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The treatment of metastatic melanoma has been revolutionised with the emergence of checkpoint inhibitors. The combination of Ipilimumab and Nivolumab offers the longest overall survival but is considerably more toxic than single-agent therapy. For patients who received single-agent immunotherapy it is unclear whether second-line immunotherapy is efficacious or tolerable. This study looked at outcomes for patients treated with sequential immunotherapy and compared them to patients who received dual immunotherapy. Fifty-eight patients received both Ipilimumab and an anti-PD-1 agent during the 5-year period, twenty-seven received dual immunotherapy, twenty received first-line Ipilimumab and eleven received an anti-PD-1 agent first line. The median overall survival (OS) was 24.8 months. The 5 year survival was greatest in patients treated with dual immunotherapy (42%) compared to first-line anti-PD-1 (33.3%) and first-line Ipilimumab (0%). As second-line treatments, anti-PD-1 agents had a median OS of 16.5 months compared to Ipilimumab at 3.4 months. 77.8% of patients had grade 3/4 toxicity with dual immunotherapy compared to 10% of patients treated with first-line Ipilimumab and 0% with anti-PD-1 agents. In the second line, 72.7% of patients treated with Ipilimumab experienced grade 3/4 toxicity, compared to 20% of patients treated with second-line anti-PD-1 agents. This study suggests Ipilimumab is not efficacious in patients who progress after anti-PD-1 agents, and this sequential approach does not avoid toxicity. The emergence of new checkpoint inhibitors will hopefully provide more efficacious treatment options for patients unable to tolerate Ipilimumab., (Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.)

Aim of Study: The aim of the study was to assess the impact of treatment with adjuvant vemurafenib monotherapy on health-related quality of life (HRQOL) in patients with resected stage IIC-IIIC melanoma., Methods: The phase 3 BRIM8 study (NCT01667419) randomised patients with BRAF V600 mutation-positive resected stage IIC-IIIC melanoma to 960 mg of vemurafenib twice daily or matching placebo for 52 weeks (13 × 28-day cycles). Patients completed the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire Core 30 (EORTC QLQ-C30) version 3 at baseline, cycle 1 (days 1, 15 and 22), cycle 2 (days 1 and 15), day 1 of every subsequent 4-week cycle, the end-of-treatment visit and each visit during the follow-up period., Results: Completion rates for the EORTC QLQ-C30 questionnaire were high (>80%). There was a mean decline in the global health status (GHS)/quality of life (QOL) score of 17.4 (±22.9) and 17.3 (±24.1) points at days 15 and 22 of cycle 1, respectively, among vemurafenib-treated patients who recovered to approximately 10 points below baseline for the remainder of the treatment period. A similar trend was observed in all functional scales except for cognitive function (<10-point change from baseline at all visits) and in the symptom scores for appetite loss, fatigue and pain. As observed for the GHS/QOL score, all scores rapidly returned to baseline after completion of planned vemurafenib treatment or treatment discontinuation., Conclusions: The schedule of HRQOL assessments allowed for an accurate and complete evaluation of the impact of acute treatment-related symptoms. Vemurafenib-treated patients experience clinically meaningful moderate worsening in some treatment- or disease-related symptoms and GHS/QOL that resolve over time., (Copyright © 2019 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Background: Systemic adjuvant treatment might mitigate the high risk of disease recurrence in patients with resected stage IIC-III melanoma. The BRIM8 study evaluated adjuvant vemurafenib monotherapy in patients with resected, BRAF V600 mutation-positive melanoma., Methods: BRIM8 was a phase 3, international, double-blind, randomised, placebo-controlled study that enrolled 498 adults (aged ≥18 years) with histologically confirmed stage IIC-IIIA-IIIB (cohort 1) or stage IIIC (cohort 2) BRAF V600 mutation-positive melanoma that was fully resected. Patients were randomly assigned (1:1) by an interactive voice or web response system to receive twice-daily adjuvant oral vemurafenib 960 mg tablets or matching placebo for 52 weeks (13 × 28-day cycles). Randomisation was done by permuted blocks (block size 6) and was stratified by pathological stage and region in cohort 1 and by region in cohort 2. The investigators, patients, and sponsor were masked to treatment assignment. The primary endpoint was disease-free survival in the intention-to-treat population, evaluated separately in each cohort. Hierarchical analysis of cohort 2 before cohort 1 was prespecified. This trial is registered with ClinicalTrials.gov, number NCT01667419., Findings: The study enrolled 184 patients in cohort 2 (93 were assigned to vemurafenib and 91 to placebo) and 314 patients in cohort 1 (157 were assigned to vemurafenib and 157 to placebo). At the time of data cutoff (April 17, 2017), median study follow-up was 33·5 months (IQR 25·9-41·6) in cohort 2 and 30·8 months (25·5-40·7) in cohort 1. In cohort 2 (patients with stage IIIC disease), median disease-free survival was 23·1 months (95% CI 18·6-26·5) in the vemurafenib group versus 15·4 months (11·1-35·9) in the placebo group (hazard ratio [HR] 0·80, 95% CI 0·54-1·18; log-rank p=0·26). In cohort 1 (patients with stage IIC-IIIA-IIIB disease) median disease-free survival was not reached (95% CI not estimable) in the vemurafenib group versus 36·9 months (21·4-not estimable) in the placebo group (HR 0·54 [95% CI 0·37-0·78]; log-rank p=0·0010); however, the result was not significant because of the prespecified hierarchical prerequisite for the primary disease-free survival analysis of cohort 2 to show a significant disease-free survival benefit. Grade 3-4 adverse events occurred in 141 (57%) of 247 patients in the vemurafenib group and 37 (15%) of 247 patients in the placebo group. The most common grade 3-4 adverse events in the vemurafenib group were keratoacanthoma (24 [10%] of 247 patients), arthralgia (17 [7%]), squamous cell carcinoma (17 [7%]), rash (14 [6%]), and elevated alanine aminotransferase (14 [6%]), although all keratoacanthoma events and most squamous cell carcinoma events were by default graded as grade 3. In the placebo group, grade 3-4 adverse events did not exceed 2% for any of the reported terms. Serious adverse events were reported in 40 (16%) of 247 patients in the vemurafenib group and 25 (10%) of 247 patients in the placebo group. The most common serious adverse event was basal cell carcinoma, which was reported in eight (3%) patients in each group. One patient in the vemurafenib group of cohort 2 died 2 months after admission to hospital for grade 3 hypertension; however, this death was not considered to be related to the study drug., Interpretation: The primary endpoint of disease-free survival was not met in cohort 2, and therefore the analysis of cohort 1 showing a numerical benefit in disease-free survival with vemurafenib versus placebo in patients with resected stage IIC-IIIA-IIIB BRAF V600 mutation-positive melanoma must be considered exploratory only. 1 year of adjuvant vemurafenib was well tolerated, but might not be an optimal treatment regimen in this patient population., Funding: F Hoffman-La Roche Ltd., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

