New Drug in Phase 1 Trial Shows Objective Responses in Metastatic Melanoma Patients

A new drug which targets a genetic mutation found in 50 percent to 60 percent of melanoma cases, 10 percent to 15 percent of colorectal tumors and 8 percent of other solid tumors, caused tumor shrinkage and extended progression-free survival among patients during a Phase 1 clinical trial. Igor Puzanov, M.D., assistant professor of Medicine, and Jeffrey A. Sosman, M.D., professor of Medicine and Ingram Professor of Cancer Research, led Vanderbilt-Ingram Cancer Center’s participation in the multi-center study. Puzanov delivered the initial findings from the study during a poster session May 31 at the American Society of Clinical Oncology conference in Orlando, Fla.

PLX4032 is a novel, oral and highly selective drug that targets the BRAFV600E cancer-causing genetic mutation which occurs in more than one-half of melanomas and subgroups of other solid tumors, including colorectal, thyroid and other cancers. In addition to tumor shrinkage and delay in tumor progression, some patients reported clinical improvement in symptoms.

PLX4032 is being developed by Plexxikon, Berkeley, Calif., and Roche, headquartered in Basel, Switzerland.

“The BRAFV600E mutation activates the MAP kinase signaling pathway, causing cells to proliferate. One of the hallmarks of cancer is this uncontrolled, unregulated cell proliferation,” said Puzanov. “The new drug is a very selective inhibitor which appears to target only this mutation, and it blocks the unregulated cell growth and causes cell death. We saw tumor responses and symptom improvement in less than a week in some cases.”

In the dose escalation phase of the study, 55 cancer patients were treated, including 24 mutation-positive melanoma patients and three mutation-positive thyroid cancer patients. An additional 28 melanoma, rectal and ovarian cancer patients, who did not have the mutation or whose mutation status was unknown, also have been treated.

In 16 BRAF mutation-positive melanoma patients treated with PLX4032 at doses of 240 mg or above twice daily (BID).
• PLX4032 was well tolerated at very high doses, with 960 mg (BID) under evaluation as the maximum tolerated dose
• Objective partial responses in nine patients by RECIST (Response Evaluation Criteria in Solid Tumors) criteria, with seven confirmed on repeat scans
• Regression of metastatic lesions in every site in which melanoma commonly spreads, including liver, lung and bone
• Minor responses in four patients showing tumor regression less than that required to meet RECIST criteria for an objective response
• Disease control lasting up to 14 months with continuous therapy, with many patients still receiving treatment
• Interim median progression-free survival of at least six months, with many responding patients still receiving treatment

In patients without the mutation, no clinical response to treatment was observed and progression-free survival was less than two months, consistent with historical data. Side effects included rash, photosensitivity, fatigue and joint pain and were more evident at higher doses. In addition, some patients developed squamous cell skin cancers, easily removed by their dermatologist.

“This is personalized medicine at its best,” said Jeffrey Sosman. “If continued trials confirm the agent works only in patients with this mutation, we can target those patients for this drug and spare other patients from undergoing a treatment that won’t work. It is very exciting to have a drug that may be effective for metastatic melanoma because these patients have few treatment options, with a median survival of less than a year.”

The research group was led by Keith T. Flaherty, principal investigator, assistant professor of Medicine, University of Pennsylvania, Philadelphia, and Paul B. Chapman, Memorial Sloan-Kettering Cancer Center, New York City. Other investigators included Antoni Ribas, University of California, Los Angeles, Kevin B. Kim, M.D. Anderson Cancer Center, Houston, Grant A. McArthur, Peter MacCallum Cancer Centre, Melbourne, Australia, Kate L. Nathanson and George Xu, Abramson Cancer Center, University of Pennsylvania, Philadelphia, Joe F. Grippo and Richard Lee, Hoffmann-La Roche, Nutley, N.J., Keith Nollop, Gideon Bollag and Peter Hirth, Plexxikon, Berkeley, Calif.

“We know this drug causes tumor shrinkage in patients with melanomas harboring the target mutation, we know it works quickly, and we know it helps patients who are terribly symptomatic,” said Puzanov. “We do not know enough about its duration of effect on tumors and whether it can improve overall survival. We hope to try to improve its effects by combining it with other drugs, including other targeted agents. We will be working with the drug developers as well as our partner investigators to answer those questions.”

Two extension studies with the drug are being conducted in mutation-positive melanoma and colorectal cancer patients and plans are in place to start Phase II and Phase III clinical trials.

The Vanderbilt-Ingram Cancer Center is a National Cancer Institute Comprehensive Cancer Center, one of two centers in Tennessee and 40 in the country to earn this highest distinction. Its nearly 300 faculty members generate more than $140 million in annual federal research funding, ranking it among the top 10 centers in the country in competitive grant support, and its clinical program sees approximately 4,000 new cancer patients each year. Vanderbilt-Ingram, based in Nashville, Tenn., recently joined with 21 of the world’s leading centers in the National Comprehensive Cancer Network, a non-profit alliance dedicated to improving cancer care for patients everywhere.

Source : www.mc.vanderbilt.edu