Discontinuation of anti-PD1 in advanced melanoma: an observational retrospective study from the Italian Melanoma Intergroup

Abstract

BackgroundImmunotherapy has improved the survival of patients with stage IV melanoma. In responders, clinical benefits may be long-lasting and persist even after treatment discontinuation. The optimal duration of anti-PD1 (anti-Programmed cell death-1) therapy in metastatic melanoma patients remains to be elucidated. Moreover, limited data are available on clinical outcomes of patients that discontinued anti-PD1 immunotherapy in a real-life setting. The aim of this study was to evaluate the progression-free survival (PFS) in patients with metastatic melanoma who interrupted anti-PD-1 treatment in the in the absence of disease progression. MethodsWe retrospectively reviewed patients with advanced/metastatic melanoma treated with anti-PD1 immunotherapy at 23 Italian Melanoma Intergroup (IMI) centres. The study investigated the risk of relapse in patients who stopped anti-PD1 therapy due to CR (Complete response), treatment-related toxicity, or by their own choice after a long period of treatment. Clinical and biological factors associated with or without recurrence were evaluated. ResultsThe study population included 237 patients. The median age of patients was 68.9 years (standard deviation: 13; range 33–95). The median time on treatment was 33 months (standard deviation: 18, 7; range 1–98). Among the 237 patients, 128 (54%) interrupted the anti-PD1 for CR, 74 patients (31.2%) for adverse events (37 patients in CR, 27 patients in partial response (PR), ten patients in stable disease (SD), and 35 patients (14.8%) by their own choice (12 patients in CR, 17 patients in PR, and 6 patients in SD). After a mean follow-up of 21 months (range 1–81), PFS after anti-PD1 discontinuation was 85.7%. Thirty-four patients (14.3%) developed disease progression after a median of 12 months (range 1–35): ten patients (29.4%) after discontinuation in CR, 17 patients (50%) after discontinuation for treatment-related toxicity (seven in CR, five in PR, five in SD), and seven (20.6%) after discontinuation due to the patient’s decision (two in CR, four in PR, one in SD). Only 7.8% of patients who interrupted in CR (10/128), along with 23% of patients who interrupted for limiting toxicity (17/74) and 20% of patients who interrupted by their own choice (7/35), developed recurrence. Regarding patients who discontinued therapy because of CR, we observed a negative association between recurrence and site of primary melanoma, especially mucosal sites (p = <0.05, HR (Hazard ratio) 15.57 IC (confidence interval) 95% 2.64–91.73). Moreover, M1b patients who achieved a CR showed a lower number of relapses (p = <0.05, HR 3.84 IC 95% 1.40–8.48). ConclusionsThis study shows in a real-life setting that, with anti-PD-1 therapy, long-lasting responses, can be maintained after anti-PD1 interruption. In 70.6% of cases, recurrences were observed among patients who did not obtain a CR at treatment discontinuation.