Inclusion Criteria:
1. ≥ 18 years of age
2. Written informed consent
3. Histologically confirmed, resectable stage II to IV cutaneous squamous cell carcinoma defined as:
Non-head and neck cuSCC:
1. stage II (T2, N0, M0)
2. stage III (T3, N0, M0; or T1-3, N1, M0)
3. stage IV (T1-3, N2 or N3, M0; or T4a or T4b, any N, M0)
Cutaneous head and neck CC:
1. stage II (T2, N0, M0)
2. stage III (T3, N0, M0)
3. stage IV (T4a or T4b, any N, M0)
4. In-transit metastases (ITM) are permitted if they are completely resectable. ITM defined as skin or subcutaneous metastases that are \> 20 mm from the primary lesion but not beyond the regional nodal basin.
5. Measurable disease according to RECIST version 1.1 criteria (≥10 mm longest diameter for primary lesions and / or ≥10 mm in shortest diameter for lymph nodes as determined by CT imaging) within 2 weeks of the start of study treatment.
6. Tumour amenable to a newly obtained core biopsy of a lesion which has not been previously irradiated. Archival tissue from a past primary or nodal cuSCC lesion (if applicable) or tissue taken for current diagnosis will also be collected.
7. Previous radiotherapy permitted if performed at a prior site of disease not seen at baseline.
8. Eastern Cooperative Oncology Group (ECOG) performance status of 0-1
9. Documented adequate haematological, hepatic, renal, and thyroid function determined by blood pathology
10. Anticipated life expectancy of \> 12 months
11. Women of childbearing potential must have a negative serum pregnancy test within 24 hours of the first dose of study treatment or within 72 hours if this is not feasible. Effective contraception should be used for the duration of study treatment and for 5 half-lives (or 5 months) after the last dose. Egg donation (ova, oocytes) should be avoided for the same period. There are no partner-pregnancy or sperm donation avoidance requirements for male patients.
Exclusion Criteria:
1. Clinical or radiographic evidence of distant metastasis
2. SCC of the eyelid, vulva, penis and perianus
3. Any contraindication to the administration of nivolumab and / or relatlimab
4. Prior anti-PD-1, CTLA-4 (Cytotoxic T-lymphocyte associated protein 4), PDL-1 (Programmed death-ligand 1) or LAG 3 (Lymphocyte-Activation Gene 3) antibody exposure, or an agent directed to another stimulatory or co-inhibitory T-cell receptor for any disease or any chemotherapy or experimental local or systemic drug treatment
5. Active autoimmune disease or a requirement for chronic steroid therapy other than hormone replacement therapy
The following are permitted:
* Vitiligo
* Type I diabetes mellitus on stable insulin therapy
* Residual autoimmune hypothyroidism on stable hormone replacement
* Resolved childhood asthma or atopy
* Psoriasis not requiring systemic treatment
* Autoimmune conditions which are not expected to recur in the absence of an external trigger.
6. Has a diagnosis of immunodeficiency or is receiving chronic systemic steroid therapy (in doses exceeding 10 mg daily of prednisone or equivalent) or any other form of immunosuppressive therapy within 14 days prior to the first dose of study treatment.
The following are permitted:
* Replacement therapy (e.g. thyroxine, insulin, or physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency, etc.)
* Inhaled or intranasal corticosteroids (with minimal systemic absorption) may be continued if patient is on a stable dose
* Non-absorbed intra-articular steroid injections.
7. Known additional malignancies (unless adequately treated) active within the previous 3 years, except for locally curable cancers that have been apparently cured.
The following malignancies, if undergone successful definitive resection or curative treatment, are permitted:
* Basal cell carcinoma of the skin
* Squamous cell carcinoma of the skin
* Carcinoma in situ (e.g. breast carcinoma, cervical cancer in situ, but excluding carcinoma in situ of the bladder) that have undergone potentially curative therapy
* Prostatic intraepithelial neoplasia
* In situ melanoma
* Atypical melanocytic hyperplasia
* Multiple primary melanomas
* Other malignancies for which the patient has been disease free for 3 years, not requiring active anti-cancer therapy.
8. Uncontrolled or significant cardiovascular disease including, but not limited to any of the following:
* Myocardial infarction (MI) or stroke/transient ischemic attack within the 6 months prior to consent
* Uncontrolled angina within the 3 months prior to consent
* Any history of clinically significant arrhythmias (such as poorly controlled atrial fibrillation, ventricular tachycardia, ventricular fibrillation, or torsades de pointes)
* QTc (corrected QT interval) prolongation \> 480 ms
* History of other clinically significant cardiovascular disease (i.e. cardiomyopathy, congestive heart failure with New York Heart Association functional classification III-IV, pericarditis, significant pericardial effusion, significant coronary stent occlusion, poorly controlled venous thrombosis, etc)
* Cardiovascular disease-related requirement for daily supplemental oxygen
* History of 2 or more M.I.s OR 2 or more coronary revascularisation procedures (regardless of the number of stent placements during each procedure)
* Patients with history of myocarditis, regardless of aetiology.
9. Troponin T (TnT) or I (TnI) \>2 × institutional ULN (upper limit of normal). Participants with TnT or TnI levels between \>1 to 2 × ULN will be permitted if repeat levels within 24 hours are ≤1 ULN. If TnT or TnI levels are between \>1 to 2 × ULN within 24 hours, the participant may undergo a cardiac consultation and be considered for treatment, following cardiologist recommendation. When repeat levels within 24 hours are not available, a repeat test should be conducted as soon as possible. If TnT or TnI repeat levels beyond 24 hours are \<2 × ULN, the participant may undergo a cardiac consultation and be considered for treatment, following cardiologist recommendation. Notification of the decision to enrol the participant following cardiologist recommendation must be made to the Lead Investigator.
10. Has a history of (non-infectious) pneumonitis/interstitial lung disease that required steroids or has current pneumonitis or current interstitial lung disease.
11. Has an active infection requiring systemic therapy.
12. Has had an allogenic tissue/solid organ transplant
13. Has a known history of Human Immunodeficiency Virus (HIV). Note: no testing for HIV is required unless mandated by local health authority.
14. Has a known history of Hepatitis B (defined as Hepatitis B surface antigen \[HBsAg\] reactive) or known active Hepatitis C virus (defined as HCV RNA \[qualitative\] is detected) infection. Note: no testing for Hepatitis B and Hepatitis C is required unless mandated by local health authority.
15. Pregnant or breast-feeding females
16. Concurrent medical or social conditions that may prevent the patient from attending assessments per schedule.
