Targeting the MAPK pathway in advanced BRAF wild-type melanoma
Authors: R.C. Massa, J.M. Kirkwood
Journal: Annals of Oncology (2019)

Checkpoint blockade immunotherapy is the current standard treatment strategy for inoperable stage IV BRAF wild-type (WT) melanoma [1.Schachter J. Ribas A. Long G.V. et al.Pembrolizumab versus ipilimumab for advanced melanoma: final overall survival results of a multicentre, randomised, open-label phase 3 study (KEYNOTE-006).Lancet. 2017; 390: 1853-1862Abstract Full Text Full Text PDF PubMed Scopus (778) Google Scholar, 2.Wolchok J.D. Chiarion-Sileni V. Gonzalez R. et al.Overall survival with combined nivolumab and ipilimumab in advanced melanoma.N Engl J Med. 2017; 377: 1345-1356Crossref PubMed Scopus (2212) Google Scholar]. Targeted treatment with BRAF and MEK inhibition has demonstrated clinical efficacy in patients with BRAF V600E or V600K mutant melanoma, and the combination of dabrafenib and trametinib, vemurafenib and cobimetinib, or encorafenib and binimetinib represent effective therapeutic options for these patients [3.Long G.V. Weber J.S. Infante J.R. et al.Overall survival and durable responses in patients with BRAFV600–mutant metastatic melanoma receiving dabrafenib combined with trametinib.JCO. 2016; 34: 871-878Crossref PubMed Scopus (209) Google Scholar, 4.Dummer R. Ascierto P.A. Gogas H.J. et al.Encorafenib plus binimetinib versus vemurafenib or encorafenib in patients with BRAF-mutant melanoma (COLUMBUS): a multicentre, open-label, randomised phase 3 trial.Lancet Oncol. 2018; 19: 603-615Abstract Full Text Full Text PDF PubMed Scopus (521) Google Scholar, 5.Ascierto P.A. McArthur G.A. Dréno B. et al.Cobimetinib combined with vemurafenib in advanced BRAF(V600)-mutant melanoma (coBRIM): updated efficacy results from a randomised, double-blind, phase 3 trial.Lancet Oncol. 2016; 17: 1248-1260Abstract Full Text Full Text PDF PubMed Scopus (649) Google Scholar]. The landscape of treatment options for advanced BRAF WT melanoma has shifted dramatically since 2011, with the regulatory approval of anti-Cytotoxic T Lymphcyte Antigen 4 monoclonal antibody ipilimumab, followed by the approval of the anti-PD1 monoclonal antibodies nivolumab and pembrolizumab, as well as the combination of nivolumab and ipilimumab by the United States Food and Drug Administration and the European Medicines Agency. Given these approvals, and growing trial options for the third-generation checkpoint blockade, the use of chemotherapy in this disease has fallen out of favor. The use of BRAF/MEK inhibitors continues to be an important therapeutic option in BRAF-mutated melanoma, but these targeted agents have failed to demonstrate significant clinical efficacy in in BRAF WT melanoma. The study by Middleton et al. in this issue of Annals of Oncology evaluates the utility of chemotherapy in combination with targeted therapy in BRAF WT melanoma—in this case the MEK inhibitor trametinib or the multi-target tyrosine kinase inhibitor pazopanib [6.Urbonas V. Schadendorf D. Zimmer L. et al.Paclitaxel with or without trametinib or pazopanib in advanced wild-type BRAF melanoma (PACMEL): a multicenter, open-label, randomized, controlled phase II trial.Ann Oncol. 2019; 30: 317-324Abstract Full Text Full Text PDF PubMed Scopus (8) Google Scholar]. This is an intriguing concept to explore the potential to expand the use of targeted agents and chemotherapy to this population. Preclinical studies of BRAF WT melanoma have identified that nearly all advanced melanomas exhibit activation of the mitogen-activated protein kinase (MAPK) signaling pathway, through a variety of mechanisms including NRAS mutations and other pathways leading to activation. Activation of extracellular signal regulated kinase (ERK), a distal component of the MAPK pathway, has been identified in the majority of melanomas [7.Kortylewski M. Heinrich P.C. Kauffmann M.E. et al.Mitogen-activated protein kinases control p27/Kip1 expression and growth of human melanoma cells.Biochem J. 2001; 357: 297-303Crossref PubMed Google Scholar]. NRAS mutations can be seen in 20% of advanced melanoma and this mutated oncogene results in cell growth, invasion, and metastasis via the activation of RAF/MEK/ERK and PI3K/AKT pathways [8.Goel V.K. Lazar A.J. Warneke C.L. et al.Examination of mutations in BRAF, NRAS, and PTEN in primary cutaneous melanoma.J Invest Dermatol. 