Discontinuation of Immune Checkpoint Inhibition in Patients with Advanced Unresectable Melanoma Achieving CR, PR, or SD.

Background: The optimal duration of immunotherapy (ITH) remains undefined for patients with metastatic melanoma, and debates on de-escalation strategies are ongoing. Patients in the pivotal KEYNOTE and CheckMate trials who experienced a complete response (CR) on ITH had long-term responses, even after treatment was terminated early because of toxicity or at the physician's discretion.

Objective: Our study explores the duration of planned ITH drug holidays-intentional ITH suspension until disease progression off treatment-in patients with unresectable and metastatic melanoma treated for at least 6 months with ITH.

Patients and methods: We enrolled 222 patients who received anti-programmed cell death protein-1-based ITH, experienced stable disease, partial response, or complete response during ITH, and had no treatment-limiting toxicities.

Results: At a median follow-up of 63 months since the first ITH cycle, median overall survival after the drug holiday start (OS3) was not reached, and the 5-year OS3 rate was 79.3%. Median progression-free survival since the start of drug holiday (PFS3) was not reached, with a 3-year PFS3 rate of 65% for all patients, and the highest rate was in the complete response group (72.3%). After the drug holidays, upon disease progression off treatment, the objective response rate to ITH reintroduction was 58.9%. Again, durable, ongoing objective responses were achieved on ITH reintroduction after drug holidays. The best radiological response achieved before drug holidays correlated with the duration of ITH drug holidays, with the longest duration of disease control without treatment for complete responders.

Conclusions: Drug holidays in patients with unresectable and metastatic melanoma after an objective response or prolonged disease stabilization during ITH result in durable control of the disease, particularly in patients with complete response.