The Multicentre Selective Lymphadenectomy Trial - 3

Inclusion Criteria:

1. Male or female patients ≥ 18 years of age at the time of consent

2. Written informed consent

3. Cytologically or histologically confirmed, resectable pathological Stage IIIB, C orD (Any T, N1b, N2b, N2c, N3b, or N3c) cutaneous or unknown primary melanoma, with orwithout primary tumour in situ

4. A minimum of one macroscopic lymph node, defined as:

• A palpable node, confirmed by pathology

• A non-palpable node, but enlarged per RECIST 1.1 criteria (≥ 15 mm in shortestdiameter) and confirmed by pathology

• An ultrasound or PET/CT scan positive lymph node of any size, confirmed bypathology.

5. Up to 3 satellite (defined as any foci of clinically evident cutaneous and/orsubcutaneous metastases occurring within 2 cm of but discontinuous from the primarymelanoma) or in-transit metastases (defined as clinically evident cutaneous and/orsubcutaneous metastases occurring >2 cm from the primary melanoma in the regionbetween the primary and the regional lymph node basin) are permitted if they arecompletely resectable.

6. Lymph node involvement in the groin (iliac, inguinal or both), axilla or neck onlyand may be unilateral or bilateral. Concurrent popliteal, epitrochlear or triangularintermuscular space (TIS) nodes permitted, as long as fully resectable.

7. Tumour amenable to a newly obtained core biopsy of a lesion which has not beenpreviously irradiated. Archival tissue from a past primary or nodal lesion (ifapplicable) or tissue taken for current diagnosis will also be collected ifavailable.

8. Systemic neoadjuvant immunotherapy is scheduled for administration with at least onePD-(L)-1 check point inhibitor (e.g. nivolumab, pembrolizumab, cemiplimab). Theimmunotherapy regimen may include other checkpoint inhibitors (e.g. ipilimumab,relatlimab, fianlimab). The patient should meet the fitness for treatmentrequirements as detailed in the relevant regulatory-approved Product Information orSummary of Product Characteristics.

9. Neoadjuvant course of treatment to be no longer than 6 weeks (allows for a maximumof 3 cycles at weeks 0, 3 and 6).

10. Eastern Cooperative Oncology Group (ECOG) performance status of 0-1.

11. Anticipated life expectancy of > 5 years.

Exclusion Criteria:

1. Uveal or mucosal melanoma.

2. Isolated satellite or in-transit metastases only (without any cytological orhistological proven lymph node involvement).

3. Involvement of any lymph node basin other than groin, axilla or neck. Concurrentpopliteal, epitrochlear or triangular intermuscular space (TIS) nodes permitted, aslong as fully resectable.

4. Clinical or radiographic evidence of distant metastasis (any AJCC 8th ed M Stage).

5. Previous history of lymph node surgery to the same nodal basin, that was moreextensive than a sentinel lymph node biopsy (SLNB).

6. Previous radiotherapy to the same nodal basin.

7. Any contraindication to the administration of nivolumab, ipilimumab, pembrolizumabor relatlimab per regulatory-approved product information and / or medicaloncologist.

8. Prior anti-PD-1, CTLA-4, PDL-1 or LAG 3 antibody exposure, or an agent directed toanother stimulatory or co-inhibitory T-cell receptor for any disease or anychemotherapy or experimental local or systemic drug treatment.

9. A plan to administer targeted therapy or any non-checkpoint inhibitor immunotherapy,or any intralesional therapy for melanoma in the neoadjuvant setting.

10. A plan to administer any experimental immunotherapy as part of a clinical trial inthe neoadjuvant setting.

11. Known additional malignancies (unless adequately treated) active within the previous 3 years, except for locally curable cancers that have been apparently cured. Thefollowing malignancies, if undergone successful definitive resection or curativetreatment, 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, butexcluding carcinoma in situ of the bladder) that have undergone potentiallycurative therapy

• Prostatic intraepithelial neoplasia

• In situ melanoma

• Atypical melanocytic hyperplasia

• Stage I melanoma

• Other malignancies for which the patient has been disease free for 3 years, notrequiring active anti-cancer therapy.

12. An active autoimmune disease or a requirement for chronic systemic steroid therapy (in dosing exceeding 10 mg daily of prednisone equivalent) or any other form ofimmunosuppressive therapy within 14 days prior to the first dose of study treatment.The following are permitted:

• Replacement therapy (e.g. thyroxine, insulin, or physiologic corticosteroidreplacement therapy for adrenal or pituitary insufficiency, etc)

• Inhaled or intranasal corticosteroids (with minimal systemic absorption) may becontinued if patient is on a stable dose

• Non-absorbed intra-articular steroid injections.

13. Has had an allogenic tissue/solid organ transplant.

14. Active Hepatitis B (defined as Hepatitis B surface antigen [HBsAg] reactive) orHepatitis C virus (defined as HCV RNA [qualitative] is detected) infection. Note: notesting for Hepatitis B and Hepatitis C is required unless mandated by local healthauthority.

15. Has a known history of Human Immunodeficiency Virus (HIV). Note: no testing for HIVis required unless mandated by local health authority.

16. Pregnant or breastfeeding females.

17. Concurrent medical or social conditions that may prevent the patient from attendingassessments or procedures per schedule.