The scientists say that their findings will probably change clinical practice for patients with metastatic uveal melanoma, which to date has been an "untreatable disease". Uveal melanoma is a rare disease, there are 2,500 diagnoses annually in the USA, half of whom develop metastatic disease. For decades, survival of patients with metastasis has remained obstinately at 9 to 12 months.
According to medical oncologist Richard D. Carvajal, MD, PFS (progression-free survival) was nearly 16 weeks for patients on selumetinib, half of whom experienced tumor shrinkage. Fifteen percent of the selumetinib patients experienced major tumor shrinkage. The participants on the current standard chemotherapy, temozolomide, experienced only 7 weeks of PFS, and none of their tumors shrank.
The team reported that selumetinib also extended overall survival to 10.8 months, compared to 9.4 months in the temozolomide group.
The researchers reported that the side effects associated with selumetinib therapy were "manageable".
Dr. Carvajal said:
"This is the first study to show that a systemic therapy provides significant clinical benefit in a randomized fashion to advanced uveal melanoma patients, who have very limited treatment options.
This clinical benefit has never been demonstrated with other conventional or investigational agents, which is all we have been able to offer patients for decades."
Selumetinib blocks the MEK proteinCarvajal and team became interested in selumetinib because it blocks a key component of the tumor-driving MAPK pathway - the MEK protein. The pathway is activated by mutations in the Gnaq and Gna11 genes, which are present in over 85% of all patients with uveal melanoma. In Carvaja's study, 84% had one of the mutations.
Apart from metastatic uveal melanoma, selumetinib (AZD6244) is being investigated for the treatment of several other cancers, including NSCLC (non-small cell lung cancer), papillary thyroid cancer, biliary cancer, colorectal cancer and ovarian cancer.
In the February 14th issue of NEJM (New England Journal of Medicine), researchers from Memorial Sloan-Kettering Cancer Center reported that selumetinib may allow some patients with advanced thyroid cancer to overcome resistance to radioiodine. In April 2011, scientists from Ohio State University found that selumetinib helped patients with advanced biliary cancer.
Uveal melanoma patients with melanoma on the skin do not respond to medications. The team in this latest trial explained that there is currently no approved medication specifically for the treatment of this cancer. Current treatment options include the surgical removal of the tumor - which in advanced cases means removing the whole eye - as well as chemotherapy and radiation therapy.
In this study, 98 patients were randomly selected to receive either selumetinib or temozolomide. 81% of the 47 selumetinib patients had a Gnaq or Gna11 mutation (86% in the 49 temozolomide group had a mutation). Two patients received no treatment.
Even though this was a cross-over study - patients whose tumors grew could switch - there was a trend towards improved survival with selumetinib. Selumetinib was described as "generally tolerable"; most side effects were treated with dose modification and conservative management.
The team is now planning to perform a multi-center, randomized trial involving about 100 patients, so that the latest findings may be confirmed.
Dr. Carvajal said:
"If we can confirm selumetinib's effectiveness in treating advanced uveal melanoma in this follow-up trial, it will become the standard therapy for this disease, forming a foundation for new drug combinations that could maximize selumetinib's MEK-inhibitor effect. It could offer a whole new way to treat this historically untreatable disease."
This study was supported by the Fund for Ophthalmic Knowledge, a Conquer Cancer Foundation of ASCO Career Development Award, and the National Institutes of Health.
Histone deacetylase (HDAC) inhibitors were found to stop metastatic tumors from growing in patients with uveal melanoma. HDAC inhibitors are used to treat seizures. Scientists from Washington University School of Medicine in St. Louis wrote that HDAC inhibitors change the tumor's DNA, making it less aggressive. They reported their findings in Clinical Cancer Research (November 2011 issue).
Written by Christian Nordqvist