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Molecular Screening Awareness Grows in Step with Adoption of Roche Melanoma Drug, Survey Finds

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A survey of more than 100 oncologists suggests that doctors are increasingly using Roche/Plexxikon's Zelboraf to treat metastatic melanoma patients whose tumors harbor BRAF gene mutations.

The survey, by BioTrends Research Group, also revealed that with rising adoption of the drug, doctors are becoming more comfortable with the use of molecular screening to inform treatment strategies for melanoma patients.

In August 2011, the US Food and Drug Administration approved Zelboraf (vemurafenib) as a treatment for patients with late-stage or unresectable melanoma in patients with BRAF-mutated tumors. Simultaneously, the agency approved Roche's BRAF V600 Mutation Test for gauging which patients will respond to the treatment. The BRAF mutation occurs in approximately 50 percent of metastatic melanoma patients (PGx Reporter 8/17/2011).

Six months after the launch of Zelboraf, BioTrends surveyed 103 oncologists and found that on average doctors are prescribing Zelboraf for first-line treatment in 22 percent of their advanced melanoma patients. Physicians are prescribing the drug in the second- and third-line setting in 18 percent and 13 percent of their patients, respectively.

For the first quarter of this year, Roche reported worldwide sales of $34 million for Zelboraf, a sequential increase over $33 million in the fourth quarter of 2011, the first quarter in which the drug was on the market. "It's definitely finding its place as one of the major therapies in this market," Dan Winkelman, therapeutics class director with BioTrends Research Group, told PGx Reporter.

Of the surveyed doctors, 29 practiced at academic or community hospitals; nine were at hospital-affiliated outpatient clinics; and 65 were in private practice.

In the BioTrends report, Zelboraf ranked among the top three treatment options available for oncologists treating metastatic melanoma patients, after Bristol-Myers Squibb's targeted immunotherapy Yervoy, which entered the market earlier in 2011, and Merck's Temodar.

"Yervoy is one of the first targeted immunotherapies in cancer and over two-thirds of medical oncologists report efficacy as a key advantage of this therapy with the survival data most often cited," BioTrends said in a statement announcing the results of the LaunchTrends report.

Among the advantages cited by surveyed oncologists were the drugs' "unique side effects," which are often manageable over time. "Surveyed specialists also noted that the response rates for Yervoy are often unpredictable, but when it does work efficacy can be sustained," BioTrends noted.

The UK's National Institute for Health and Clinical Excellence in October recommended against the National Health Service paying for Yervoy, citing the lack of a pharmacogenomic strategy to identify best responders as one of the key reasons (PGx Reporter 10/19/2011).

BioTrends's survey revealed that doctors on average were prescribing Yervoy to 25 percent, Zelboraf to 22 percent, and Temodar to 21 percent of their patients. In the second-line setting, Yervoy had 27 percent patient share, followed by Temodar and Zelboraf, both with 18 percent patient share. As a third-line treatment, Temodar is the first choice for physicians, with 24 percent patient share, followed by paclitaxel with or without carboplatin at 21 percent, and Zelboraf at 13 percent.

"[Zelboraf] is becoming more of a first- or second-line option," Winkelman said. "It's not really reserved for third line."

Patient groups have raised concerns about the high price of both drugs. Yervoy costs $120,000 for a complete course at 3 mg/kg; a full treatment schedule involves four infusions at $30,000 over three months. A six-month course of treatment with Zelboraf costs $56,400.

The steep drug prices don't seem to be deterring adoption of these treatments, however. "Doctors are aware that these are expensive agents," Winkelman said. "They did state they have had some reimbursement issues. But they said that it's not a major concern for them. It's not stopping them from prescribing the drugs."

Based on in-depth interviews with 15 doctors, BioTrends found that difficulties around reimbursement for Zelboraf itself seem to be more of a barrier to prescribing it than reimbursement for the companion diagnostic to gauge whether patients have BRAF-mutated tumors. At the time of Zelboraf's launch, Roche said that its BRAF mutation test would likely cost between $120 and $150 per test.

"Managed care puts in criteria for [prescribing] this drug and have said, 'Look, the patients must be BRAF positive,'" Winkelman noted. "So, they have to make the test available. They can't say, "The patients have to be BRAF positive and we're not going to pay for the test.'"

