Oncologists Audition Yervoy and Zelboraf for First-line Roles

Oncologists Audition Yervoy and Zelboraf for First-line Roles, With New Combos in Near Sight

The Pink Sheet Daily. 2012 Jun 18, E Hayes

A year ago, the arrival of two breakthrough therapies for metastatic melanoma stole the show at the American Society of Clinical Oncology annual meeting. This year, debate continued on how Bristol-Myers Squibb Co.’s immunotherapy Yervoy and Roche’s targeted Zelboraf should be used in practice: what is the best first-line option, and, especially with more agents coming, what is the potential for sequential and combination use?

Conventional thinking is that Yervoy (ipilimumab) may be the best first-line treatment for metastatic melanoma when disease is less advanced, while Roche’s targeted Zelboraf (vemurafenib) is an obvious choice for BRAF-mutation positive patients with a high tumor burden and risk of dying fast. But the debate is far from over and there is a critical need for more information to make informed treatment decisions, experts say.

The approvals of the CTLA-4 inhibitor Yervoyin May 2011 and BRAF inhibitor Zelboraf in August of that year marked a revolution in the treatment of melanoma after a decade of stagnation in the field. About half of metastatic melanoma patients test positive for the BRAF V600E mutation and are candidates for Zelboraf based on results from Roche’s cobas 4800 V600 Mutation test, approved by FDA in tandem with the drug. Yervoy response is not dependent on BRAF mutation and thus is an option for that subgroup as well.

Since both drugs are cleared across lines of metastatic melanoma therapy, a battle ensued for dominance in first-line treatment and has stirred debate in the field. Trials of Zelboraf demonstrated a strong early anti-tumor response, though it is often followed by development of treatment resistance. Ipilimumab, in contrast, is slow to take effect and only about one in four patients respond, but responses can be highly durable.

Options for sequencing strategies for new melanoma drugs were featured during an ASCO session on June 2. Speakers did not issue firm prescriptions, but did suggest that a year out, popular thinking is that positive mutation status doesn’t mean that a BRAF inhibitor is the best first choice. Yervoy might turn out to be a better option for patients in earlier stages of disease, when immunotherapy has a better chance for success, while Zelboraf seems a shoo-in for patients with a high risk for dying quickly and/or who need palliative treatment for symptoms due to a high tumor burden, they said.

Head-to-head data would help answer the questions about how and when to sequence Zelboraf vs. Yervoy in BRAF-positive patients. The Eastern Cooperative Oncology Group is planning the E1612 study to test ipilimumab followed by vemurafenib against vemurafenib followed by ipilimumab, noted Michael Atkins, deputy director of the Georgetown-Lombardi Comprehensive Cancer Center.

“We absolutely, positively need data, more definitive randomized data, such as could be provided … by the cooperative group trial that has been proposed and hopefully will ensue,” said Keith Flaherty, director of developmental therapeutics at Massachusetts General Hospital, and another session presenter.

Clinicians hope to launch the study in early 2013, but the study hasn’t been approved by all parties yet.

Melanoma: Current Lay Of The Land

Adoption of diagnostic testing provides an indication of how quickly the field has adapted to the introduction of new treatments. According to Roche Molecular Diagnostics, tests have been ordered for some 80% of eligible patients with late-stage melanoma. For the first quarter of 2012, Roche reported sales of CHF 32 million ($33.7 million) for Zelboraf and noted that it had a 79% share of first-line treatment and a 70% share of the second-line market.

Meanwhile, Yervoy sales reached $154 million in the first quarter of 2012, up slightly from $144 million in the fourth quarter of 2011. Product sales in the first 12 months of launch reached $514 million.

Ipilimumab also is now approved in the EU, albeit for a more limited indication. Bristol has launched in some countries and is planning to gain access and reimbursement in almost all countries in the region by the end of 2012, execs said in a Jan. 26 earnings call. Bristol also has an aggressive development program for Yervoy, with trials under way in prostate and lung cancer.

In keeping with Roche’s report about testing, a survey of oncologists done at the end of March/early April by BioTrends Research Group, a Decision Resources subsidiary, found high adoption of BRAF mutation testing, particularly in patients with Stage IV disease. The survey polled about 100 oncologists that treat at least 10 melanoma patients per month in a variety of settings, including community and academic hospitals.

Even though they are newest to market, Yervoy and Zelboraf have the highest awareness levels among oncologists, according to the survey. Absent prompting of product names, 90% of those surveyed were aware of Yervoy and 76% knew about Zelboraf.

BioTrends is analyzing the melanoma market with three rounds of surveys. The first was done at the end of September/early October 2011, the second one was done at the end of March/early April 2012, and the third will be performed in October 2012.

At the end of the first quarter – about one year after the Yervoy launch and six months after the introduction of Zelboraf – over 80% of providers had prescribed these therapies to at least some patients, according to the survey.

Both drugs continued to gain first-line market share at the expense of older drugs like temozolomide (Merck & Co. Inc.’s Temodar) and dacarbazine, compared to the previous survey. Yervoy’s first-line take was up 5% to 25% while Zelboraf rose from 12% to 22%Interviews with oncologists suggest the decision to use Zelboraf is based on several factors aside from the BRAF mutation, said Dan Winkelman, oncology therapeutic class director at BioTrends. For example, if patients have brain metastases, oncologists might be more likely to consider Temodar. For those who choose Yervoy first in BRAF-positive patients, “the rationale is that Yervoy is slow but sustainable, while Zelboraf has a good response rate but limited duration,” Winkelman explained in an interview.

