Adjuvant immunotherapy with anti-PD-1 monoclonal antibody Pembrolizumab (MK-3475) versus placebo after complete resection of high-risk Stage III melanoma: A randomized, double- blind Phase 3 trial of the EORTC Melanoma Group

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• Patient enrollment will follow a three steps procedure as illustrated in Section 4 (step 1 registration, step 2 central confirmation of PD-L1 expression, step 3 enrollment and randomization through IVRS). Patients must meet all of the criteria described in Section 3 to be eligible for enrollment. 1) Registration- step 1 (ORTA Step 1) Before patient registration, written informed consent for tumor testing must be given according to ICH/GCP, and national/local regulations. Note: if a patient signs the Registration Informed Consent before the complete lymph node dissection (CLND) was performed, please contact the medical monitor to assess eligibility before registering in ORTA. ♦ At least 18 years of age. ♦ No mucosal or ocular melanoma. ♦ Melanoma with unknown origin of the primary is eligible. ♦ Complete resection of Stage III melanoma (AJCC R0) with histologically confirmed cutaneous melanoma metastatic to lymph node, classified as (AJCC, 2010): Stage IIIA with metastasis > 1 mm; any Stage IIIB or IIIC. No past or current in-transit metastases or satellitosis. ♦ Patient population IIIA (> 1 mm metastasis) is capped at a maximum of 20% of the total patient population. ♦ Mandatory to ship tumor sample for evaluation of PD-L1 expression. A tumor sample obtained at resection or tissue obtained from the biopsy must not be previously irradiated. During the screening period, the tumor sample must be sent to the central pathology laboratory for PD-L1 expression testing. Patients will be eligible to participate regardless of the level of PD-L1 expression. ♦ PD-L1 testing is mandatory: tumor material will be collected from positive lymph nodes (LN) embedded in paraffin. If the resection samples from LNs are not adequate for PD-L1 testing, the primary melanoma must be collected. Patients whose samples are inadequate for PD-L1 determination will not be enrolled. ♦ In addition the primary melanoma may also be collected if available to evaluate the PD-L1 expression.
• 2) Central confirmation of PD-L1 expression - step 2 This central confirmation through EORTC is required for enrolling the patient in step 3.
• 3) Enrollment and randomization -step 3 (ORTA Step 2) Before patient enrollment, written informed consent to participate in the trial must be given according to ICH/GCP, and national/local regulations. ♦ The resection of Stage III lymph nodes must have been performed in complete compliance with the Criteria for adequate surgical procedures for CLND that is displayed in Appendix F. This must be documented in the medical file (including pathology report); patients without documentation of adequate resection are not eligible. ♦ To be considered as adequate, the surgical and pathological procedures should have included at least the following: ♦ Head and Neck ♦ Minimum of 15 pathologically investigated nodes ♦ Face, ear, and anterior scalp: parotidectomy plus modified radical neck dissection ♦ Posterior scalp: modified radical neck dissection plus suboccipital nodes. For this specific localization, a CLND will be considered as adequate if at least 5 LN have been investigated ♦ Upper Extremity ♦ Minimum of 10 pathologically investigated nodes ♦ Axillary node dissection included at least 10 nodes taken from Levels I and II ♦ Level III nodes dissected if they were clinically involved ♦ Pectoralis minor muscle may be divided or sacrificed with the specimen at the discretion of the surgeon ♦ Lower Extremity ♦ Minimum of 5 pathologically investigated nodes ♦ Superficial inguinal node dissection was performed for nonpalpable nodal involvement ♦ If Cloquet’s node was positive, a deep inguinal node dissection was performed ♦ Lymph Node Dissection for Nodal Recurrence
• 3) Enrollment and randomization -step 3 (ORTA Step 2) – Continues ♦ Regional node recurrence was treated using the appropriate lymphadenectomy as above ♦ Diagnosis of regional node recurrence was made by fine needle aspiration technique to avoid contaminating the region with tumor, followed by CLND as above ♦ The maximum duration from surgery to first study drug treatment is 13 weeks. Treatment should start only after complete wound healing from the surgery. Note: if there is a delay of 1-7 days exceeding 13 weeks due to extreme unforeseen circumstances, the eligibility should be discussed with the medical monitor. ♦ Disease status for the post-surgery baseline assessment must be documented by full Chest/Abdomen/Pelvis CT and/or MRI with Neck CT and/or MRI (for Head and Neck primaries) and complete clinical examination after the informed consent and prior to enrollment. Note: if a patient had laboratory/imaging tests as part of local routine guidelines (standard of care) prior to