2006; 126: 154-160Abstract Full Text Full Text PDF PubMed Scopus (311) Google Scholar, 9.Platz A. Egyhazi S. Ringborg U. Hansson J. Human cutaneous melanoma; a review of NRAS and BRAF mutation frequencies in relation to histogenetic subclass and body site.Mol Oncol. 2008; 1: 395-405Crossref PubMed Scopus (219) Google Scholar]. Of note, NRAS mutations are generally mutually exclusive with BRAF V600E/K mutations [10.Curtin J.A. Fridlyand J. Kageshita T. et al.Distinct sets of genetic alterations in melanoma.N Engl J Med. 2005; 353: 2135-2147Crossref PubMed Scopus (2126) Google Scholar]. Other mutations less frequently identified in melanoma that result in activation of the MAPK signaling pathway include NF1, GNAQ, GNA11, MEK1/2, KRAS, HRAS, and RAF1 [11.Hodis E. Watson I.R. Kryukov G.V. et al.A landscape of driver mutations in melanoma.Cell. 2012; 150: 251-263Abstract Full Text Full Text PDF PubMed Scopus (1843) Google Scholar]. Growth factor receptors including MET, EGFR, VEGFR, and KIT may be overexpressed or mutated [12.Johnpulle R.A. Johnson D.B. Sosman J.A. Molecular targeted therapy approaches for BRAF wild-type melanoma.Curr Oncol Rep. 2016; 18: 6.Crossref PubMed Scopus (20) Google Scholar]. Therefore, the MAPK pathway is a potential therapeutic target in advanced BRAF WT melanoma, and this understanding led to the development of the phase II PACMEL study to evaluate paclitaxel with or without trametinib or pazopanib in advanced BRAF WT melanoma. PACMEL reports a statistically significant improvement in the primary end point of 6-month progression-free survival (PFS) with the combination of paclitaxel and trametinib as compared with paclitaxel alone (time ratio, 1.47; 90% confidence interval 1.08–2.01, P = 0.04). The initial statistical plan entailed the enrollment of 120 patients. However, due to slow recruitment the statistical plan was revised and 111 patients were randomized to treatment and were included in the analyses. The authors comment that despite the reduced number of enrolled subjects, this sample size provided the necessary number of events for the calculated power. Certainly, a limitation of 6-month PFS as the primary end point is that 6-month PFS assesses only a short interval, and whether this difference would be borne out over a longer evaluation period is unanswered by this study. There was a statistically significant improvement in the secondary end point of objective response rate (42% versus 13%; P = 0.01), with no statistically significant effect on overall survival (OS). There was no benefit seen with the addition of pazopanib to paclitaxel in 6-month PFS, ORR, or OS, and over half of the patients in the pazopanib arm discontinued treatment due to toxicities. Pazopanib was selected for this study given its inhibition of MEK and ERK, but with the toxicity and lack of clinical benefit observed in this study, and the availability of other more selective targeted agents, pazopanib is unlikely to have a meaningful role in the treatment of melanoma. Previously published studies of MEK inhibition alone in BRAF WT melanoma, such as the NEMO trial comparing the MEK inhibitor binimetinib to dacarbazine failed to demonstrate an improvement in PFS, ORR, or OS [13.Dummer R. Schadendorf D. Ascierto P.A. et al.Binimetinib versus dacarbazine in patients with advanced NRAS-mutant melanoma (NEMO): a multicentre, open-label, randomised, phase 3 trial.Lancet Oncol. 2017; 18: 435-445Abstract Full Text Full Text PDF PubMed Scopus (276) Google Scholar] A trial evaluating chemotherapy and MEK inhibition in BRAF WT melanoma, the DOC-MEK study of docetaxel with or without the MEK1/2 inhibitor selumetinib, did not meet its primary PFS end point but did report objective response with the combination in 32%, compared with 14% with chemotherapy alone (P = 0.059) [14.Gupta A. Love S. Schuh A. et al.DOC-MEK: a double-blind randomized phase II trial of docetaxel with or without selumetinib in wild-type BRAF advanced melanoma.Ann Oncol. 