Comprehensive Clinical Trial Data Summation for BRAF-MEK Inhibition and Checkpoint Immunotherapy in Metastatic Melanoma

Abstract

Background Immune checkpoint inhibitors, along with BRAF and MEK inhibitors, have dramatically changed the management of and outlook for patients with metastatic melanoma. Analyses of long‐term follow‐up data and subanalyses based on disease characteristics may inform clinical decision making. Methods Reports of clinical trials in metastatic melanoma published between January 1, 2012, and August 30, 2018, were identified using PubMed (terms: melanoma AND [dabrafenib OR trametinib OR vemurafenib OR cobimetinib OR encorafenib OR ipilimumab OR nivolumab OR pembrolizumab]) and were systematically reviewed. Relevant congress proceedings were also assessed. Efficacy data from key phase III trials were analyzed and trends identified. Results Substantial improvements in objective response rates, progression‐free survival, and overall survival were documented across 14 identified publications. Subgroup findings supported that patients with lower disease burden derive greater benefit than patients with more advanced disease, limiting the value of disease burden in the clinical decision‐making process. However, these agents consistently conferred benefits despite the presence of poor prognostic features. Several clinically relevant questions remain, including how best to sequence immune checkpoint inhibitors and combination targeted therapy. Conclusion This research, coupled with ongoing investigations, including those on predictive biomarkers, suggests that the treatment decision‐making process is likely to become more nuanced. Implications for Practice The management of melanoma has been rapidly advancing with new classes of agents, including immune checkpoint and BRAF inhibitors. With long‐term follow‐up, their impact on response rates and survival outcomes is well documented. Additional findings from subgroup analyses suggest that patients with lower disease burden derive greater benefit, yet both consistently confer benefit in patients with higher disease burden. Currently, there is a paucity of data to guide first‐line treatment selection between immunotherapy and BRAF‐targeted therapy in clinical practice or to estimate their impact when sequenced. Gaining these insights will facilitate a more nuanced management approach.

BRAF Inhibitors: Molecular Targeting and Immunomodulatory Actions

“…It has been reported that single-agent checkpoint inhibitors produced a clear clinical benefit over chemotherapy in metastatic melanoma, and these benefits appeared to be consistent across patient subgroups [66]. Moreover, combination of nivolumab plus ipilimumab, an anti-CTLA-4, was significantly more effective in term of objective response rate, progression-free survival and overall survival relative to ipilimumab used alone [66]. However, because checkpoint receptors play important roles in regulating autoimmunity, the major toxicities associated with the use of these drugs include autoimmune symptoms.…”

“…This led to an interest in immunotherapeutic agents to extend the therapeutic effect and induce long-acting anti-melanoma effects, and immune checkpoint inhibitors are another important treatment option for patients with advanced melanoma [11,16,52]. It has been reported that single-agent checkpoint inhibitors produced a clear clinical benefit over chemotherapy in metastatic melanoma, and these benefits appeared to be consistent across patient subgroups [66]. Moreover, combination of nivolumab plus ipilimumab, an anti-CTLA-4, was significantly more effective in term of objective response rate, progression-free survival and overall survival relative to ipilimumab used alone [66].…”

Trends in the prognosis of metastatic melanoma in the era of targeted therapy and immunotherapy: A single‐institution survey in Japan

“…Although the 5‐year OS is speculated to be in the range of 20% based on the Kaplan–Meier curves, it does not reach the satisfactory level. The 5‐year OS for advanced melanoma that has been reported in some global clinical trials has improved to as high as 50–60% 2 . However, due to some eligibility restrictions, some discordance may be expected with regard to the prognosis between clinical trials and real‐world clinical data, and so it may prove difficult to apply those clinical trial data to our practice in Japan.…”

“…One of these two approaches is small-molecule inhibitors of the B-Raf proto-oncogene (BRAF) and the mitogen-activated protein kinase; the other involves immunotherapeutic antibodies directed at cytotoxic T-lymphocyte-associated protein 4 (CTLA) and programmed death 1 (PD-1). 2 These new agents have now been approved in several countries, including Japan. 3 Although prolonged long-term OS of patients with advanced melanoma has been shown in clinical trials, it is important for clinicians to know the "real-world" efficacy in clinical practice.…”

Usefulness of Monitoring Circulating Tumor Cells as a Therapeutic Biomarker in Melanoma with BRAF Mutation

“…Molecularly targeted therapies and immune checkpoint inhibitors have improved the prognosis of advanced melanoma. Although the objective response rates to those treatments range from 40-70% in clinical trials [1], real-world outcomes are inferior [2]. Therefore, prediction of drug response and optimization of treatment order are required.…”