Sharing again…Sometimes I think I have no life beyond melanoma!

First-Line Market for Melanoma Not a Lock for Bristol or Roche

The Pink Sheet Daily. 2011 Jun 6, MJ Laffler

First-Line Market for Melanoma Not a Lock for Bristol or Roche

The Pink Sheet Daily. 2011 Jun 6, MJ Laffler

CHICAGO Both Roche's vemurafenib and Bristol-Myers Squibb's Yervoy (ipilimumab) could have a role in front-line treatment of metastatic melanoma, following the release of two much-anticipated studies at the American Society of Clinical Oncology annual meeting June 5.

The BRIM3 study of Roche's BRAF inhibitor and the Study 024 of Bristol's CTLA-4 inhibitor were the breakthrough highlights of the showcase for oncology research- and were each warmly welcomed as breakthroughs in the treatment of metastatic melanoma.

BRIM3 showed that in patients with the BRAF V600E mutation, which occurs in roughly half of melanomas, vemurafenib produced a 63% reduction in the risk of death and a 74% reduction in the risk of progression or death compared to dacarbazine at three months, the first interim analysis of the trial. The trial was halted after that analysis, when the data safety monitoring board recommended dacarbazine patients be switched to vemurafenib. Roche recently submitted for FDA approval, based on BRIM3 and the Phase II BRIM2 trial in previously treated patients, and could see approval by year-end.

Yervoy cleared FDA in March, based on a trial (020) in the second-line setting that showed an overall survival advantage – the first time that has been shown in melanoma. Ipilimumab also has the second trial showing a survival benefit with the 024 trial when added to dacarbazine in the first-line setting. An immunotherapy that activates T cell response against the tumor by blocking CTLA-4, ipilimumab showed median overall survival of 11.2 months compared to 9.1 months for dacarbazine alone. The ipilimumab studies included patients with BRAF mutations.

After the two trials were presented at the plenary session, Kim Margolin, University of Washington, put up a slide overlaying the curves of both trials – which showed both had notable effects, but at very different times.

The selection of which agent to use "is undoubtedly going to be an increasingly complex question," Margolin said in discussing the trials' presentations. "Acquired and intrinsic resistance need to be studied over the years so we can design better combinations and sequences."

There has been great excitement about the potential to combine the two drugs; the mechanisms can work in concert and there is potential to make up for the resistance that plagues BRAF inhibition. Roche and Bristol announced the start of a combination trial on the eve of ASCO.

Which To Choose?

While vemurafenib has excellent performance in the mutation-selected population in first-line treatment, as shown by BRIM3, ipilimumab has also produced solid results that show it also has value as initial treatment, including in patients with BRAF mutations.

Margolin sees it as a "decision between starting with a drug with very rapid onset and very early evidence of anti-tumor activity but potentially limited duration of control versus starting with an agent that has a slower, mechanism-dependent onset – but may provide a plateau of long-term disease control in a substantial number of patients."

"Vemurafenib is appropriate for patients who have symptoms and need to respond fast," she concluded. "It remains to be tested whether the smaller disease burden at the time of relapse from an excellent response to vemurafenib will have an advantage for the next therapy, which could well be ipilimumab."

But, "for those patients whose tumor burden is relatively low, minimally symptomatic and whose long term goal is durable benefit and who are not in urgent need of the physical and emotional relief associated with a quick tumor regression, ipilimumab may well be the preferred choice."

Neither drug is a simple option, she noted. Both will require monitoring and management of toxicities, and compliance will be essential. And, "the definition of regression has also gotten a lot trickier with the advent of ipilimumab, and the decisions about when to offer a different therapy to patients who have regressed on ipilimumab may differ as well as [for] those with a BRAF mutant melanoma who may have the opportunity to go on vemurafenib after ipilimumab."

One thing Margolin does see as clear: there no longer is a role for dacarbazine as background therapy for ipilimumab. "In view of the increased hepatotoxicity of ipilimumab plus DTIC in combination and the strong sense that there was no therapeutic advantage to the addition of the cytotoxic agent, it would not be advisable to include this agent in the standard clinical use of ipilimumab at any dose or schedule."

Beyond the combination therapy trial, additional research is needed to guide clinical practice. The most pressing question for ipilimumab is the appropriate dose and duration, which differed between the trials, Margolin said. For vemurafenib, she sees the major need as better understanding of the resistance and escape mechanism that affects BRAF, as well as research on the role of different sequences of therapies and combinations with other drugs.

There is also strong biologic rationale for other combinations to attack melanoma; various options are already being considered within and between pharmaceutical companies. And that research has implications beyond the field of melanoma, as it becomes clear that there is real potential for synergistic effects in the treatment of cancer.