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Available 4- and 5-year updates for progression-free and for overall survival demonstrate a lasting clinical benefit for melanoma patients receiving anti-PD-directed immune checkpoint inhibitor therapy. However, at least one-half of the patients either do not respond to therapy or relapse early or late following the initial response to therapy. Little is known about the reasons for primary and/or secondary resistance to immunotherapy and the patterns of relapse. This review, prepared by an interdisciplinary expert panel, describes the assessment of the response and classification of resistance to PD-1 therapy, briefly summarizes the potential mechanisms of resistance, and analyzes the medical needs of and therapeutic options for melanoma patients resistant to immune checkpoint inhibitors. We appraised clinical data from trials in the metastatic, adjuvant and neo-adjuvant settings to tabulate frequencies of resistance. For these three settings, the role of predictive biomarkers for resistance is critically discussed, as well as are multimodal therapeutic options or novel immunotherapeutic approaches which may help patients overcome resistance to immune checkpoint therapy. The lack of suitable biomarkers and the currently modest outcomes of novel therapeutic regimens for overcoming resistance, most of them with a PD-1 backbone, support our recommendation to include as many patients as possible in novel or ongoing clinical trials.

The mOS of real-world patients treated with first-line BRAF-MEK with characteristics corresponding to the trial eligibility criteria (n¼95) was 21.9 (17.3-35.9) months and the 2-year OS was 47%.Conclusions: Long-term survival of real-world patients treated with first-line BRAF-MEK is significantly lower than of trial patients, mainly due to poorer baseline characteristics of real-world patients. Long-term survivors had more favorable characteristics compared to patients not reaching long-term survival. Based on these 2year OS results, real-world 5-year survival is expected to be lower than in trials.Legal entity responsible for the study: The authors.

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Background: Based on the first-line CheckMate 067 trial, nivolumab + ipilimumab (NIVO+IPI) has become a standard treatment in stage III/IV melanoma. However, limited data are available from prospective clinical trials on the effectiveness and tolerability of this combination in pretreated patients. Here, real-world data are presented especially for NIVO+IPI and also for NIVO in first and subsequent lines of therapy.Methods: NICO is a prospective, observational, multicenter study in Germany associated with ADOREG. Enrolled patients with advanced melanoma begin treatment with NIVO or NIVO+IPI according to the marketing authorization. Patients are followed for up to 5 years. The primary objective is overall survival (OS) in patients receiving NIVO+IPI. Secondary objectives include OS in patients treated with NIVO, progression-free survival, safety profiles and adverse event management, treatment patterns, and patient-reported outcomes.Results: To date (4th interim data cut, December 31, 2020), 762 patients with advanced melanoma have been enrolled; 486 patients received NIVO+IPI (62% in firstline, 34% in subsequent lines) and 276 patients received NIVO (74% first-line, 24% subsequent lines). Among pretreated patients, in both treatment arms approximately two-thirds had received 1 and around one-quarter had received 2 prior systemic therapies. In these pretreated patients, palliative radiotherapies were used 2e4 times more frequently at baseline compared with therapy-naïve patients (NIVO+IPI, 16.9% vs 3.7%; NIVO, 10.6% vs 4.4%). Objective response rates for NIVO+IPI and NIVO were similar in first (49% vs 50%) and subsequent (35% vs 36%) therapy lines. The corresponding median OS was superior for therapy-naïve patients (NIVO+IPI, 34.2 vs 11.2 months; NIVO, 31.1 vs 17.7 months). The general safety profiles of both immunooncology therapies were confirmed with no distinct treatment lineerelated differences.Conclusions: Overall, both therapies, NIVO and NIVO+IPI, in first and subsequent therapy lines exhibit effective and safe treatment options for patients with advanced melanoma in routine care in Germany.