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NEJM Paper Yields Positive Efficacy Results for Roche/Plexxikon's PGx Melanoma Drug

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By Turna Ray

A study published last week in the New England Journal of Medicine provides promising early results that a melanoma drug being developed by Roche and Plexxikon may be efficacious in patients carrying certain BRAF mutations.

However, according to the researchers, the study also suggests the need for more investigation to characterize the genetic complexities underlying patients' resistance to the investigational treatment and to determine whether the drug improves overall survival.

The study, led by Keith Flaherty of the University of Pennsylvania's Abramson Cancer Center and published Aug. 26 in NEJM, showed that 81 percent, or 26 of 32 of patients, with V600E mutations in the gene encoding the serine-threonine protein kinase BRAF, had either a complete or partial response to Plexxikon's melanoma drug PLX4032. The study was divided in to a dose-determining phase (55 patients) and an extension phase (32 patients) to gauge tumor response.

In terms of drug toxicity, approximately one-third of the patients in the extension phase of the study developed squamous-cell carcinoma-keratoacanthoma type, and 40 percent of patients receiving a 960-mg, twice-daily dose of the drug required a dose reduction to 720, 600, or 480 mg twice daily, due to grade 2 adverse events. Researchers noted in the paper that BRAF inhibitors' impact on the MAP kinase pathway may drive some of these side effects associated with PLX4032.

Despite the response seen in V600E mutated patients treated with PLX4032, the study leaves open questions about the mechanisms underlying drug resistance in patients. Particularly of concern was that some patients with V600E mutations were resistant to therapy before they exhibited an early response. Whether "gatekeeper" BRAF mutations are at play in conferring resistance to PLX4032 "requires more investigation," the researchers wrote in the paper.

According to the researchers, V600E mutations account for 90 percent of variation in the BRAF gene. As many as between 40 percent and 60 percent of melanoma patients carry a mutation in the BRAF gene.

Roche has previously said that it is developing a companion test for PLX4032, and intends to market the drug with a companion genetic test (PGx Reporter 09/23/09).

A Roche spokesperson told Pharmacogenomics Reporter this week that Roche Molecular Systems and Berkeley, Calif.-based Plexxikon are co-developing a real-time PCR-based diagnostic test to detect V600E mutations in BRAF called the Cobas 4800 BRAF V600 Mutation Test. "It is too early to speculate on the timing of potential regulatory submissions," the spokesperson stated.

Flaherty told PGx Reporter in an e-mail that the commercial diagnostic test developed by Roche will likely be submitted along with clinical data for PLX4032, to attempt to get approval of the drug and diagnostic at the same time. "But, there are currently and will be at that time several venues for getting testing that don't involve [Roche's] test," Flaherty said. "So, no one (except Roche) is holding their breath on how the test is handled by the US Food and Drug Administration."

Massachusetts General Hospital, MD Anderson Cancer Center, Esoterix, and others have laboratory-developed tests that gauge BRAF mutations.

Study Details

The NEJM paper presented data from a multicenter, Phase I dose-escalation study in 55 patients, followed by an extension phase in which 32 patients were given the maximum tolerated dose of PLX4032 to gauge tumor response.

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In the extension study, 32 patients harboring BRAF V600E mutations were treated with 960 mg of PLX4032 twice daily. Gene mutations were gauged using Life Technologies' Applied Biosystems TaqMan PCR assays.

The aim of the study was to define the safety and efficacy of PLX4032; determine the maximum dosing that could be administered to patients without intolerable adverse events; and to determine the objective response rate, duration of response, and the rate of disease progression in patients with BRAF V600E mutations given the investigational drug at a dose of 960 mg, twice daily.

In the dose-escalation cohort, out of 16 patients with V600E mutations and treated with 240 mg or higher doses of the drug, 10 experienced a partial response and one had a complete response. In addition, 24 of 32 patients in the extension portion of the study had a partial response and two saw a complete response.

As part of the study, researchers also biopsied certain patients' tumors at baseline and at 15 days. Tumor specimens were analyzed by immunohistochemistry for phosphorylated extracellular signal-regulated kinase, protein cyclin D1, and the monoclonal antibody Ki-67.

Pharmacokinetic analysis revealed that tumor levels of phosphorylated ERK, cyclin D, and Ki-67 were "markedly reduced" at 15 days of treatment compared to before the start of therapy. "This finding suggests that PLX4032 inhibited the MAP kinase pathway, resulting in decreased cyclin D1 levels and decreased proliferation," the researchers wrote. "In virtually all patients, a marked decrease in tumor uptake of [fludeoxyglucose] was noted at day 15."

