Targeted Treatments for Melanoma

“There’s no question that there have been major advances made in the field over the last 5 years or so,” Weber said.

Conventional chemotherapies include the use of alkylating agents that produce cytotoxic effects and block cell replication, but these agents exhibit minimal clinical response and do not increase overall survival. Also, these agents are limited to use in patients with non-BRAF mutations or in those who have developed resistance to other therapies.¹

Since the approval of the BRAF inhibitor vemurafenib in 2011, focus has been on subverting drug resistance to this agent. A BRAF inhibitor now under evaluation, dabrafenib (Tafinlar), received US Food and Drug Administration (FDA) approval in 2013 for treatment of unresectable or metastatic melanoma with the BRAF mutation.1 Although in the same class as vemurafenib, dabrafenib appears to exhibit more effectiveness in treatment of melanoma brain metastasis.²

MEK Inhibitors

Another recently approved BRAF inhibitor, trametinib (Mekinist), is indicated for unresectable or metastatic melanoma with BRAF V600E or V600K mutations. Trametinib is a highly specific, potent inhibitor of the mitogen-activated protein kinases 1 and 2 (MEK1 and MEK2) and BRAF downstream kinases, resulting in response rates of approximately 20% in patients with a BRAF mutation.^1,3MEK kinases, located immediately downstream of the BRAF kinase, trigger activation of pathways that lead to tumor development. Several agents that block this pathway are under development. In a phase III trial, the forementioned trametinib demonstrated objective response rates (ORRs) in 22% of patients observed, and almost three-fourths of patients experienced tumor regression to some degree.⁴AZD6244, another MEK inhibitor that binds selectively to MEK1 and MEK2, is in phase II studies of patients with late-stage melanoma.⁵

PD-1/PD-L1 Pathway

In early 2014, the FDA approved the combination of dabrafenib and trametinib for treatment of patients with unresectable or metastatic melanoma with BRAF V600E or V600K mutations. In a phase I/II study, median progression-free survival in the combination full-dose group was 9.4 months compared with 5.8 months in the dabrafenib monotherapy group (hazard ratio, 0.39; 95% confidence interval, 0.25-0.62). In the combination group, 76% of patients experienced either complete or partial response compared with 54% in the monotherapy group.⁶The programmed death (PD)-1 receptor is expressed on activated T cells and impacts T-cell function during the effector phase of tumor rejection. The PD-1 ligand (PD-L1) is expressed on epithelial and endothelial cells, as well as other types of immune cells, such as dendritic cells, macrophages, and B cells. PD-L1 may be upregulated when inflammation is present; some researchers hypothesize that tumors may exploit this function in efforts to avoid a tumor-directed T-cell response.

Expression of PD-L1 in tumors has characteristically been associated with poor prognosis; however, in patients with melanoma, recent reports have challenged this idea. An “adaptive resistance” mechanism, in which PD-L1 expression is a reflection for the melanoma being attacked by T cells, is the explanation for the improved prognosis. Positive results from phase I studies have led to fast-paced development of agents to target both PD-1 and PD-L1, and research is ongoing. To date, data have been reported for PD-1-specific antibodies nivolumab (MDX-1106; ONO-4538) and lambrolizumab (MK-3475), as well as PD-L1—specific antibodies BMS936559 (MDX-1105) and MPDL3280A.⁷

Lambrolizumab received the FDA Breakthrough Therapy designation for promising new drugs in April 2013. In a recent phase IB trial in patients with advanced and unresectable melanoma, 135 patients with advanced melanoma were treated with lambrolizumab at 3 different dosages. A significant proportion of patients had visceral metastases, including brain metastases. The ORR for the highest dosage cohorts were reported to be 38% and 52%; no difference in response rate was observed between patients who had received prior treatment with ipilimumab versus those with no prior treatment. Most responses were seen at the time of the first tumor assessment (12 weeks). Durability of response was suggested by the fact that the median duration of response and median overall survival had not been reached after 11 months of follow-up. Phase II and III studies are under way.⁸