signing informed consent, the procedures will be acceptable for screening purposes if they are within the window required by the protocol. ♦ Disease-free (no loco-regional relapse or distant metastasis); no clinical evidence for brain metastases. ♦ BRAF mutation status (known or not done). ♦ ECOG performance status of 0 or 1. ♦ Patient demonstrates adequate organ function ♦ Prior treatment for melanoma ♦ In case of an indication for post lymph node dissection radiotherapy, this must have been completed within the 13 weeks post-surgery period and prior to treatment start. Note: radiotherapy may alter the process of wound healing. If the wound healing is not complete patient will not be eligible. ♦ No prior therapy for melanoma except surgery for primary melanoma lesions; patients who have previously received IFN for thick primary melanomas without evidence of lymph node involvement are eligible. ♦ No history of (non-infectious) pneumonitis that required steroids or current pneumonitis. No history of or current interstitial lung disease. ♦ No history of another malignancy or a concurrent malignancy. Exceptions include patients who have been disease-free for 5 years, or patients with a history of completely resected nonmelanoma skin cancer or successfully treated in situ carcinoma are eligible, for example cervical cancer in situ. ♦ No active autoimmune disease that has required systemic treatment in past 2 years (i.e. with use of disease modifying agents, corticosteroids or immunosuppressive drugs). Replacement therapy (eg., thyroxine, insulin, or physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency, etc.) is not considered a form of systemic treatment. ♦ No active infection requiring therapy. ♦ Patients with hyperthyroidism or hypothyroidism but that are stable on hormone replacement will not be excluded. ♦ No diagnosis of immunodeficiency, no systemic steroid therapy or any other form of immunosuppressive therapy within 7 days prior to the first dose of study treatment
• 3) Enrollment and randomization -step 3 (ORTA Step 2) continues ♦ No known history of human immunodeficiency virus (HIV), active Hepatitis B or Hepatitis C. ♦ Patients who received treatment with live vaccines within 30 days prior to the first dose of study medication are not eligible. Examples of live vaccines include, but are not limited to, the following: measles, mumps, rubella, chicken pox, shingles, yellow fever, seasonal flu, H1N1 flu, rabies, BCG and typhoid vaccine. ♦ Patient must not have received prior treatment with any anti-CTLA4 monoclonal antibody or anti-PD-1, or PD-L1 or PD-L2 agent. Examples of PD-1 inhibitors (include, but are not limited to): pembrolizumab (MSD); Nivolumab (also known as BMS-936558, MDX- 1106, ONO-4538) (Bristol-Myers Squibb); Pidilizumab (CT-11) (Cure- Tech/Teva); and AMP-224 (Amplimmune). Examples of PD-L1 inhibitors (include, but are not limited to): BMS- 936559 (also known as MDX-1105) (Bristol-Myers Squibb); MPDL3280A (also known as RG7446) (Roche Genentech); and MEDI4736 (MedImmune). ♦ Patient is not currently participating and receiving study therapy or has not participated in a study of an investigational agent and received study therapy or used an investigation device within 4 weeks prior to the first dose of treatment ♦ Women of child bearing potential (WOCBP) must have a negative serum (or urine) pregnancy test within 72 hours prior to the first dose of study treatment. ♦ WOCBP should use adequate birth control methods, as defined by the investigator, during the study treatment period and for a period of 120 days after the last dose of study drug. A highly effective method of birth control is defined as those which result in low failure rate (i.e. less than 1% per year) when used consistently and correctly. ♦ Note: abstinence is acceptable if this is established and preferred contraception for the patient and is accepted as a local standard. ♦ Appendix N is to be used where applicable for specific countries and sites adhering to Clinical Trial Facilitation Group guidelines for clinical trials (e.g. United Kingdom, Norway, Sweden, Portugal, etc). ♦ Female patients who are breast feeding should discontinue nursing prior to the first dose of study treatment and until 120 days after the last dose of study drug . ♦ Absence of any condition hampering compliance with the study protocol and follow-up schedule; those conditions should be discussed with the patient before registration in the trial. ♦ Patient will not be eligible: if patient is or has an immediate family member (e.g., spouse, parent/legal guardian, sibling or child) who is investigational site or Sponsor staff directly involved with this trial, unless prospective IRB approval (by chair or designee) is given allowing exception to this criterion for a specific subject. Once eligibility has been verified, the treatment arm will be randomly allocated to the patient. Important note: All eligibility criteria must be adhered to.