2014; 25: 968-974Abstract Full Text Full Text PDF PubMed Scopus (53) Google Scholar]. Therefore, it is of interest that PACMEL reported in this issue indicates improved objective response rate with trametinib added to paclitaxel as compared with paclitaxel alone in the BRAF WT population. The publication of trials incorporating chemotherapy in melanoma is a welcome event, and the question that arises is which chemotherapy backbone is optimal for studies of MEK inhibition or other targeted therapies. Taxanes were selected for DOC-MEK and PACMEL, and there is evidence from mouse models that while selumetinib alone is cytostatic in melanoma, the addition of docetaxel is cytotoxic and induces tumor regression. Haass et al. also reported that docetaxel monotherapy had minimal antitumor activity [15.Haass N.K. Sproesser K. Nguyen T.K. et al.The mitogen-activated protein/extracellular signal-regulated kinase kinase inhibitor AZD6244 (ARRY-142886) induces growth arrest in melanoma cells and tumor regression when combined with docetaxel.Clin Cancer Res. 2008; 14: 230-239Crossref PubMed Scopus (204) Google Scholar]. Before the advent of immunotherapy, dacarbazine was frequently utilized for advanced melanoma, albeit with response rates of 9% to 20% and limited median durations of response [16.Serrone L. Zeuli M. Sega F.M. Cognetti F. Dacarbazine-based chemotherapy for metastatic melanoma: thirty-year experience overview.J Exp Clin Cancer Res. 2000; 19: 21-34PubMed Google Scholar]. The combination of carboplatin and paclitaxel has reported objective response rates of 18% in cooperative group trials [17.Flaherty K.T. Lee S.J. Zhao F. et al.Phase III trial of carboplatin and paclitaxel with or without sorafenib in metastatic melanoma.J Clin Oncol. 2013; 31: 373Crossref PubMed Scopus (166) Google Scholar]. Dacarbazine and its oral congener temozolomide are well tolerated, and given their historic activity in melanoma may have a role in future trials. However, given the well-established clinical efficacy of immune checkpoint blockade in advanced BRAF WT melanoma, anti-PD1 may be a more intriguing backbone to assess as an earlier priority for the disease. Many trials utilizing anti-PD1 in combination with novel immunotherapeutic agents are actively enrolling patients, and adaptive trials with a common control arm to build upon PD1 in anti-PD1 nonresponsive patients are now a priority of the field [18.Saville B.R. Berry S.M. Efficiencies of platform clinical trials: a vision of the future.Clin Trials. 2016; 13: 358-366Crossref PubMed Scopus (149) Google Scholar]. In light of the PACMEL results indicating activity of MEK inhibition in BRAF WT advanced melanoma combined with chemotherapy that has minimal single-agent activity, it would be of interest to understand the safety and utility of MEK inhibition together with PD1 blockade. A study evaluating the safety and preliminary efficacy of pembrolizumab plus trametinib in BRAF WT melanoma is ongoing [19.ClinicalTrials.gov [Internet]. A Study of the Safety and Efficacy of Pembrolizumab (MK-3475) in Combination with Trametinib and Dabrafenib in Participants with Advanced Melanoma (MK-3475-022/KEYNOTE-022). Bethesda, MD: National Library of Medicine 2004; https://clinicaltrials.gov/ct2/show/NCT02130466 (10 November 2018, date last accessed).Google Scholar] Basket trials evaluating PDL1/PD1 combinations with a wide variety of additional agents are in progress [20.ClinicalTrials.gov [Internet]. Study of Efficacy and Safety of Novel Spartalizumab Combinations in Patients with Previously Treated Unresectable or Metastatic Melanoma (PLATforM). Bethesda, MD: National Library of Medicine 2018; https://clinicaltrials.gov/ct2/show/NCT03484923 (10 November 2018, date last accessed).Google Scholar]. It is a brighter time for melanoma patients and investigators, and it will be gratifying to understand the ways in which we may incorporate existing and novel tools in the armamentarium, including potentially chemotherapy and MAPK inhibition, to improve upon the rapid progress we have seen to date. None declared.