Melanoma Trial Results Lead to ‘Unprecedented’ Options

June 07, 2011 - BioWorld Today

By Anette Breindl
Science Editor

CHICAGO – Much-anticipated full results for two new melanoma drugs were reported at the 47th annual meeting of the American Society of Clinical Oncology (ASCO), and published online in The New England Journal of Medicine, on Sunday: the BRIM3 trial of Vemurafenib (PLX4032/RG7204, Plexxikon Inc./Roche AG) and the 024 study on Yervoy (Ipilimumab, Bristol-Myers Squibb Co.)

Between them, the two trials have opened up options for melanoma patients that the lead investigators of both trials called unprecedented. Vemurafenib reduced the risk of death by 63 percent and the risk of tumor progression by 74 percent compared to chemotherapy, while adding Yervoy to standard chemotherapy reduced the risk of death by 28 percent and of tumor progression by 24 percent.

Top-line results from both trials had already been released and showed survival benefi ts. (See BioWorld Today, Jan. 20, 2011 , and March 23, 2011 .)

But doctors, patients and analysts were eagerly awaiting the details of those benefi ts. And they were not disappointed: Mark Schoenebaum of ISI group called the Vemurafenib hazard ratio “remarkable” and noted that it is “one of the lowest we’ve ever seen for OS in any metastatic cancer trial.”

48.4 percent of patients with an activating BRAF mutation that Vemurafenib targets responded to treatment with the drug. That response rate was nine times higher than that of the unfortunates originally assigned to the dacarbazine arm, who showed a 5.5 percent response rate. But it was lower than the eye-popping 81 percent rate reported for the drug’s Phase I trial. (See BioWorld Today, Aug. 27, 2010.)

Lead author Paul Chapman of Memorial Sloan-Kettering Cancer told BioWorld Today that the widely reported 81 percent response rate was “a little misleading,” because it included any tumor that shrank by at least 30 percent for any period of time. To meet RECIST criteria, such shrinkage has to last for at least a month.

By those criteria, he said, the Phase I trial had a response rate of 56 percent, which was “in line” with the 48 percent now seen in the BRIM3 trial.

The magnitude of the overall survival benefit, in fact, is still not clear. But for now, median survival is estimated at 10.5 months and increasing vs. 7.8 months for patients in the chemotherapy arm. Vemurafenib reduced the risk of death for melanoma patients by nearly two-thirds.

At any rate, Chapman argued, “median survival is not the statistic of interest. What patients want to know is ‘what’s my chance of being alive in fi ve years?’”

The data to answer that question will not be available for some time; the BRIM3 trial accrued patients through December 2010. The trial was halted early and crossover of patients from the chemotherapy arm was permitted after a planned interim analysis showed a clear benefit of Vemurafenib.

But Chapman was optimistic. “I’m hoping that it will be a substantial proportion.”

Data from a trial using Yervoy with chemotherapy as front-line treatment for newly diagnosed patients that were also released on Sunday include follow-up of at least three years, and so are much closer to being able to answer the patient’s central question of what their chances are of making it for five years.

The answer: Not terribly good. But better with Yervoy than without.

In their study, the authors compared a combination regimen of Yervoy with chemotherapy to chemotherapy alone. The median overall survival was 11.2 months for patients on the combination treatment, vs. 9. 1 months for those receiving placebo with their chemotherapy.

But in patients who did benefit, the benefit could be long-lasting: Those receiving Yervoy had a significantly higher survival rate at every time point the investigators tested. At three years, the survival rates were 21 percent vs. 12 percent. Those results, along with those of last year’s registration trial, make Yervoy “the first drug for melanoma to improve response proportion, progression-free survival and overall survival” and “a foundation which our field can build upon” lead investigator Jedd Wolchok told reporters at a press conference.

The two new stars are teaming up already. Last week Roche and Bristol-Myers Squibb announced that they have entered into a clinical collaboration agreement to test the use of both agents as combination treatment.

Wolchok said that “based upon the results that you heard about today, this [combination trial] is a very important next step for the field.” Vemurafenib’s rather spectacular early response rate, combined with the slower onset but more durable responses to Yervoy, he said, could potentially be synergistic when given together.

“They complement each other quite nicely,” Wolchok said.

Plexxikon, which was bought recently by Daiichi Sankyo Co. Ltd., filed marketing applications in the U.S. and Europe last month for Vemurafenib – just 4.5 years after starting clinical development. (See BioWorld Today, May 12, 2011 .)

The Japanese pharma firm shelled out $805 million up front to buy Plexxikon, even though it will only have U.S. copromotion rights to Vemurafenib under Plexxikon’s existing collaboration with Basel, Switzerland-based Roche. Another $130 million in milestones from Daiichi are tied to the drug’s commercial success. (See BioWorld Today, March 2, 2011 .)