BackgroundWe have previously reported significantly longer overall survival (OS) with ipilimumab 10 mg/kg versus ipilimumab 3 mg/kg in patients with advanced melanoma, with higher incidences of adverse events (AEs) at 10 mg/kg. This follow-up analysis reports a 5-year update of OS and safety.MethodsThis randomized, multicenter, double-blind, phase III trial included patients with untreated or previously treated unresectable stage III or IV melanoma. Patients were randomly assigned (1:1) to ipilimumab 10 mg/kg or 3 mg/kg every 3 weeks for 4 doses. The primary end point was OS.ResultsAt a minimum follow-up of 61 months, median OS was 15.7 months (95% CI 11.6 to 17.8) at 10 mg/kg and 11.5 months (95% CI 9.9 to 13.3) at 3 mg/kg (HR 0.84, 95% CI 0.71 to 0.99; p=0.04). In a subgroup analysis, median OS of patients with asymptomatic brain metastasis was 7.0 months (95% CI 4.0 to 12.8) in the 10 mg/kg group and 5.7 months (95% CI 4.2 to 7.0) in the 3 mg/kg group. In patients with wild-type or mutantBRAFtumors, median OS was 13.8 months (95% CI 10.2 to 17.0) and 33.2 months (95% CI 19.4 to 45.2) in the 10 mg/kg group, and 11.2 months (95% CI 9.2 to 13.8) and 19.7 months (95% CI 11.6 to 25.3) in the 3 mg/kg group, respectively. The incidence of grade 3/4 treatment-related AEs was 36% in the 10 mg/kg group vs 20% in the 3 mg/kg group, and deaths due to treatment-related AEs occurred in four (1%) and two patients (1%), respectively.ConclusionsThis 61-month follow-up of a phase III trial showed sustained long-term survival in patients with advanced melanoma who started metastatic treatment with ipilimumab monotherapy, and confirmed the significant benefit for those who received ipilimumab 10 mg/kg vs 3 mg/kg. These results suggest the emergence of a plateau in the OS curve, consistent with previous ipilimumab studies.Trial registration numberNCT01515189.

Background: Current standard of care for patients (pts) after resection of high-risk stage II melanoma is observation. In the phase 3 double-blind KEYNOTE-716 trial we evaluated pembrolizumab (pembro) versus placebo in pts with resected AJCC-8 stage IIB or IIC melanoma. We present results of the first recurrence-free survival (RFS) interim analysis.Methods: Eligible pts aged !12 years with complete resection of cutaneous stage IIB or IIC melanoma with negative sentinel lymph node biopsy were randomized 1:1 to pembro 200 mg (2 mg/kg for pediatric pts) or placebo Q3W for 17 cycles (up to 1 year). Randomization was stratified by T category 3b, 4a, 4b (adults) with a separate stratum for pediatric pts. Treatment continued until disease recurrence or unacceptable toxicity. The primary endpoint was RFS per investigator assessment. Safety was also evaluated. The data cutoff date for the interim analysis was December 4, 2020.Results: Overall, 976 pts (64% stage IIB; 34.8% stage IIC) were randomized (487 pembro; 489 placebo). At median follow-up of 14.4 months, pembro significantly prolonged RFS vs placebo (HR 0.65, 95% CI 0.46-0.92; P¼0.00658; median not reached for both). 54 (11.1%) vs 82 (16.8%) pts had a recurrence with almost halving of distant recurrence events in the pembro (23) vs placebo (38) group. The 12-month RFS rate was 90.5% vs 83.1%. Grade !3 any-cause AEs occurred in 125 (25.9%) vs 83 (17.1%) pts in the pembro vs placebo group. Grade !3 drug-related AEs occurred in 78 (16.1%) vs 21 (4.3%) pts; 74 (15.3%) vs 12 (2.5%) discontinued due to a drug-related AE. No deaths due to any-cause AE or drug-related AEs occurred with pembro; four deaths due to any-cause AEs occurred with placebo. Immunemediated AEs occurred in 36.2% vs 8.4%, most commonly hypothyroidism (15.7% vs 3.5%) and hyperthyroidism (10.4% vs 0.6%). Most were grade 1-2 in severity.Conclusions: Adjuvant pembrolizumab for resected stage IIB and IIC melanoma decreased the risk of disease recurrence or death by 35% compared with placebo and was associated with significantly prolonged RFS and a favorable benefit-risk profile.

Background Checkpoint inhibitors in melanoma can lead to self-immune side-effects such as vitiligo-like depigmentation (VLD). Beyond the reported association with favorable prognosis, there are limited data regarding VLD patient features and their echo on the therapeutic outcomes. Methods To assess the association between VLD and a series of clinical and biological features as well as therapeutic outcomes, we built an observational cohort study by recruiting patients who developed VLD during checkpoint inhibitors. Results A total of 148 patients from 15 centers (101 men, median age 66 years, BRAF mutated 23%, M1c 42%, Eastern Cooperative Oncology Group (ECOG) status 0/1 99%, normal lactate dehydrogenase 74%) were enrolled. VLD was induced by ipilimumab, programmed cell death-1 (PD-1) inhibitors, and their combination in 32%, 56%, and 12%, respectively. The median onset was 26 weeks and it was associated with other skin and nonskin toxicities in 27% and 28%, respectively. After 3 years of VLD onset, 52% (95% confidence interval 39% to 63%) were progression free and 82% (95% confidence interval 70% to 89%) were still alive. The overall response rate was 73% with 26% complete response. Univariable analysis indicated that BRAF V600 mutation was associated with a better overall survival ( P = 0.028), while in multivariable analysis a longer progression-free survival was associated with BRAF V600 ( P = 0.093), female sex ( P = 0.008), and M stage other than 1a ( P = 0.024). When VLD occurred, there was a significant decrease of white blood cell (WBC) count ( P = 0.05) and derived WBC-to-lymphocytes ratio (dWLR; P = 0.003). A lower monocyte count ( P = 0.02) and dWLR ( P = 0.01) were also reported in responder patients. Conclusions Among VLD population, some features might help to identify patients with an effective response to immunotherapy, allowing clinicians to make more appropriate choices in terms of therapeutic options and duration.

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