Zelboraf’s uptake in Europe is rockier. The drug was turned down in draft guidance from the U.K.'s National Institute for Health and Clinical Excellence, released for consultation on June 15. The appraisal committee accepted that vemurafenib was a "step change" in the treatment of advanced malignant melanoma, but it found the long-term effects on survival were highly uncertain, because patients in the dacarbazine control arm of the pivotal trial were moved onto vemurafenib or ipilimumab when their disease progressed, making comparisons difficult.

NICE said that vemurafenib met less stringent criteria for being cost-effective because it was an "end-of-life" therapy. However, taking into account the uncertainty around its effects on survival, and even with the discount from the patient access scheme offered by Roche, the cost per QALY for vemurafenib would still be considerably more than the usual maximum of £50,000 per QALY gained for end-of-life therapies. Roche in fact estimated that the cost would be £56,000 per QALY gained, the appraisal committee noted. The company has the opportunity to discount the cost further by submitting another patient access scheme. Currently, one week's supply of Zelboraf costs £1,750, and with the average duration of therapy being seven months, the average cost of treatment works out at £52,500.

Sequencing Strategies At ASCO

Based on new research presented at the 2012 ASCO meeting, as well as previously known research, Atkins made his case for using ipilimumab as a first-line therapy prior to vemurafenib in appropriately selected BRAF-mutation positive patients.

Atkins drew attention to the results of a small retrospective poster study done by Beth Israel’s Allison Ackerman and colleagues. The study compared treatment response in 43 clinical trial patients with the BRAF V600E mutation treated with immunotherapy prior to or after vemurafenib between 2009 and 2012. All of the patients received vemurafenib and ipilimumab or interleukin 2, an earlier immunotherapy that works similarly to Yervoy.

All of the patients who initially received immunotherapy and progressed went on to get vemurafenib as a second-line treatment. Response rates were in line with the drug’s known efficacy.

Those who progressed on vemurafenib as first-line or second-line therapy for the most part deteriorated rapidly and were less able to benefit from ipilimumab. Median OS was 4 months. Treatment and survival were insufficient to accurately evaluate response to ipilimumab following vemurafenib, and a randomized trial is needed to make a full comparison in the same patient population. Further research is also needed into the rapid deterioration associated with vemurafenib progression.

During another session on June 4, Atkins noted that in the BRIM3 first-line trial of vemurafenib vs. dacarbazine, the overall survival benefit was demonstrated mostly in patients with the most aggressive, symptomatic disease, and there was lower benefit relative to dacarbazine in terms of overall survival for patients with earlier stage metastatic disease.

Based on the limited non-randomized data and clinical experience, Atkins concluded: “BRAF inhibitor therapy may not be the best initial option for patients with BRAF V600 melanoma.” Current data suggests some patients with BRAF V600E melanoma, particularly those who are asymptomatic and have normal serum LDH (lactate deyhydrogenase, a measure of tissue damage) have a chance at long-term benefit, “without compromising benefit from subsequent BRAF inhibitor therapy,” he said.

Weighing The Risk Of Waiting

Depending on a patient’s short-term survival prospects, which can be difficult to predict, there may not be time to wait for Yervoy to work, Mass General’s Flaherty said during the June 2 session on sequencing. The first assessment of Yervoy treatment takes place after three months, but some patients progress rapidly and may die within six months.

In contrast, Zelboraf has demonstrated “early and profound activity,” so in patients who are symptomatic and have a high tumor burden, sequencing decisions are much more clear-cut, he said: “We have relatively few choices other than to offer what we think is the best palliative treatment.”

After treatment with Zelboraf, however, “early experience suggests, unfortunately, many cannot be transitioned” to ipilimumab he said.

If a combination of Yervoy/Zelboraf emerges as a safe alternative, “this would make the whole concern about sequential therapy go away,” and those perceived to be at risk of short-term survival could receive both therapies, Flaherty said. A Phase I/II trial testing this combination is enrolling patients.

The discussion at ASCO suggests that it might be in the BRAF-mutation positive patient’s interest to reserve treatment with BRAF inhibitors for later, Vernon Sondak, chair of cutaneous oncology at the Moffitt Cancer Center, commented in an interview. It makes sense to use ipilimumab early when a patient’s immune system is intact and overall condition is better.

“If they have a chance of being cured or at least having long, long term success, why not give them that chance?” he said.

The introduction of new drugs in the arsenal would further complicate decision-making. At the ASCO meeting, GlaxoSmithKline PLC released data for its MEK inhibitor tremetinib and BRAF inhibitor dabrafenib and is expected to file for approval of both as monotherapies later in 2012 (see sidebar). Combining MEK with BRAF could improve the BRAF resistance profile and eliminate some of BRAF associated toxicity. Phase III combination trials are under way, following the release of an early-stage combination trial at the ASCO meeting.

“We haven’t got all the answers, and clinical trials and ongoing research at specialized centers [are] still going to be important. … We have some great new drugs that are working better than anything we ever had but we still have a lot of questions about how to do even better,” Sondak said.

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