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 tobe 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 pembrolizumabmaintenance therapy.

• Response evaluation according to RECIST v1.1 30 using a diagnostic CT documentingtarget 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 lesionsare measurable for response evaluation according to RECIST v1.1 criteria 30

• in case of asymptomatic brain metastases prior to start of first-lineipilimumab-nivolumab, intracerebral tumor response should be confirmed using anMRI for response evaluation prior to inclusion in this study.

• Patients should be included after first CR/PR or first confirmed CR/PR according toRECIST 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 forinclusion

• planned and willing to discontinue nivolumab within 4(+1) weeks afterinclusion, 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 todiscontinuation of ipilimumab-nivolumab)

• Participants with previously locally treated brain metastases may participate incase 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 thisexclusion include the following: malignancies that were treated curatively and havenot recurred within 2 years prior to start of study treatment; completely resectedbasal cell and squamous cell skin cancers and any completely resected carcinoma insitu.

• 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 tostudy entry Note: An incidental epileptic seizure caused by a brain lesion isnot 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 inclusionor patients who need or needed any other second-line immunosuppressive therapy (e.g.infliximab, mycophenolate mofetil) for the treatment of immune related adverseevents (irAEs). Note: local steroids such as topical, inhaled, nasal and ophthalmicsteroids are allowed.

• Any psychological, familial, sociological or geographical condition potentiallyhampering compliance with the study protocol and follow-up schedule; thoseconditions should be discussed with the patient before registration in the trial