Purpose: Dabrafenib and trametinib combination therapy (dab + tram) is indicated to treat BRAF V600 mutation–positive unresectable/metastatic melanoma and as adjuvant treatment for resected stage III disease. Dab + tram–related pyrexia may require early therapy discontinuation. A modified Delphi panel was conducted to develop consensus on the optimal management of dab + tram–related pyrexia in patients with melanoma. Methods: In all, 10 UK oncologists experienced in melanoma management participated in a three-round modified Delphi study (Round 1: one-to-one interview; Rounds 2 and 3: email survey). In each round, participants rated the extent of their agreement with statements about defining and managing dab + tram–related pyrexia. Consensus was defined as >80% agreement for critical management (CM) and >60% for non-critical management (NCM) statements. Results: All 10 participants completed Round 1; 9 completed Rounds 2 and 3. Consensus was reached on 42/66 statements (20 CM and 22 NCM). Drug-related pyrexia was agreed as being strictly an elevation of body temperature, although other symptoms may be present (89% agreement). Panelists agreed on the need for simple and generic guidance on dab + tram–related pyrexia management that does not differentiate between patient groups (100%), and that management of first and second dab + tram–related pyrexia episodes should be the same regardless of treatment intent (100%). Regarding CM, participants agreed that both dab and tram should be interrupted for pyrexia (100%) without considering the use of steroids (89%); patients on dab + tram presenting to non-oncology services with pyrexia should be directed to an oncology-specific service as soon as possible and assessed for infection (100%). NCM statements on steroid use following dab + tram interruption and when to restart dab + tram did not reach consensus. Conclusions: These consensus statements provide a framework on optimal management of dab + tram–related pyrexia in patients with melanoma which should inform future guidelines. [ABSTRACT FROM AUTHOR]

Treatments for melanoma have significantly advanced with the approval of targeted treatments against the BRAF/MEK pathway and immunotherapy in the form of checkpoint inhibitors. Studies have shown the effectiveness of these treatments against brain metastases. However, the optimum treatment strategy utilising CNS-directed treatments such as stereotactic radiosurgery (SRS) and neurosurgical resection is less clear. Over six years, 70 patients with metastatic melanoma were treated for brain metastases at a tertiary treatment centre. The median overall survival (OS) for all patients was 10.2 months. 51 patients received localised treatment; 7 resection (median OS 10 months), 11 resection and SRS (median OS 17.3 months) and 33 SRS alone (median OS 17.4 months). For patients treated with SRS those who had <2 cm3 treated had a better median OS (20.5 months) compared to those who had >2 cm3 treated (12 months). 69 Patients received systemic treatment. The median OS of patients who did not have CNS-directed treatment was poor (median OS 1.2 months). Patients treated with first line dual immunotherapy had the best median OS (26.7 months), compared to anti-PD-1 (14.1 months), ipilimumab (14.3 months) and kinase inhibitors (10.9 months). Despite advancements in treatment, the development of brain metastases in melanoma is associated with worse outcomes. A combination of CNS-directed and systemic treatment is important to improve survival. Dual immunotherapy appears to be the most effective systemic treatment and the use of SRS improved outcomes. As metastatic melanoma treatments evolve there need to be an ongoing focus to ensure these strategies adequately treat intracranial disease. [ABSTRACT FROM AUTHOR]