Inclusion Criteria:
* Patients 18 years or older with pathology-confirmed recurrent and/or metastatic (R/M) squamous cell carcinoma (SCC) who have not received systemic therapy specifically for R/M SCC. Tumors reported as mixed histology are ineligible. Patients must have 1-5 R/M lesions. Contiguous matted nodal conglomerates will be counted as a single lesion.
* Initial primary site of disease is not restricted and may include the head and neck, lung, skin, urogenital, gynecological, anal canal, gastrointestinal, or squamous cell carcinoma of an unknown primary site.
* Patients must have measurable disease under RECIST v1.1. A superficial lesion may be measured with calipers if it meets RECIST clinical measurability requirements and is documented reproducibly. Baseline target lesions and measurement methods must be recorded before radiotherapy.
* Patients may have recurrent disease as a single lesion or multiple metastatic deposits. If a single recurrent lesion, it must be considered unresectable by the treating oncologic surgeon, either technically or functionally (i.e., morbidity of resection outweighs potential benefit of resection).
* Any PD-L1 combined positive score (CPS).
* Disease may be human papillomavirus (HPV)-positive or HPV-negative.
* Prior anti-PD-1 and/or anti-CTLA-4 therapy given with curative intent for the initial primary cancer, including neoadjuvant, definitive or adjuvant treatment, is permitted. Recurrence during or after such therapy is eligible without a minimum recurrence-free interval, provided no systemic therapy has been initiated specifically for R/M SCC. Patients cannot have had Grade ≥3 irAEs or an immune-mediated event for which rechallenge is contraindicated.
* Eastern Cooperative Oncology Group (ECOG) performance status of 0-2.
* Obtain Thyroid-Stimulating Hormone (TSH) and free T4 at screening; repeat as specified. A thyroid abnormality alone is not exclusionary if clinically stable on appropriate management.
* Female patients must meet one of the following:
1. Postmenopausal for at least one year before the screening visit, or
2. Surgically sterile (i.e., undergone a hysterectomy or bilateral oophorectomy), or
3. If subject is of childbearing potential (defined as not satisfying either of the above two criteria), meet either (i) or (ii):
* Use effective contraception from consent through at least 5 months after the last Opdualag dose and at least 90 days after the last vilastobart dose, whichever ends later. Acceptable methods and pregnancy potential must be documented under institutional practice. This protocol retains a two-method approach, unless a highly effective method or qualifying abstinence is documented by the investigator.
* Agree to practice true abstinence for the full prevention interval in (i) when this is in line with the preferred and usual lifestyle of the subject. (Periodic abstinence \[e.g., calendar, ovulation, symptom-thermal, post ovulation methods\] and withdrawal are not acceptable contraception methods).
* Male patients, even if surgically sterilized (i.e., status post vasectomy), must meet (a) or (c), and also comply with (b) when applicable:
1. Use effective barrier contraception throughout treatment and for at least 90 days after the last vilastobart dose, or longer if subsequently required by an approved protocol amendment. If the partner can become pregnant, use an additional effective method unless qualifying abstinence applies.
2. Also adhere to any applicable study-specific pregnancy prevention program; this is additional to (a) or (c).
3. Agree to practice true abstinence throughout treatment and for at least 90 days after the last vilastobart dose when this is in line with the preferred and usual lifestyle of the subject. (Periodic abstinence \[e.g., calendar, ovulation, symptom-thermal, post-ovulation methods\] and withdrawal are not acceptable methods of contraception.)
* Ability to understand a written informed consent document, and the willingness to sign it.
Exclusion Criteria:
* Central nervous system metastasis.
* Greater than 5 metastatic deposits. Contiguous matted nodal conglomerates will be counted as a single lesion.
* Any patient with a lesion requiring acute cytoreduction through use of induction chemotherapy, as determined by the treating medical oncologist.
* Solid organ transplant or autoimmune disease requiring chronic systemic immunosuppression. Stable autoimmune disease that does not require systemic immunosuppression is permitted after PI review, with specialist input when indicated. Active autoimmune disease that makes immunotherapy unsafe is exclusionary until adequately controlled. Physiologic hormone replacement and topical or inhaled therapy alone do not constitute chronic systemic immunosuppression. Prior severe immune-related toxicity and contraindications to rechallenge remain exclusionary under Section 4.5.1 of the study protocol.
* Performance status Eastern Cooperative Oncology Group (ECOG) ≥ 3.
* A concurrent active separate metastatic malignancy of a different histology than SCC. However, any previously treated malignancy considered in remission at the time of enrollment is permitted.
* Any of the following severe laboratory abnormalities within 14 days of registration:
1. Sodium \<128 mmol/L or \>155 mmol/L.
2. Potassium \<3.0 mmol/L or \>6 mmol/L.
3. Glucose \<40 mg/dl or \>400 mg/dl.
4. Total serum calcium, adjusted for albumin, \<7 mg/dL or \>12.5 mg/dL. These limits do not apply to ionized calcium.
5. Magnesium \<0.9 mg/dl or \>3 mg/dl.
6. estimated glomerular filtration rate (eGFR) ≤40 mL/min.
7. aspartate aminotransferase (AST) / alanine aminotransferase (ALT) ≥3 x upper limit of normal (ULN).
8. Total bilirubin ≥1.5 x ULN. Participants with documented Gilbert syndrome may have total bilirubin ≤3 x ULN. Assess for active hepatic disease or obstruction when clinically indicated; treatment-emergent hepatic toxicity is managed.
9. Absolute Neutrophil Count (ANC) ≤1 ×10\^9/L
10. Platelets ≤50 ×10\^9/L
11. Hemoglobin (Hgb) ≤8 g/dL
12. Abnormal values corrected into the acceptable range are permitted. Document qualifying repeat results within the required screening window before confirming eligibility and registration.
* Unstable angina and/or congestive heart failure requiring hospitalization within 3 months prior to enrollment.
* Transmural myocardial infarction within 3 months prior to enrollment.
* Medical or psychiatric illness that would compromise treatment tolerance or study participation, including uncontrolled clinically significant infection. Defer registration until such infection is adequately controlled. Well-controlled HIV, hepatitis B or hepatitis C does not by itself exclude participation. The principal investigator must document infection control, adequate organ function and a treatment/monitoring plan, with infectious-disease or hepatology input when needed, including antiviral therapy and reactivation monitoring where indicated.
* Pregnancy, breastfeeding, or inability/unwillingness to follow the contraception requirements above. Breastfeeding is prohibited during study treatment and until at least 5 months after the last Opdualag dose and 90 days after the last vilastobart dose, whichever is later.
