Immunotherapy Discontinuation in Metastatic Melanoma: Lessons from Real-Life Clinical Experience

Abstract

Background: Immunotherapy has revolutionized outcomes for melanoma patients, by significantly prolonging survival and probably even curing a fraction of metastatic patients. In daily practice, treatment for responding patients is often discontinued due to treatment-limiting toxicity, or electively, following a major tumor response. To date, the criteria for a safe stop and the optimal duration of treatment remain unclear. Patients and methods: This is a real-world single-site cohort of 106 advanced melanoma patients who were treated with immunotherapy and who discontinued treatments in the absence of disease progression. Here, we describe their long-term outcomes, and analyze the differential characteristics between patients who ultimately experienced progression and those who remained in unmaintained durable response. Results: Patients were treated with anti-PD-1 monotherapy (81%) or in combination with ipilimumab (19%) for a median of 15.2 m (range, 0.7–42.3 m). Upon discontinuation, 75.5% had achieved a complete response (CR). After a median follow-up of 20.8 m (range, 6–58) from discontinuation, 32% experienced disease progression. Median time to progression was 8.5 m (range, 1.5–37). Response to re-induction with anti-PD-1 was observed in 47%. On multivariate analysis, achieving a non-CR response, immunotherapy given in advanced line, and shorter treatment duration were significantly associated with lesser progression-free survival. Conclusions: This is one of the few reports on real-world melanoma patients who discontinued immunotherapy while responding to treatment. This study reveals the key factors to bear in mind when considering an elective treatment cessation. Specifically, patients with non-CR as best response and patients treated in an advanced-line setting should be treated for longer periods, and elective discontinuation should not take place prior to 18 m.

Prognoses of patients with melanoma who continue/discontinue anti-programmed death-1 therapy after achieving a complete response in a real-world setting: a multicentre retrospective study

“…Asher et al . described 19 (24%) relapses among 80 patients who achieved a CR 6 . These studies and our results indicate that, in the real world, 80–90% of patients who achieved a CR had good outcomes even if the treatment had been discontinued.…”

“…Dear Editor , It is not known how long anti‐programmed death‐1 (anti‐PD‐1) therapy should be continued for patients with melanoma who have achieved a good response. Only a few studies have investigated this topic, and most did not include acral or mucosal melanomas 1–6 . We retrospectively analysed 57 patients with advanced melanoma (including 12 patients with unresectable lymph node involvement) treated with anti‐PD‐1 monotherapy who achieved a complete response (CR) from 16 collaborating institutions treated during the period from 1 September 2014 to 31 July 2019.…”

Immune Checkpoint Activity Regulates Polycystic Kidney Disease Progression

“…Hence, long-term use of ICIs, as needed for the treatment of ADPKD, is likely not translatable. However, several cancer studies suggest a durable response and progression-free survival after discontinuation of mono-or combination ICI therapy for 6-12 months depending on the type of cancer (68)(69)(70). The underlying mechanisms associated with this treatment-free survival remain unclear but likely correspond to a permanent remodeling of the TME associated with innate and adaptive immune memory.…”

Factors Determining Long-Term Antitumor Responses to Immune Checkpoint Blockade Therapy in Melanoma

“…In a single cohort study examining patients with advanced melanoma treated with anti-PD-1 monotherapy of nivo + ipi, multivariate analysis revealed that patients with a non-CR to treatment as best overall response (BOR) and in cases where immunotherapy was given in the advanced line (where previous lines of treatment included ipilimumab monotherapy, targeted therapy, prior pembrolizumab, or nivo + ipi) should be treated for longer periods of time, with elective discontinuation discouraged prior to the 18-month timepoint ( 48 ). Finally, in another study examining CR in patients following anti-PD-1 treatments, 102 patients stopped treatment after a CR after a median duration of 9.4 months.…”