CHICAGO — A drug that targets metastatic melanoma with mutations in the BRAF oncogene may be the first step on a path to individualized chemotherapy for patients with these formerly untreatable cancers.
“We are rapidly unraveling the molecular underpinnings of these tumors, and discovering the mechanisms by which they drive melanoma growth. These insights allow us to develop and select drugs on the basis of every patient’s individual genome,” Dr. Hensin Tsao said at the American Academy of Dermatology’s 2010 meeting.
Courtesy Bill Truslow/Massachusetts General Hospital
PLX4032 is the first drug to successfully shrink both cutaneous and internal metastases of BRAF-mutated melanomas, said Dr. Hensin Tsao.
PLX4032 is the first drug to successfully shrink both cutaneous and internal metastases of BRAF-mutated melanomas, said Dr. Tsao, a dermatologist who is director of the Massachusetts General Hospital Melanoma Genetics Program in Boston.
His colleague, Dr. Keith Flaherty, is about to publish data from the drug’s phase II trial of 87 patients; 81% of those with the BRAF-mutated melanoma responded with a 30% or more shrinkage of the targeted lesions.
After a phase I safety and dose-finding trial, investigators settled on an oral dose of 960 mg twice daily for the phase II study. The effect was little short of remarkable, Dr. Flaherty, director of developmental therapeutics at the Massachusetts General Hospital Cancer Center, said in an interview.
“My first responding patient had cutaneous and internal metastases, and the cutaneous metastases were clearly getting better right in front of our eyes,” he said. “We have seen this in some other areas of cancer, but never in melanoma, which before this was a clinical scenario with an unmet need for therapy.”
PLX4032, first engineered by the Berkeley, Calif., company Plexxikon Inc. and being developed in partnership with Roche, is not a foolproof cure, Dr. Tsao said in an interview. “It’s clearly a huge leap forward for the patients who responded so rapidly, yet most are still progressing despite being on the drug. It’s the best stun we’ve ever seen for melanoma, but it’s not a permanent kill.”
Sustained response in the phase I and II trials has varied from only 2 months to up to 2 years, Dr. Flaherty said. He could find no significant predictors of progression or response among the group except for initial tumor number and size. Typically, he said, the patients with the greatest mass of metastatic disease had the shortest duration of response, while those with a smaller tumor burden had a longer duration of response.
“When you have metastatic melanoma, your days are numbered—and numbered in a way we can’t predict when metastatic disease is diagnosed,” Dr. Flaherty said. “What this therapy does is push out the time until the disease worsens. We are not yet smart enough to understand what it is that allows a tumor to work its way around the drug’s activity.”
Chemotherapy-resistant cancers are nothing new, Dr. Tsao noted. What will be new is the full investigation of melanoma’s genetic pathways, and the development of drugs to block them in multiple ways. “The next frontier will be to understand all the ways that melanoma can outsmart treatment. We may have to use multiple therapies to corner it. So a full discovery of all melanoma’s potential vulnerabilities is very important.”
There is already at least a hint that PLX4032 has a very narrow target—only BRAF tumors with the V600E subtype. “There is some laboratory evidence that if you give this drug to a tumor that may be mutated at another gene you may be worsening things,” Dr. Tsao said. “This has yet to be borne out in clinical studies, but bench-side data suggest that you have to be very precise with this drug, because the wrong choice could be potentially deleterious.”
In vitro and in vivo experiments did suggest that PLX4032 was ineffective against non-BRAF melanomas, Dr. Flaherty said. “In a lab, the drug will kill a cancer cell with a BRAF mutation but not with another mutation. Whether it can facilitate the growth of others is an interesting concept supported by some laboratory data, with the observation that this and drugs like it can transiently stimulate other cancer cells with RAS mutations. In these, the drug basically activates the BRAF pathway instead of blocking it. We don’t know the relevance of this finding to humans. It is interesting, but it may have no real clinical impact.”
Discovering the best targets for molecular therapies is typically a long process, Dr. Tsao said, but the race to treat BRAF metastatic melanoma has so far been a fast one. “In 2002, the first BRAF mutation in melanoma was published, and the first drug is already coming to clinical fruition. This is pretty fast for something we’ve been fooling around with ineffectively for 20 years.”