Zosia Chustecka

June 01, 2013

CHICAGO — For the first time, a systemic therapy has shown efficacy in a rare form of melanoma that affects the eye, uveal melanoma. New data showing activity with the investigational drug selumetinib, an MEK inhibitor under development by AstraZeneca, was hailed as a research "breakthrough" here at the 2013 Annual Meeting of the American Society of Clinical Oncology (ASCO®).

"Uveal melanoma is one of the most difficult cancers to treat," commented ASCO spokesperson and melanoma expert Lynn Schuchter, MD, from the Abramson Cancer Center in Philadelphia, Pennsylvania.

This is the first clinical trial to identify a drug that improves clinical outcomes in advanced disease, she commented: "This represents a first real advance for these patients."

Dr. Schuchter predicted that these data will ultimately be practice changing, adding: "A MEK inhibitor will be used in the treatment of this disease, whether it is this one or another one."

At present, the drug that was tested is still some 2 years away from the market. Selumetinib has shown activity in a number of cancers in phase1/2 clinical trials, and AstraZeneca is planning to start soon a phase 3 clinical trial in metastatic non-small-cell lung cancer (NSCLC) that has tested positive for KRAS mutations.

In the meantime, however, another MEK inhibitor has become available: trametinib (Mekinist, GlaxoSmithKline) has just been approved for use in cutaneous melanoma; it is the first MEK inhibitor to be commercially available.

However, when asked about potentially using this available MEK inhibitor in patients with uveal melanoma, Richard Carvajal, MD, medical oncologist at Memorial Sloan-Kettering Cancer Center, New York City, urged caution. "The best thing to do is to enroll these patients in clinical trials," he said.

Responses Were "Quite Remarkable"

Dr. Carvajal was discussing the data on selumetinib in uveal melanoma at a press briefing, ahead of his presentation at the meeting later today. All of the patients in this trial had previously untreated metastatic uveal melanoma, and about 90% of patients had metastases in the liver, he noted. The median survival for these patients is about 9 to 12 months.

The results were "quite remarkable," he said, because it is very rare to see radiologic shrinkage of tumor in this disease. In fact, he noted, during the last decade, in 8 clinical trials investigating chemotherapy, targeted therapy, and immunotherapy and involving a total of 157 patients, only 2 patients showed major tumor shrinkage.

In the current trial, 48 patients received selumetinib: of these, 50% showed some tumor shrinkage, and 15% achieved major tumor shrinkage, Dr. Carvajal reported.

In contrast, no significant tumor shrinkage was seen among the 50 patients in the control arm of the trial, who received chemotherapy with temozolomide (Temodar, Merck Sharp & Dome Corp.). This is a long-time standard therapy used in cutaneous melanoma, and it was "felt to be a reasonable choice" to use for uveal melanoma, for which there is no standard therapy, Dr. Carvajal explained.

Progression-free survival was significantly improved to 15.9 weeks with selumetinib, more than double the 7 weeks on temozolomide (hazard ratio, 0.46; P = .0003).

In addition, the data for overall survival showed a trend favoring selumetinib (10.8 months vs 9.4 months, P = .4), although this did not reach statistical significance.

This is a major breakthrough driven by science... Dr. Michael Atkins

"This is a major breakthrough driven by science and tumor molecular profiling," said Michael Atkins, MD, a melanoma clinician and deputy director of Georgetown Lombardi Comprehensive Cancer Center, in Washington, DC, who was not involved in the study.

"This is the first time any systemic therapy has been shown to work in patients with ocular melanoma. This disease has been viewed as practically untreatable until now," he commented.

"This opens the door not only for treatment of patients with metastatic uveal melanoma but also for testing more potent MEK inhibitors, MEK inhibitors–based combinations, and even testing MEK inhibitors in the adjuvant setting for patients with tumors containing high-risk features," he added.

Further Studies

This study proves that this approach is effective, Dr. Carvajal concluded.

The MEK inhibitor works by inhibiting the mitogen-activated protein kinase (MAPK) pathway. Many patients with metastatic uveal melanoma have tumors with GNAQ and GNA11 alterations, which activate this pathway, leading to uncontrolled cell growth, and so blocking the pathway in these patients was hoped to lead to clinical benefits.

However, from the results of the trial so far, it is "unclear" where the genetic alterations need to be present for the drug to have a clinical benefit, Dr. Carvajal told Medscape Medical News. These data are still being analyzed, he added, but so far it appears that there is no difference in clinical benefit between patients who have and those who do not have the gene alteration.

There is still work to be done in this field, he suggested. Next up is a large international clinical trial, organized through the International Rare Cancer Initiative, in which patients with metastatic uveal melanoma will be randomly assigned to receive either trametinib or trametinib in combination with an investigational agent, an AKT inhibitor that acts on the same pathway.

There is also other work in progress with selumetinib. The drug has shown activity in a number of different cancers, and at the ASCO meeting, results are due to be presented from studies in melanoma (abstracts 9004 and 9068), in advanced colorectal cancer that is positive for KRAS mutations (abstract 3587), and also in metastatic pancreatic cancer after chemotherapy (abstracts TPS4145 and 4104). A phase 2 study showing promise with selumetinib in NSCLC patients positive for KRAS mutations was highlighted at last year's ASCO meeting and has since been published. This is the indication that is now going into phase 3.

Dr. Carjaval reports no relevant financial relationships.

2013 Annual Meeting of the American Society of Clinical Oncology. Abstract CRA9003. Presented June 1, 2013.


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