The dose-escalation phase of the study also revealed to the sponsor the most effective formulation for PLX4032. This portion of the study had to be initially halted because there was a bioavailability problem with the crystalline formulation of the drug. The researchers decided to reformulate the compound as a microprecipitated bulk powder.

According to Flaherty, the exact reason why the crystalline formulation didn't work is unknown. "Formulation … is a bit of a black box even to the medicinal chemists who work on it. Some formulations simply work better than others in terms of getting drugs into the bloodstream," Flaherty said. "Because the first formulation couldn't deliver the drug from stomach to bloodstream well enough, there wasn't enough [of the] drug floating around to sufficiently inhibit BRAF in melanoma cells."

Toxicities

Because BRAF inhibitors such as PLX4032 may also activate cells that lack BRAF mutations in the MAP kinase pathway, this may also be driving drug-related toxicities seen in the study, the authors wrote.

During the dose-escalation phase, patients did not experience dose-limiting toxicities until receiving the 720-mg twice-daily dose. In the extension cohort that received the 960-mg twice-daily dose, 13 out of 32 patients needed to have their doses reduced. Ten patients went down to 720 mg twice daily, one patient reduced to 600 mg twice daily, and two patients took the drug at 480 mg twice daily.

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This observation will help Roche/Plexxikon dose PLX4032 in Phase III studies. "For now, we will stick with the same dosing strategy in Phase III," Flaherty said. "Start at 960 mg and reduce [the dose] if side effects dictate. We can't predict who is going to have a tougher time, but these aren't life threatening side effects."

The most common grade 2 and grade 3 toxicities in the study were arthralgia, rash, nausea, photosensitivity, fatigue, cutaneous squamous-cell carcinoma, pruritus, and palmar-plantar dysesthesia. Around 89 percent of toxicities were grade 1 or grade 2. Eight patients in the dose-escalation study and 10 in the extension phase had cutaneous squamous-cell carcinoma, but upon review, researchers identified only one that appeared to be a keratoacanthoma.

Due to this incidence of squamous-cell carcinoma-keratoacanthoma type, the study protocol was amended to conduct dermatological evaluations of patients every two months. Researchers also monitored patients for lesions suggesting cancer at a new site using computed tomographic scans. The majority of carcinomas were resected, and no patients in the study had squamous-cell carcinoma metastasize to other organs.

Resistance and Overall Survival

Although the findings of the NEJM study show that melanoma patients with V600E mutations will likely have an early response to PLX4032, the study also illustrates that these patients will eventually develop resistance to the drug.

"The majority of patients have shown resistance by virtue of the fact that their tumors have begun to grow again while still on therapy," Flaherty said. "We are intensely studying what might be driving their tumors at that point, but the jury is still out."

In the study, researchers noted that some patients with V600E mutations did not respond to PLX4032, and appeared to be resistant to treatment from the start. "The mechanism of this primary refractory state is currently under investigation," the researchers wrote. "To date, we have not seen 'gatekeeper' BRAF mutations in resistant tumors."

Flaherty explained that "gatekeeper mutations" in BRAF are new mutations in BRAF, other than V600E, that impede the ability of PLX4032 to inhibit BRAF. "Such mutations have been seen in CML and [gastrointestinal stromal tumors] to explain resistance to Gleevec and other drugs in those diseases," he noted.

Finally, the NEJM study did not elucidate whether PLX4032 will improve overall survival in melanoma patients, an endpoint that may be significant for Roche and Plexxikon when it comes time for the companies to submit their marketing application to the FDA.

As of Jan. 31, 16 out of 32 patients remained on the study. Although these patients had a median progression-free survival of seven months, researchers acknowledged in the paper that they do not yet know whether PLX4032 will improve overall survival.

The drug's impact on overall survival is being explored in a randomized Phase III study, called BRIM3, which is expected to complete enrollment next year. This study, according to the Roche spokesperson, involves patients with previously untreated BRAF V600E mutation-positive metastatic melanoma. Data from this study will be part of the company's marketing application to the FDA for PLX4032.

In a Phase II study called BRIM2, Roche is also investigating PLX4032 in people with previously treated BRAF V600E mutation-positive metastatic melanoma. Roche completed enrolling this study in the first quarter of this year.

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