A second PD-1 inhibitor, nivolumab, has also demonstrated favorable results in patients with melanoma. In a recent phase I study, 61% and 44% of patients survived to 1 and 2 years, respectively, according to data presented at the American Society of Clinical Oncology 2013 meeting. The median overall survival was reported to be 16.8 months, and the objective response rate was 31%. Median duration of response was 104 weeks.⁷

Cytotoxic T-Lymphocyte Antigen and PD-1/PD-L1 Combination

BMS936559, a fully human anti—PD-L1 monoclonal antibody, was associated with objective tumor responses in 17% of patients with advanced melanoma. MPDL-3280A, a fully human monoclonal PD-L1–specific antibody of the IgG4 isotype, is undergoing early-phase studies in patients with advanced melanoma^.7Some evidence suggests that synergy exists between cytotoxic T-lymphocyte antigen (CTLA-4) and PD-1/PD-L1, providing a rationale for combination treatment for patients with advanced-stage melanoma. A phase I trial evaluated treatment with the anti—PD-1 agent nivolumab and the anti–CTLA-4 agent ipilimumab in 53 patients with advanced melanoma. Combination treatment was followed by single-agent nivolumab administerd every 3 weeks for 4 doses, then maintenance with nivolumab and ipilimumab every 12 weeks for up to 8 doses. Twenty-one of 52 (40%) patients experienced a confirmed response. Importantly, most of these responses were rapid in onset and deep (≥80% tumor reduction at 12 weeks). Responses were observed in patients with extensive and bulky disease.

According to Weber, “The combination, despite a fair amount of toxicity, has a very impressive response rate. Many patients become complete responders, which is very encouraging.” This impressive tumor activity has led to rapidly expanding clinical trial programs in many solid tumor types.9,10 Studies evaluating other combinations are being done, such as checkpoint blockade with novel vaccines, angiogenesis inhibition, inhibition of the mitogenactivating protein kinase (MAPK) pathway, and other directly targeted immunosuppressive pathways.

References

1. Bertolotto C. Melanoma: from melanocyte to genetic alterations and clinical options. published online December 12, 2013.Scientifica. 2013;2013:635203. doi: 10.1155/2013/635203.
2. Hauschild A, Grob JJ, Demidov LV, et al. Dabrafenib in BRAF-mutated metastatic melanoma: a multicentre, open-label, phase 3 randomised controlled trial.Lancet. 2012;380(9839):358-365.
3. Ascierto PA, Schadendorf D, Berking C, et al. MEK162 for patients with advanced melanoma harbouring NRAS or Val600 BRAF mutations: a non-randomised, open-label phase 2 study.Lancet Oncol. 2013;14(3):249-256.
4. Pretto F, Neri D. Pharmacotherapy of metastatic melanoma: emerging trends and opportunities for a cure.Pharmacol Ther. [Published online May 2, 2013.]
5. ClinicalTrials.gov. MEK inhibitor AZD6244 in treating patients with stage III or IV melanoma. http://clinicaltrials.gov/ ct2/show/study/NCT00866177. Accessed February 20, 2014.
6. Flaherty KT, Infante JR, Daud A, et al. Combined BRAF and MEK inhibition in melanoma with BRAF V600 mutations.N Engl J Med. 2012;367(18):1694-1703.
7. Onclive 2014. http://www.onclive.com/publications/contemporary- oncology/2014/february-2014/immune-checkpointblockade- in-cancer-inhibiting-ctla-4-and-pd-1pd-l1-withmonoclonal- antibodies/3#sthash.udDXKdvy.dpuf. Accessed March 1, 2014.
8. Hamid O, Robert C, Daud A, et al. Safety and tumor responses with lambrolizumab (anti-PD-1) in melanoma.N Engl J Med. 2013;369(2):134-144.
9. Curran MA, Montalvo W, Yagita H, Allison JP. PD-1 and CTLA- 4 combination blockade expands infiltrating T cells and reduces regulatory T and myeloid cells within B16 melanoma tumors.Proc Natl Acad Sci U S A. 2010;107:4275-4280.
10. Wolchok JD, Kluger H, Callahan MK, et al. Nivolumab plus ipilimumab in advanced melanoma.N Engl J Med. 2013;369(2):122-133.