Clinical activity of ipilimumab for metastatic uveal melanoma: a retrospective review of the Dana-Farber Cancer Institute, Massachusetts General Hospital, Memorial Sloan-Kettering Cancer Center, and University Hospital of Lausanne experience.

BACKGROUND: Uveal melanoma exhibits a high incidence of metastases; and, to date, there is no systemic therapy that clearly improves outcomes. The anticytotoxic T-lymphocyte-associated protein 4 (anti-CTLA-4) antibody ipilimumab is a standard of care for metastatic melanoma; however, the clinical activity of CTLA-4 inhibition in patients with metastatic uveal melanoma is poorly defined. METHODS: To assess ipilimumab in this setting, the authors performed a multicenter, retrospective analysis of 4 hospitals in the United States and Europe. Clinical characteristics, toxicities, and radiographic disease burden, as determined by central, blinded radiology review, were evaluated. RESULTS: Thirty-nine patients with uveal melanoma were identified, including 34 patients who received 3 mg/kg ipilimumab and 5 who received 10 mg/kg ipilimumab. Immune-related response criteria and modified World Health Organization criteria were used to assess the response rate (RR) and the combined response plus stable disease (SD) rate after 12 weeks, after 23 weeks, and overall (median follow-up, 50.4 weeks [12.6 months]). At week 12, the RR was 2.6%, and the response plus SD rate was 46.%; at week 23, the RR was 2.6%, and the response plus SD rate was 28.2%. There was 1 complete response and 1 late partial response (at 100 weeks after initial SD) for an immune-related RR of 5.1%. Immune-related adverse events were observed in 28 patients (71.8%) and included 7 (17.9%) grade 3 and 4 events. Immune-related adverse events were more frequent in patients who received 10 mg/kg ipilimumab than in those who received 3 mg/kg ipilimumab. The median overall survival from the first dose of ipilimumab was 9.6 months (95% confidence interval, 6.3-13.4 months; range, 1.6-41.6 months). Performance status, lactate dehydrogenase level, and an absolute lymphocyte count ≥ 1000 cells/μL at week 7 were associated significantly with survival. CONCLUSIONS: In this multicenter, retrospective analysis of 4 hospitals in the United States and Europe of patients with uveal melanoma, durable responses to ipilimumab and manageable toxicity were observed

New challenges in endpoints for drug development in advanced melanoma

During the past 3 decades, the field of clinical research for the treatment of advanced melanoma lacked significant advances. Available drugs had low antitumor activity and no proven benefit in overall survival. Recently, new drugs developed based on an in-depth understanding of the biology of this disease have shown significant benefit, with ipilimumab and vemurafenib having recently shown a positive impact in overall survival in patients with metastatic melanoma leading to approval in this indication by the U.S. Food and Drug Administration. This rapid introduction of new active agents is likely to challenge current notions on how to develop future agents for the treatment of melanoma. The strong evidence of benefit for initial agents that modulate immune regulatory checkpoints or target driver oncogenes has spurred great interest in developing other similarly acting agents. However, this will pose problems in the choice of endpoints for the future definitive clinical trials, and the hurdles for achieving these endpoints will be higher given the similar activity for comparator agents or the availability of competing agents for salvage therapy. This new reality will likely require tailoring registrational clinical trial endpoints to the patient benefits shown in early clinical testing. In this perspective article, we illustrate the challenges in the choice of endpoints for registrational trials in metastatic melanoma and that, with an improved understanding of the agent being developed, the design of the registrational programs can be informed by earlier mechanistic studies to define the assumptions for definitive clinical testing. ©2011 AACR

An organometallic protein kinase inhibitor pharmacologically activates p53 and induces apoptosis in human melanoma cells

Unlike other tumors, melanomas harbor wild-type (WT) p53 but exhibit impaired p53-dependent apoptosis. The mechanisms for the impaired p53 activation are poorly understood but may be linked to the high expression of the p53 suppressor Mdm2, which is found in >50% of melanoma lesions. Here, we describe an organometallic glycogen synthase kinase 3β (GSK3β) inhibitor (DW1/2) as a potent activator of p53 and inducer of cell death in otherwise highly chemoresistant melanoma cells. Using RNA interference and pharmacologic approaches, we show that p53 is required for the cytotoxic effects of this organometallic inhibitor. The DW1/2 compound was barely able to induce cell death in melanoma cells with p53 mutations, further confirming the requirement for p53-WT in the cytotoxic effects of the GSK3β inhibition. Mechanistic analysis of the p53-dependent cell death indicated an apoptotic mechanism involving depolarization of mitochondrial membrane potential, caspase cleavage, and elevated NOXA expression. The effect of p53 was not simply due to passive up-regulation of protein expression as adenoviral-mediated overexpression of p53 was not able to induce cell death. Treatment of melanoma cells with DW1/2 was instead found to decrease levels of Mdm2 and Mdm4. The importance of Mdm2 down-regulation in DW1/2-induced apoptosis was confirmed by treating the p53-WT cells with the p53/Mdm2 antagonist Nutlin-3. Taken together, our data provide a new strategy for the pharmacologic activation of p53 in melanoma, which may be a viable approach for overcoming apoptotic resistance in melanoma and offer new hope for rational melanoma therapy

Survival of patients with advanced metastatic melanoma: the impact of novel therapies–update 2017

