The survival rates for patients with early-stage primary melanoma following surgical removal are a stark contrast to the daunting mortality rates seen among patients who are diagnosed with advanced disease; this disparity is largely due to advanced tumors’ resistance to traditional chemotherapies.
But an improved understanding of the molecular landscape of melanoma during recent years has yielded an increasing number of potential prognostic biomarkers and molecular targets for treatment. The 2002 discovery of a common melanoma point mutation in the BRAF gene, for example, eventually led to the development of vemurafenib and dabrafenib, which in turn ushered in the current era of targeted BRAF inhibition.1,2 Melanoma immunotherapies, like the programmed death PD-1 agents nivolumab and lambrolizumab, and the anti-CTLA-4 targeted monoclonal antibody ipilimumab, have also made recent headlines.3
A New Player in Melanoma Therapy
In May 2013, trametinib was announced as the first Food and Drug Administration–approved MEK inhibitor, involving a different target in the BRAF/MEK/ERK signaling pathway for the treatment of patients with unresectable or metastatic melanoma harboring BRAF V600E or BRAF V600K mutations.4 Like vemurafenib and dabrafenib BRAF-inhibition monotherapies, trametinib can improve survival times, but tumor resistance frequently develops. Ultimately, the occurrence of resistance has prompted the study of regimens that combine BRAF and MEK inhibition.4 The drug therapy combination of dabrafenib plus trametinib improves survival and response rates, but acquired resistance remains a challenge, further highlighting the need to identify the genetic and genomic mechanisms of resistance.4
Pipeline Research Focusing on MEK Inhibition
Trametinib is not the only MEK inhibitor being researched. The MEK inhibitor selumetinib is under clinical development for treatment of uveal (eye) melanomas, which are very difficult to treat. Selumetinib reduced the size of uveal melanoma tumors in 50% of patients and doubled median progression-free survival (PFS) time compared to temozolomide therapy, according to the final analysis of crossover phase 2 study data for 98 patients, reported by researchers from Memorial Sloan-Kettering Cancer Center at this year’s American Society of Clinical Oncology (ASCO) Annual Meeting.5 Results showed selumetinib was associated with a median PFS of 15.9 weeks compared to 7 weeks for patients receiving temozolomide (hazard ratio, 0.46; P=0.0005).5
“Selumetinib is the first drug to ever show improved clinical activity in uveal melanoma relative to temozolomide,” lead author Richard D. Carvajal, MD, reported. “Selumetinib could be considered a new standard for patients with advanced uveal melanoma and provides a platform for the development of new combinatorial therapeutic approaches.”5
A separate analysis by the same researchers suggests a possible trend toward sustained selumetinib inhibition of pERK and cyclin D1 at day 14, predicting which patients will experience subsequent clinical benefits on selumetinib therapy (P=0.07).6 If those relationships are demonstrated in larger, subsequent studies and achieve statistical significance, pERK and cyclin D1 could prove to be useful prognostic biomarkers of selumetinib treatment efficacy.
Could Prognostic Molecular Biomarkers Improve Treatment Personalization?
Other prognostic serum and genetic biomarkers are also under investigation. Once validated in large clinical studies, these might allow better personalization and modification of treatment regimens. Therapy with ipilimumab or nivolumab, for example, appears to be associated with superior clinical benefits when treating patients who have NRAS mutations.7 Separate preliminary studies also suggest serum angiopoietin 2 (Ang-2) and PD-L1 expression might be useful biomarkers, respectively, for predicting outcomes with lenvatinib, and for neoadjuvant (presurgical) temozolomide and interferon therapy. The first study found that baseline serum Ang-2 levels are associated with improved clinical outcomes with lenvatinib in patients with NRAS mutations and PIK3CA wild-type status, although larger studies are needed to clarify the predictive power of each.8
The second study revealed that lower PD-L1 expression in tumor-infiltrating lymphocytes and melanoma cells are associated with improved overall survival (OS) in patients undergoing treatment with neoadjuvant pegylated interferon plus temozolomide.9
New Clues to Targeted Melanoma Therapy Resistance
The identification of MEK1 mutations in tumors with acquired resistance to the BRAF inhibitors vemurafenib or dabrafenib by Eliezer Mendel van Allen of the Dana-Farber Cancer Institute in Boston, MA, and coauthors, highlights the importance of longitudinal biopsies and genetic profiling of melanoma tumors before and after targeted treatment.10 Longitudinal whole-genome and exome sequencing also afforded preliminary insight into which acquired mutations (MEK1 and MEK2) appear to be driving resistance to dabrafenib-plus-trametinib combination therapy. Collectively, this data suggests that this form of resistance is rooted in MAPK pathway reactivation.4
While the development of MEK inhibitor therapy and the discovery of candidate prognostic biomarkers have provided new options for treating advanced melanoma and its acquired resistance to certain agents, further research will help to better assess how targeted therapies can be refined and tailored to achieve more promising outcomes for patients with this notoriously hard-to-treat cancer.
1. Davies H, Bignell GR, Cox C, et al. Mutations in the BRAF gene in human cancer. Nature. 2002;417(6892):949-954. 2. Flaherty KT, Puzanov I, Kim KB, et al. Inhibition of mutated, activated BRAF in metastatic melanoma. N Engl J Med. 2010;363(9):809-819.
3. Unleashing the immune system to treat metastatic melanoma. Chemotherapy Advisor.com. http://www.chemotherapyadvisor.com/unleashing-the-immune-system-to-treat-metastatic-melanoma/printarticle/293243/
4. Wagle N, van Allen EM, Frederick DT, et al. Whole exome and whole transcriptome sequencing in melanoma patients to identify mechanisms of resistance to combined RAF/MEK inhibition. J Clin Oncol. 2013; 31 (suppl; ASCO 2013 abstract).
5. Carvajal RD, et al. Phase II study of selumetinib (sel) versus temozolomide (TMZ) in gnaq/Gna11 (Gq/11) mutant (mut) uveal melanoma (UM). J Clin Oncol. 2013; 31 (suppl; ASCO 2013 abstract CRA9003).
6. Carvajal RD, Ambronsini G, Wolchok JD, et al. Pharmacodynamic activity of selumetinib to predict radiographic response in advanced uveal melanoma. J Clin Oncol. 2013; 31 (suppl; ASCO 2013 abstract 8598).
7. Johnson DB, Lovly CM, Flavin M, et al. NRAS mutation: a potential biomarker of clinical response to immune-based therapies in metastatic melanoma (MM). J Clin Oncol. 2013; 31 (suppl; ASCO 2013 abstract 9019).
8. Sachdev P, Hamid O, Kim K, et al. Analysis of serum biomarkers and tumor genetic alterations from a phase II study of lenvatinib in patients with advanced BRAF wild-type melanoma. J Clin Oncol. 2013; 31 (suppl; ASCO 2013 abstract 9058).
9. Chakravarti N, Ivan D, Ross MI, et al. Biomarker study in patients with resectable AJCC stage IIIc or state IV (M1a) melanoma treated in a randomized phase II neoadjuvant trial. J Clin Oncol. 2013; 31 (suppl; ASCO 2013 abstract 9047). 10. Van Allen EM, Wagle N, Carter SL, et al. The genetic landscape of clinical resistance to RAF inhibition in melanoma. J Clin Oncol. 2013; 31 (suppl; ASCO 2013 abstract 11009).