Precision Radiation of Immune Checkpoint Therapy Resistant Melanoma Metastases

Inclusion criteria

• Age 18 and above
• ECOG performance status of 0-1
• Signed and dated written informed consent before the start of specific protocol procedures.
• Patient has initiated PD-1 inhibitor treatment (alone or in combination with CTLA-4 inhibitor) as the first line of therapy for unresectable metastatic cutaneous melanoma and been on the treatment for at least 3 months and progressed on the treatment. Patients with primary or secondary resistance to the PD-1 inhibitor treatment will be included. Progression is defined as at least 30% enlargement of at least one metastasis or appearance of new metastasis. A fine-needle aspiration (FNA) biopsy from a progressing lesion or a new lesion is recommended to confirm the presence of viable tumor cells.
• Patients on adjuvant treatment with PD-1 inhibitors that during the treatment develop unresectable biopsy confirmed metastases can also be included in the study.
• Have at least one new or progressing lesion safely amenable to irradiation in the opinion of the treating radiation oncologist AND at least one, not-to-be-irradiated new or progressing lesion measurable by CT or MRI per RECIST 1.1 criteria where up to four radiation target fields are allowed
• No contraindication for continuing immunotherapy after the radiotherapy intervention

Exclusion criteria

• Inability to understand given information or undergo study procedures according to protocol
• Pregnant or breast-feeding. Patients must agree to use safe contraception during and for 3 months after study treatment.
• A condition requiring systemic treatment with either corticosteroids (\> 10 mg daily prednisone equivalents) or other immunosuppressive medications within 30 days before start of study treatment. Inhaled or topical steroids and adrenal replacement doses \>10 mg daily prednisone equivalents are permitted.
• Has an active infection requiring systemic therapy.
• Concomitant therapy with any anti-tumor medications, other than PD-1/CTLA-4 inhibitors or 30 days before and after treatment in this trial.
• Prior radiotherapy preventing the study intervention with precision radiotherapy
• Location, size or number of metastases is deemed as excessive or not appropriate for precision radiotherapy
• Central nervous system (CNS) metastases at baseline, with the exception of those subjects who have previously-treated CNS metastases (surgery ± radiotherapy, radiosurgery, or gamma knife) and who meet both of the following criteria: a) are asymptomatic and b) have no requirement for steroids or anticonvulsants.
• Prior malignancy. Subjects who have had another malignancy should be disease-free for 5 years, or should have a history of completely resected non-melanomatous skin carcinoma or successfully treated in situ carcinoma