any condition that jeopardizes the safety of the patient or interferes with the
assessment of the study, as judged by the Investigator.

21. Any of the following hepatic conditions:

- Current hepatic encephalopathy, hepatorenal syndrome, or Child-Pugh Class B or
more severe cirrhosis.

- Cirrhosis or current unstable liver or biliary disease per Investigator
assessment, defined by the presence of ascites, encephalopathy, coagulopathy,
hypoalbuminemia, esophageal/gastric varices, or persistent jaundice.

o Note: Stable noncirrhotic chronic liver disease (including Gilbert's syndrome
or asymptomatic gallstones) or hepatobiliary involvement of malignancy is
acceptable if the participant otherwise meets entry criteria.

- Documented presence of HBsAg, HBcAb, or HBsAb (except when HBsAb is
attributable to previous vaccination) at screening or within 3 months prior to
the first dose of study intervention.

- Positive HCV antibody test result at screening or within 3 months prior to the
first dose of study intervention.

o Note: Participants with a positive HCV antibody test result due to prior
resolved disease may be enrolled if a confirmatory negative HCV RNA test is
obtained and the participant otherwise meets entry criteria.

- Positive HCV RNA test result at screening or within 3 months prior to the first
dose of study intervention.

- Note: The HCV RNA test is optional; participants with a negative HCV
antibody test are not required to undergo HCV RNA testing.

22. Has received prior anticancer therapy and has not completed a washout period of at
least 5 half-lives or 28 days, whichever is shorter, prior to the first dose of
study intervention, or requires continued use these medications during the study.

23. History of local palliative radiotherapy within 2 weeks prior to the first dose of
study treatment. Extensive field radiotherapy requires a washout of 4 weeks prior to
the first dose of study treatment.

24. Concurrent use of the following medications within 7 days prior to the first dose of
study intervention, or need to continue during the study