The treatment of metastatic melanoma is still undergoing a process of major change. The two most important novel therapeutic strategies, selective kinase inhibitors and immune checkpoint blockers, both significantly prolong survival times of patients with advanced metastatic disease. Different agents, dose regimens and combinations have been tested against each other vigorously within these two groups. However, results from prospective head-to-head comparative studies of both strategies are still lacking. We performed an exploratory analysis of survival data from selected clinical trials representative for the new treatment strategies in advanced metastatic melanoma. Eighty-three Kaplan-Meier survival curves from 25 trials were digitised and grouped by therapeutic strategy and treatment line. For each of these groups, mean survival curves were generated for progression-free (PFS) and overall survival (OS) by weighted averaging. Survival curves grouped together by therapeutic strategy revealed a high concordance, particularly in the first-line setting. For kinase inhibitors, the most favourable PFS and OS in all therapy lines were observed for combined BRAF plus MEK inhibition. For immune checkpoint inhibitors, combined PD-1 plus CTLA-4 inhibition demonstrated the best survival outcome in all categories except for OS in first-line therapy. For the latter, combined PD-1 plus CTLA-4 inhibition showed similar outcomes as single-agent PD-1 inhibition. Comparison of kinase inhibitors and checkpoint blockers revealed a superiority of combined BRAF plus MEK inhibition within the first 6 months, later changing to a superiority of PD-1 blockers alone or in combination with CTLA-4 blockers. These results need confirmation by prospective clinical trials

Update on tolerability and overall survival in COLUMBUS: landmark analysis of a randomised phase 3 trial of encorafenib plus binimetinib vs vemurafenib or encorafenib in patients with BRAF V600–mutant melanoma

Background: BRAF/MEK inhibitor combinations are established treatments for BRAF V600–mutant melanoma based on demonstrated benefits on progression-free survival (PFS) and overall survival (OS). Here, we report an updated analysis of the COLUMBUS (COmbined LGX818 [encorafenib] Used with MEK162 [binimetinib] in BRAF mutant Unresectable Skin cancer) trial with long-term follow-up. Methods: In part 1 of the COLUMBUS trial, 577 patients with advanced/metastatic BRAF V600–mutant melanoma, untreated or progressed after first-line immunotherapy, were randomised 1:1:1 to 450 mg of encorafenib QD + 45 mg of binimetinib BID (COMBO450) vs 960 mg of vemurafenib BID (VEM) or 300 mg of encorafenib ENCO QD (ENCO300). An updated analysis was conducted that included PFS, OS, objective response rate, safety and tolerability and analyses of results by prognostic subgroups. Results: At data cutoff, there were 116, 113 and 138 deaths in the COMBO450, ENCO300 and VEM treatment arms, respectively. The median OS was 33.6 months (95% confidence interval [CI], 24.4–39.2) for COMBO450, 23.5 months (95% CI, 19.6–33.6) for ENCO300 and 16.9 months (95% CI, 14.0–24.5) for VEM. Compared with VEM, COMBO450 decreased the risk of death by 39% (hazard ratio [HR], 0.61; 95% CI, 0.48–0.79). The updated median PFS for COMBO450 was 14.9 months (95% CI, 11.0–20.2), ENCO300 was 9.6 months (95% CI, 7.4–14.8) and VEM was 7.3 months (95% CI, 5.6–7.9). PFS was longer for COMBO450 vs VEM (HR, 0.51; 95% CI, 0.39–0.67). Landmark OS and PFS results show consistent results for each year analysed. Subgroups all favoured COMBO450 vs VEM. Conclusions: Updated PFS and OS results for COMBO450 from the COLUMBUS trial demonstrate a long-term benefit in patients with advanced BRAF V600–mutated melanoma. © 2019 The Author

Adverse events associated with encorafenib plus binimetinib in the COLUMBUS study: incidence, course and management

Background: Dual inhibition of the mitogen-activated protein kinase pathway with BRAF/MEK inhibitor (BRAFi/MEKi) therapy is a standard treatment for BRAFV600-mutant metastatic melanoma and has historically been associated with grade III pyrexia or photosensitivity depending on the combination used. The objective of this study was to fully describe adverse events from the COLUMBUS study evaluating the most recent BRAF/MEK inhibitor combination encorafenib+binimetinib. Patients and methods: Patients with locally advanced, unresectable or metastatic BRAFV600-mutant melanoma were randomised to receive encorafenib 450 mg once daily plus binimetinib 45 mg twice daily, encorafenib 300 mg once daily or vemurafenib 960 mg twice daily. Adverse events that represent known effects of available BRAFi and/or MEKi were evaluated. Results: The safety population included a total of 570 patients (encorafenib+binimetinib = 192; encorafenib = 192; vemurafenib = 186). Median duration of exposure was longer with encorafenib+binimetinib (51 weeks) than with encorafenib (31 weeks) or vemurafenib (27 weeks). Common BRAFi/MEKi toxicities with encorafenib+binimetinib were generally manageable, reversible and infrequently associated with discontinuation. Pyrexia was less frequent with encorafenib+binimetinib (18%) and encorafenib (16%) than with vemurafenib (30%) and occurred later in the course of therapy with encorafenib+binimetinib (median time to first onset: 85 days versus 2.5 days and 19 days, respectively). The incidence of photosensitivity was lower with encorafenib+binimetinib (5%) and encorafenib (4%) than with vemurafenib (30%). The incidence of serous retinopathy was higher with encorafenib+binimetinib (20%) than with encorafenib (2%) or vemurafenib (2%), but no patients discontinued encorafenib+binimetinib because of this event. Conclusion: Encorafenib+binimetinib is generally well tolerated and has a low discontinuation rate in patients with BRAFV600-mutant melanoma, with a distinct safety profile as compared with other anti-BRAF/MEK targeted therapies. Trial registration: ClinicalTrials.gov (Identifier: NCT01909453) and with EudraCT (number 2013-001176-38). © 2019 The Author(s