Safe Stop Ipilimumab-nivolumab (IPI-NIVO) Trial

Inclusion criteria

• 18 years of age or older
• Irresectable stage III or metastatic melanoma
• Treated with at least one dose of first-line ipilimumab-nivolumab and considered to be a candidate for maintenance treatment with nivolumab:

• previous systemic treatment, including immune-checkpoint inhibitors, in (neo)adjuvant setting for resectable melanoma is allowed
• in this protocol, nivolumab maintenance is interchangeable with pembrolizumab maintenance therapy.
• Response evaluation according to RECIST v1.1 30 using a diagnostic CT documenting target lesions every 12 (-2/+6) weeks from the start of ipilimumab-nivolumab:

• for patients with CR on a diagnostic CT at response evaluation, a low-dose CT (which is usually part of 18FDG-PET/CT) is allowed at baseline
• for patients with PR on a diagnostic CT at response evaluation, a low-dose CT (which is usually part of 18FDG-PET/CT) is allowed if sufficient target lesions are measurable for response evaluation according to RECIST v1.1 criteria 30
• in case of asymptomatic brain metastases prior to start of first-line ipilimumab-nivolumab, intracerebral tumor response should be confirmed using an MRI for response evaluation prior to inclusion in this study.
• Patients should be included after first CR/PR or first confirmed CR/PR according to RECIST v1.1 30:

• inclusion should take place no later than 5 weeks after first confirmed CR/PR
• in case of SD at first response evaluation, confirmed CR/PR is required for inclusion
• planned and willing to discontinue nivolumab within 4(+1) weeks after inclusion, i.e. first CR/PR or first confirmed CR/PR
• no later than 9 months after start of treatment with ipilimumab-nivolumab
• Presence of MRI brain for the screening of brain metastases (prior to discontinuation of ipilimumab-nivolumab)
• Participants with previously locally treated brain metastases may participate in case they meet the following criteria:

• completely asymptomatic brain metastases at inclusion
• MRI of brain at baseline and for response evaluation during treatment
• Signed and dated informed consent form

Exclusion criteria

• Patients with SD/PD according to RECIST v1.1
• Malignant disease other than being treated in this study. Exceptions to this exclusion include the following: malignancies that were treated curatively and have not recurred within 2 years prior to start of study treatment; completely resected basal cell and squamous cell skin cancers and any completely resected carcinoma in situ.
• Presence of symptomatic brain metastases:

• prior to first-line treatment with ipilimumab-nivolumab, or;
• when defined as new or progressive brain metastases at the time of study entry;
• brain metastases with need for steroid treatment in the last 8 weeks prior to study entry Note: An incidental epileptic seizure caused by a brain lesion is not considered an exclusion criterion.

(provided that the other in- and exclusion criteria are met);

• Presence of leptomeningeal metastases;
• Systemic chronic steroid therapy (>10mg/day prednisone or equivalent) at inclusion or patients who need or needed any other second-line immunosuppressive therapy (e.g. infliximab, mycophenolate mofetil) for the treatment of immune related adverse events (irAEs). Note: local steroids such as topical, inhaled, nasal and ophthalmic steroids are allowed.
• Any psychological, familial, sociological or geographical condition potentially hampering compliance with the study protocol and follow-up schedule; those conditions should be discussed with the patient before registration in the trial