BioTrends asked doctors to quantify the proportion of patients they screen for disease-related biomarkers in their practice overall. The survey revealed that six months ago oncologists were screening 49 percent of all patients and they are now screening 46 percent — not a statistically significant decrease.

In melanoma, however, the percentage of patients receiving molecular screening increased over the period of six months to 67 percent from 62 percent. "So we're seeing an acceptance of [Zelboraf] as an agent with a biomarker [strategy], and the testing is becoming pretty standardized," Winkelman said.

One doctor Winkelman interviewed said there was more of an effort at his practice to educate nurses and dermatologists about sending patient samples for mutational analysis. Alternatively, doctors are also asking labs to hold on to patient samples for future mutational analysis. "Doctors are educating the other stakeholders on the need [for] collecting the tissue and sending it out for testing," Winkelman reflected.

While physicians are still performing the bulk of genetic testing in line with Zelboraf's FDA-approved indication, for patients in later stages of the disease, there are signs that physicians will likely molecularly screen patients much earlier in the treatment continuum. Oncologists surveyed by BioTrends said that they are molecularly testing 64 percent of their stage III unrescectable melanoma patients and 78 percent of stage IV patients.

"What's interesting is if you go to the earlier stage patients, like stage I, where they are following patients with observation or removing the tumor with surgery, doctors are testing 8 percent of patients and 11 percent of stage II patients," Winkelman said. "So, there's this feeling [among doctors] that they should start to get as much information as possible, so they can have all the information they need to treat the patient."

According to BioTrends, 91 percent of physicians said that it took them six months or less to add BRAF testing to their practices. It is currently unknown how much of this increase in melanoma screening translates to greater availability and adoption of Roche's BRAF test.

Shortly after the drug's launch last year, Roche said that some large hospitals had balked at incorporating its FDA-cleared test, choosing instead to continue to perform BRAF testing using existing laboratory-developed platforms (PGx Reporter 9/28/2011). Winkelman noted that oncologists he spoke to don't know if the FDA-approved kit is being used to test samples for BRAF mutations.

A spokesperson for Roche Molecular Diagnostics told PGx Reporter that the company was offering testing with its BRAF mutation kit at three sites when Zelboraf launched last August. By the end of the first quarter this year, the company is performing testing at more than 10 sites.

"The increased adoption is being driven by clinician demand who want to use a test that is FDA approved and clinically validated in the pivotal trials," the spokesperson said. "Some clinicians have commented that are impressed by the test's rapid turnaround time so they can get their patients on therapy sooner." The spokesperson added that adoption of Roche's test has been bolstered by third-party payors who have instituted requirements that FDA-approved kit be used for reimbursement.

Finally, Winkelman noted that while most doctors — 66 oncologists out of 103 — aren't familiar with new melanoma treatments currently under development, "for those that do know, the BRAF and MEK inhibitors are the big ones" that interest them. He added that physicians who are knowledgeable of upcoming drugs have a "high awareness" that there is a study ongoing to investigate Yervoy/Zelboraf as a combination agent.

The FDA approved Yervoy just over a year ago. At the American Society of Clinical Oncology's annual meeting last June, BMS announced it was investigating whether combining Yervoy with Zelboraf could further improve outcomes in molecularly defined subpopulations of melanoma patients (PGx Reporter 6/8/2011).

The study showed that some physicians also were keeping up with the development programs for GlaxoSmithKline's BRAF inhibitor dabrafenib and MEK inhibitor trametinib, as well as Array BioPharma and AstraZeneca's MEK inhibitor selumetinib.

GSK is studying dabrafenib and trametinib as melanoma treatments as single agents and in combination, hoping that targeting the RAF and MEK pathways simultaneously could improve efficacy and safety as compared to when the drugs are used individually. According to Clinicaltrials.gov, Massachusetts General Hospital, in collaboration with AstraZeneca, the NCI, and others, is studying selumetinib in cancers with BRAF mutations.

BioTrends will continue to track the use of Yervoy and Zelboraf for another six months, and will publish its findings in a report in October.

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