Planned drug holidays during immunotherapy in advanced and metastatic melanoma patients: A nation-wide study

The optimal duration of immunotherapy (ITH) for patients(pts) with unresectable/metastatic melanoma has not been defined and de-escalation strategies are under debate. Drug holidays are defined as intentional cessation of immunotherapy for period of time, in pts with therapy benefits, till potential progression (PD). While avails of drug holidays include reduction of toxicity and treatment cost as well as increased quality of pts' life, there are also potential risks including PD. Our study aimed to describe disease control upon drug holidays in melanoma pts treated with palliative ITH. Pts with advanced unresectable/metastatic melanoma were treated with anti-PD1-based ITH. Patients were referred for drug holidays after ≥12 months of ITH. Pts who stopped the treatment due to toxicity were excluded from analysis. During study patients had imaging every 3 months. Primary endpoint was overall survival (OS), and secondary endpoints were median duration of drug holiday, 2nd progression-free survival (PFS2) after PD on drug holidays. 175 patients (80F/95M) treated for advanced unresectable/metastatic melanoma were referred for drug holidays. 116(67.4%) were BRAF-negative melanoma patients. 84 pts were treated with nivolumab, 6 with nivolumab+ipilimumab, 85 with pembrolizumab; and 152(86.9%) were treated in first line. Patients treated for ≥24 months(m) before drug holidays had significantly longer OS (p=0.003) and longer PFS till disease PD on drug holidays(p=0.00053) in multivariate analysis. PFS was dependent on best response before drug holidays with the longest in CR group (p=0.011). The median duration of drug holidays was 17 m (IQR: 8-24). At the median follow-up of 48 m (95%CI: 45-51), median OS was not reached, and 5-year OS rate was 89% (95%CI: 83-96). At ITH retreatment objective response was 64% and PFS2 rate at 1-year was 69% (95%CI: 48-99). At the time of analysis 141 pts were still on drug holidays and 11 died due to melanoma PD. For melanoma pts drug holidays may be offered to ITH responders. The majority of melanoma patients on drug holidays are progression-free at 24m after ITH discontinuation. ITH rechallenge allows achieving disease control after initial progression on drug holidays.