Response Rates Confirmed, But Resistance Is Emerging to Melanoma Drug

Zosia Chustecka

November 25, 2010

November 25, 2010 — The experimental drug PLX4032 (Plexxicon/Roche) for melanoma was hailed as a "major breakthrough" earlier this year after showing unprecedented response rates in a phase 1 study.

Those high response rates have now been confirmed in a phase 2 study, which also suggests that there is a progression-free-survival advantage.

A phase 3 study is now in progress.

However, excitement over this drug has been tempered somewhat by the emergence of resistance, seen after only several months of treatment. But new research into the mechanism behind this resistance has yielded a rather surprising finding, and points the way forward for further drug development.

First Targeted Therapy in Melanoma

PLX4032 is the first targeted agent for melanoma. It homes in on the BRAF mutation, which drives the disease in about 50% of melanoma patients.

This BRAF mutation is also found in other cancers, including lung and colon, and is thought to occur in 8% of solid tumors.

Early results in melanoma — from a phase 1 study of 32 melanoma patients with a BRAF mutation — showed responses in a "remarkable 81% of patients," which "represent a major breakthrough," enthused the authors of an editorial that accompanied the publication of the study in the New England Journal of Medicine (2010;363;809-819, 876-879).

The latest clinical results, presented recently at the International Melanoma Research Congress of the Society for Melanoma Research in Sydney, Australia, confirm the high response rates.

They come from an open-label phase 2 trial of 132 patients with previously treated advanced melanoma positive for the BRAF mutation. Researchers report that 82% of patients had a response (52%) or stable disease (30%), and 52% had a decrease in their tumor size of 30% or more.

The median progression-free survival was 6.2 months in these patients; typically progression-free survival for such patients is only about 2 months, according to the researchers. Overall survival is typically around 6 to 9 months, they add, but the median overall survival has not yet been reached in the trial.

The safety profile is similar to that already reported for the experimental agent, and includes the development again of the grade 3 cutaneous squamous cell carcinoma, this time in 26% (34 of 132) patients. In these cases, the cutaneous squamous cell carcinoma lesions were excised and the patients continued with the experimental therapy. In addition, abnormal liver function was reported in 14% of patients, joint pain/arthritis in 11%, and gastrointestinal symptoms (including gastritis and pancreatitis) in 10%. Rash, photosensitivity, and hair loss were also reported.

These response rates are amazing.

"These response rates are amazing," said Antoni Ribas MD, from the Jonsson Comprehensive Cancer Center at the University of California in Los Angeles, who was involved in both the phase 1 and phase 2 clinical trials.

"So far in advanced melanoma, we have seen responses to drug therapy in only about 10% of patients, yet here we are seeing some sort of response in nearly every patient," he told Medscape Medical News in an interview.

"This is a huge step forward; in fact, it's a paradigm shift," he said.

The responses are not durable; they last for an average of about 7 months before the disease progresses, Dr. Ribas noted. Even so, he speculates that the response to the drug might lead to an improvement in survival by shifting the first part of the survival curve over by a few months.

Studying Resistance to the Drug

The decline in response indicates resistance to the drug, which means that these patients will need to be treated with other drugs.

New studies on the mechanisms involved in the emergence of this resistance has been reported in 2 letters published online November 24 in Nature.

In one of these studies, a team from the Jonsson Comprehensive Cancer Center, which included Dr. Ribas, looked at tissue from patients participating in the trials, and came up with a surprising finding.

Initially, the team presumed that the resistance to the BRAF inhibitor developed because BRAF had mutated further, but this was not the case.

This is an important finding, which will save both time and effort, the team believes, because it means that second-generation drugs targeting BRAF will not work, and therefore should not be developed.

"We were surprised that we couldn't find a single case [in which] a secondary mutation in BRAF was driving the resistance," Roger Lo, MD, assistant professor of dermatology at the Jonsson Comprehensive Cancer Center and corresponding author of the letter, said in a statement.

"In a big portion of known cases [in which] certain cancers acquire resistance to targeted drugs, the oncogene being targeted by the drug finds a way to get around the drug by developing other mutations," he said. It's almost like "you hit it with an axe, but the cancer soon finds a way to mitigate the effects of the axe," he explained.

But in the case of PLX4032 and BRAF inhibition, other mechanisms are involved. Dr. Lo and colleagues found 2 mutually exclusive mechanisms that explain the acquired resistance in about 40% of patients. One mechanism involves a cell-surface protein that the cancer cell begins to overexpress, creating an alternate survival pathway for the cancer when BRAF is blocked by PLX4032. The other mechanism involves a second oncogene, NRAS, which becomes mutated and allows the cancer to short circuit the PLX4032-inhibited BRAF mutation and reactivate the BRAF survival pathway.

"We've found 2 mechanisms in 2 subsets of melanoma, and we'll need different drugs to treat those 2 subsets," Dr. Lo said.

There are certainly other mechanisms of acquired resistance, he added, in the remaining 60% of patients.

In the second study, another mechanism of resistance was reported by a team from the Dana-Farber Cancer Institute in Boston, Massachusetts. They identified a novel cancer gene encoding COT (known as MAP3K8), and found that it became elevated during BRAF inhibitor treatment or the development of drug resistance. In some cases, high levels of the COT protein were evident in tissue from patients whose tumors returned or relapsed after drug treatment.

"Although we need to extend these results to larger numbers of samples, this is tantalizing clinical evidence that COT plays a role in at least some relapsing melanomas," said senior author of the letter Levi Garraway, MD, medical oncologist and assistant professor at Dana-Farber and Harvard Medical School.

This research suggests that one way forward in the development of new drugs is to focus on a combination of therapies directed against the MAP kinase pathway — a pathway in which both BRAF and COT are known to act. Such agents could be effective in overcoming the resistance that develops to PLX4032, they speculate.

"In melanoma, as well as in several other cancers, there is a critical need to understand the resistance mechanism, which will enable us to be smarter up front in designing drugs that can yield more lasting clinical responses," Dr. Garraway said in a statement.

"Biology is showing us where to hit in order to develop new drugs," Dr. Ribas concluded.

Nature. Published online November 24, 2010.

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