ASCO 2009: Investigational Targeted Therapy for Metastatic Melanoma Shrinks Tumors, Causes Stir at Meeting

Nick Mulcahy

June 04, 2009

June 4, 2009 (Orlando, Florida) — The targeted-therapy revolution in oncology could be coming to melanoma, especially if the results of a phase 1 trial of an investigational agent are followed by similar results in subsequent trials, according to melanoma experts attending the American Society of Clinical Oncology 45th Annual Meeting.

We are on the verge of a paradigm shift for melanoma therapy.

"We are on the verge of a paradigm shift for melanoma therapy," said melanoma expert Boris Bastion, MD, from the University of California at San Francisco, who was not involved in the trial. "This is a decisive step toward personalized medicine," he added.

Dr. Bastion was a discussant at a meeting session on melanoma at which studies of 2 targeted therapies for malignant melanoma were presented, 1 of which is the investigational PLX4032 (Plexxicon Inc). This oral agent targets the oncogenic BRAF gene mutation known as V600E, which occurs in about 60% of malignant melanoma patients, according to the study authors.

In a dose-escalation, proof-of-concept study, more than half of metastatic melanoma patients with this BRAF mutation who received high doses of PLX4032 had tumor shrinkage, said lead study author Keith T. Flaherty, MD, from the Abramson Cancer Center of the University of Pennsylvania in Philadelphia.

"We were able to give enough drug to block mutated BRAF, and that resulted in clinical benefit in a majority of patients treated at higher doses," Dr. Flaherty told Medscape Oncology. Specifically, 9 out of 16 patients with BRAF mutations had an objective response by RECIST criteria. Of the remaining 7 patients, 5 had tumor shrinkage, but not enough to count as an objective response, and 2 had growth, he added.

Among the 16 patients with BRAF mutations, median progression-free survival "appears to be 6 months," said Dr. Flaherty, adding that the time period is "likely to change" as more data are collected.

These early responses happen with remarkable reliability.

"These early responses happen with remarkable reliability," Dr. Flaherty told the audience, adding that the agent is not useful for patients without the BRAF mutation.

"The magnitude of response is better than we expected," he continued.

PLX4032 is important because it represents an advance in targeting BRAF, explained another melanoma expert, David Fisher, MD, PhD, from Massachusetts General Hospital Cancer Center in Boston.

"Others have attempted to use kinase inhibitors to block the BRAF gene. This agent was designed to specifically block the oncogenic mutated form of BRAF," Dr. Fisher, who was also not involved in the study, told Medscape Oncology.

Historic Change, Quickly

Before entering the meeting room for the late afternoon session, the attendees buzzed with conversation. When asked by Medscape Oncology if the attendees were excited about his study, Dr. Flaherty laughed: "They might be or they might be hungry for dinner."

Nevertheless, Dr. Flaherty acknowledged that the treatment of melanoma is moribund. "Eight-five percent of patients don't respond to the 2 available drugs. It's almost as if we are starting off from ground zero in terms of treating the disease," he said.

Dr. Bastion suggested the same. "In 1840, advanced melanoma was described as untreatable," he said, adding that not much has improved since. "I feel this is about to change," he continued.

The development of targeted therapies for malignant melanoma has occurred rapidly, said Dr. Bastion. "It took 7 years to move from the discovery of the target to drug development," he said, contrasting this timeline with the 30-plus years that it took for the same activity to occur in chronic myelogenous leukemia.

Dr. Bastion also reminded the audience that the findings were "early results with many questions to be answered."

Further Details

In the study, supported by Plexxicon, 55 cancer patients were enrolled, 49 of whom had melanoma. Of these 49 melanoma patients, 28 received doses too low to determine efficacy; the other 21 received sufficiently high doses (at least 240 mg twice daily). Five of these patients did not have BRAF mutations and did not respond to PLX4032. However, 16 did have the mutation and therefore were suited to the drug. As noted above, 9 of the 16 were responders and 7 were not.

However, Dr. Flaherty noted that some of the 28 patients who received low doses of PLX4032 had "some evidence of benefit."

The agent was well tolerated, with adverse events that were dose-related and that tended to be mild, said Dr. Flaherty. For instance, the most common event, rash, occurred in 29% of patients, but it was of grade 3 in only 2%.

V600E BRAF is also found in colorectal carcinomas (10%), some anaplastic and papillary thyroid carcinomas, and low-grade serous ovarian carcinomas, the study authors noted.

Dr. Flaherty has served as a consultant to Plexxikon and Hoffman-LaRoche; some of his coauthors are employees of Hoffmann-La Roche and Plexxikon Inc. Dr. Bastion disclosed relationships with Novartis and Alnylam. Dr. Fisher has disclosed no relevant financial relationships.

American Society of Clinical Oncology (ASCO) 45th Annual Meeting: Abstract 9000. Presented May 30, 2009.

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