UVEAL MELANOMA

Recent discoveries about the genetics and molecular biology of uveal melanoma are providing a foundation for developing targeted therapy, and with that step have come some encouraging clinical results.

In a paper published in the June 18, 2014 issue of JAMA (JAMA. 2014;311(23):2397-405), investigators in a Phase II clinical trial reported that treatment with oral selumetinib (AstraZeneca), an investigational MEK1/2 inhibitor, improved clinical outcomes compared to chemotherapy in patients with advanced uveal melanoma.

Richard D Carvajal MD, director of the Developmental Therapeutics Program and member of the Melanoma and Immunotherapeutics of Memorial Sloan Kettering Cancer Center, New York, is the lead author of the JAMA article.

He told EuroTimes: “This is the first randomised comparative study to show that a systemic therapy provides significant clinical benefit for patients with advanced uveal melanoma. We consider it an important step forward for this patient population that currently has a poor prognosis and very limited treatment options.”

He noted that an international Phase III study [Selumetinib in Metastatic Uveal Melanoma (SUMIT)] is now under way comparing selumetinib plus dacarbazine versus chemotherapy alone.

“SUMIT is the first study with registration intent to be conducted for patients with advanced uveal melanoma, and we hope that it will confirm the efficacy of MEK inhibition observed in our Phase II trial,” Dr Carvajal said.

The Phase II study randomised 101 chemotherapy-naïve patients with metastatic uveal melanoma to selumetinib 75mg twice daily or chemotherapy using oral temozolomide (Temodar, Merck) or intravenous dacarbazine. Median treatment duration was 16.1 weeks for selumetinib and eight weeks for the control group.

Endpoint analysis

The primary endpoint analysis showed selumetinib significantly prolonged progression-free survival compared to chemotherapy (15.9 vs seven weeks). In addition, only selumetinib-treated patients achieved tumour regression (49 per cent) or an objective radiographic response (14 per cent). Selumetinib also improved overall survival compared to chemotherapy (median 11.8 vs 9.1 months). Although the difference between groups did not achieve statistical significance, the investigators noted that determination of a survival benefit for selumetinib may have been confounded by the fact that 86 per cent of the control patients crossed over to selumetinib after experiencing disease progression while on chemotherapy.

Almost all patients experienced treatment-related adverse events in the selumetinib group. Consistent with the safety profile of other MEK inhibitors, the most common adverse events were acneiform rash, creatine kinase elevation, fatigue and liver enzyme elevations.

The selumetinib dose was reduced for management of an adverse event in 37 per cent of patients and six per cent of patients discontinued treatment because of an adverse event.

The rationale for investigating selumetinib as a treatment for metastatic uveal melanoma derives from understanding that about 80 per cent of patients with uveal melanoma harbour oncogenic mutations in GNAQ or GNA11 leading to activation of the mitogen-activated protein kinase (MAPK) pathway. MEK is a key enzyme in the MAPK pathway, and previous studies conducted using uveal melanoma cell lines demonstrated an anti-tumour effect of MEK inhibition.

Dr Carvajal noted that in addition to SUMIT, two Phase II clinical trials are under way investigating MEK inhibition as a platform for novel combinatorial therapeutic strategies. One study is comparing a commercially available MEK inhibitor trametinib (Mekinist, GSK) with or without an investigational AKT inhibitor (GSK2141795).

“These studies are based on preclinical data indicating that it may be possible to build upon the efficacy observed with single agent MEK inhibition through the addition of AKT or PKC inhibition,” Dr Carvajal said.

In another recent paper (Cancer Cell. 2014;25(6):822-30), Kun-Liang Guan PhD and colleagues reported that GNAQ/GNA11 mutations drive uveal melanoma tumorigenesis by activating the Yes-associated protein (YAP). Based on that information and evidence that verteporfin (Visudyne, Valeant) acts as a YAP inhibitor, they tested the anti-tumour efficacy of the commercially available photosensitizer and found that it slowed uveal melanoma growth both in cell culture and in vivo in an animal model.

Richard D Carvajal: carvajar@mskcc.org

Kun-Liang Guan: kuguan@ucsd.edu