Selumetinib increased PFS, reduced tumor size in uveal melanoma

Issue: July 25, 2013

CHICAGO — Selumetinib decreased tumor size in 50% of patients with metastatic uveal melanoma and was associated with a twofold increased PFS when compared with temozolomide, according to phase 2 study results presented at the ASCO Annual Meeting.

Perspective from Nikhil Khushalani, MD; Gregory A. Masters, MD, FACP; Lynn M. Schuchter, MD

“This study is the first to ever demonstrate efficacy for any systemic therapy in patients with metastatic uveal melanoma,” Richard D. Carvajal, MD, medical oncologist at Memorial Sloan-Kettering Cancer Center, said during a press conference. “Selumetinib could be considered a new standard for patients with uveal melanoma and provides a platform for the development of new combinatorial therapeutic approaches.”

About 2,000 new cases of uveal melanoma are diagnosed annually in the United States. The standard therapy for skin melanoma, temozolomide (Temodar, Schering-Plough), has shown little effect on uveal melanoma. Therefore, no known effective systemic therapy exists for these patients.

Gnaq and Gna11 alterations, which occur in 85% of patients with uveal melanoma, activate the MAPK pathway and fuels cell growth. Selumetinib blocks the MEK protein, a key component of the MAPK pathway, according to background information provided by the researchers.

For the multicenter, randomized study, Carvajal and colleagues randomly assigned 98 patients with uveal melanoma to selumetinib (n=48) or temozolomide (n=50).

All tumors were tested for mutations at baseline. Thirty-seven percent of patients had a Gnaq mutation, 44% had Gna11 mutations and 19% had an Exon 5 wild-type mutation.

Randomization was stratified according to mutation status, extent of disease and number of prior therapies.

PFS served as the primary outcome measure. Secondary outcome measures were response rate and OS.

Median PFS was 15.9 weeks among patients assigned to selumetinib compared with 7 weeks for patients assigned to temozolomide (HR=0.46; P=.0003). Median OS was 10.8 months with selumetinib vs. 9.4 months with temozolomide (P=.4).

Tumor shrinkage occurred in 50% of patients assigned to selumetinib vs. 11% of patients assigned to temozolomide. Fifteen percent of patients in the selumetinib arm achieved significant tumor shrinkage, whereas no patients in the temozolomide arm achieved significant tumor shrinkage.

“This is quite remarkable because radiographic shrinkage in this disease is quite uncommon,” Carvajal said. “In fact, if you look at previously published studies, response rates are less than 5%.”

For more information:

Carvajal RD. Abstract #CRA9003. Presented at: ASCO Annual Meeting; May 31-June 4, 2013; Chicago.

Disclosure: The study was supported in part by the Conquer Cancer Foundation of ASCO Career Development Award, the NIH, Cycle for Survival and the Fund for Ophthalmic Knowledge.

Perspective

Nikhil Khushalani, MD

Metastatic uveal melanoma has traditionally been a very difficult disease to treat, with limited options and survival of less than 1 year. For the first time, we have a drug that has shown significant clinical activity in this setting following a very rational development by understanding the molecular aberrations that highlight the majority of these tumors (GNAQ and GNA11). These mutations result in activation of the MAPK pathway. Selumetinib targets MEK, which is a downstream molecule in this pathway.

In essence, we are tailoring treatment to target what may be one of the drivers in this cancer. The drug resulted in tumor shrinkage in half of the patients and clearly more than doubled the time to progression when compared with chemotherapy.

Although an improvement in OS was not demonstrated in this study, it was likely related to the fact that most patients who progressed on temozolomide crossed over to receive selumetinib, which may have helped control the disease for a longer period of time.

The sobering fact remains that these patients eventually succumb. But by demonstrating efficacy in uveal melanoma, it gives us a “ray of hope” that this drug and others in this class may now serve as a platform to develop novel combinations of therapy for a difficult disease. We certainly are “MEKing” the right moves in uveal melanoma.

Nikhil Khushalani, MD

Section chief of soft tissue and melanoma

Associate professor or oncology

Roswell Park Cancer Institute

Buffalo, N.Y.

Disclosures: Khushalani reports grant funding from the National Comprehensive Cancer Network from general research support provided by Allos, Pfizer and Roche; funding for investigator-initiated clinical trials from Merck and Pfizer; a speaker’s bureau role with Prometheus and an advisory board role with Genentech.

Perspective

Gregory A. Masters, MD, FACP

It’s exciting to see this breakthrough data on this rare type of melanoma. I think in many ways we are now thinking of more and more cancers as rare cancers because, as we understand the biology and the science of each of these malignancies, we now have to target specific therapies in ways that each tumor grows and spread. This is the first of many studies that will support this.

Gregory A. Masters, MD, FACP

Director, medical oncology fellowship

Medical Oncology Hematology Consultants

Member, ASCO Cancer Communications Committee

Disclosures: Masters reports no relevant financial disclosures.

Perspective

Lynn M. Schuchter, MD

Uveal melanoma is one of the most difficult cancers to treat. Uveal melanoma patients are now also benefiting from the targeted therapy revolution. This new pill focuses on the genes broken in uveal melanoma. This represents the first real advance for these patients. MEK inhibitors make important biological sense. Ultimately, I think a MEK inhibitor will be practice-changing in patients with metastatic uveal melanoma.

Lynn M. Schuchter, MD

C. Willard Robinson Professor of Hematology-Oncology

University of Pennsylvania School of Medicine

Disclosures: Schuchter reports no relevant financial disclosures.