Uveal (ocular) melanoma is a difficult-to-treat type of melanoma found in the eye. Remarkably resistant to chemotherapy and prone to metastasis, it is often treated with surgery and/or radiation. Earlier this year, I wrote about new scientific findings that could lead to new targeted treatments for uveal melanoma. These would take advantage of abnormal molecular characteristics of tumor cells. Now, another targeted drug called selumetinib has entered the spotlight. It was recently tested in patients in a clinical trial with promising results.
Selumetinib targets a known molecular vulnerability of uveal melanoma. Unlike melanomas of the skin that often (almost half of the time) have mutations in the BRAF gene, most uveal melanomas harbor mutations in two other cancer-causing genes: GNAQ or GNA11. These mutations have, at least in part, the same effects as BRAF: activation of a protein called MEK. Mutant BRAF activates MEK too strongly in skin melanomas; mutant GNAQ or GNA11 activates it too strongly in uveal melanoma. All three result in uncontrolled cell division, a hallmark of cancer.
Because of its role in promoting several types of cancer, researchers have already developed drugs that inhibit MEK. These drugs have been shown to inhibit the abnormal MEK-activating effects of mutant BRAF in skin melanoma. They may also inhibit MEK in uveal melanoma with mutations in GNAQ or GNA11.
The U.S. Food and Drug Administration (FDA) has approved a MEK-inhibitor drug called trametinib (brand name: Mekinist). It is used to treat BRAF-mutant melanoma in combination with the BRAF-inhibitor drug dabrafenib (Tafinlar). Unfortunately, trametinib does not seem to benefit people with uveal melanoma. But a new MEK inhibitor called selumetinib (AZD6244) is currently being tested in more than 20 clinical trials for different kinds of cancer. Selumetinib passed a phase I safety trial in 2008; one uveal melanoma patient who was enrolled in that trial had a positive response to the treatment.
A phase II trial of selumetinib in uveal melanoma was initiated in 2010, the results of which were reported this summer. In the trial, patients received either selumetinib or standard chemotherapy. Patients in the chemotherapy group were allowed to switch to selumetinib at the time of radiographic progression (ie, if their cancer did not respond to chemotherapy)—a thoughtful option, in retrospect. The patients who took selumetinib experienced a median of 15.9 weeks without a worsening of their cancer, compared to just 7.0 weeks in the chemotherapy group. Moreover, almost half of the patients who took selumetinib experienced tumor shrinkage, while none in the chemotherapy group did.
Selumetinib is not without side effects—more than one-third of the patients in the selumetinib group had side effects severe enough to require a lower dose. Moreover, while selumetinib did significantly increase time without worsening cancer, it did not improve overall survival. Still, it is a game changer in treatment of uveal melanoma.
Selumetinib was developed by the drug company Astra Zeneca, but was not pursued for uveal melanoma because drug companies don’t often consider rare diseases worth their investment. Luckily, the National Cancer Institute funded the phase II study described above, while Astra Zeneca just supplied the drug.
Now, based on the results of the phase II study, Astra Zeneca has started a phase III, randomized study of selumetinib in uveal melanoma. The clinical trial (ID number NCT01974752) aims to recruit 159 volunteer patients in 43 different locations in the U.S., Canada, and Europe. Hopefully, the results will pave the way for adopting selumetinib as the first targeted treatment for this rare, but life-threatening cancer.