ASCO 2012|June 3, 2012 10:41 pm

Sequence and Timing of Melanoma Therapy

What does a (relative) wealth of melanoma treatment “riches” create?

Several words come to mind. Confusion. Creativity. Imagination. Dialogue. Conflict. Bias. Conviction (of ideas).

Such is the state of the disease over the past year, since the approval of ipilimumab (Yervoy) and vemurafinib (Zelboraf). For patients whose melanoma has the required BRAF mutation (because patients without the mutation who are “wild-type” should never get Zelboraf), which treatment should come first? When should the treatment be switched (“cross-over”)? Where do other treatments factor into the equation, like chemotherapy and IL2?

The first thing that is certain in some respects and evolving in others is that ALL patients with metastatic melanoma should have their tumor tested for the BRAF mutation. The argument could also be made that they should be tested for cKIT, NRAS and perhaps even GNAQ and GNAQ11. All of these tests may have as yet unclear prognostic significance and also may influence treatment choices, sooner rather than later.

But leaving the other treatment choices aside and focusing just on BRAF mutant melanoma patients, and further assuming that those patients have no clinical trial either options or interest, which treatment should come first? These topics were the focus of a forum at ASCO on June 2, 2012. Headlined by three major players in the melanoma world, Mike Atkins, Keith Flaherty and Jeff Sosman, this was a fascinating and incredibly well-attended discussion of these issues.

Should Yervoy be used first? Many believe that is appropriate unless the patient has symptomatic, high volume, aggressive and/or symptomatic disease, since Zelboraf can more reliably rapidly reduce tumor volume. Yet Zelboraf may not have as durable a benefit, and can induce cellular biochemical resistance that seems in some cases to promote even more aggressive tumor growth resistant to other therapies. Yervoy on the other hand typically works much slower but can induce durable long term (as far as we can tell so far…) responses.

Maybe Zelboraf should be used first. If it works, which is true for up to 90% of patients on some level, tumor size reduction happens quite quickly and dramatically. It may also provide a better environment for eventual immunotherapy but releasing tumor antigen proteins that can better stimulate an immune system subsequently treated with Yervoy.

But how to know when to switch? The reversal of both Yervoy and Zelboraf benefits can be quite insidious and difficult to detect without constant follow up, examinations and imaging studies. Also, some patients treated with Yervoy will initially progress before they respond, making it even more difficult to know the appropriate cross-over moment.

What about emerging combination therapies, particularly the BRAF/MEK inhibitor studies to be presented on June 4, 2012 at ASCO? Or the accelerating interest in anti-PD-1 antibody treatment, which seems to have similar efficacy as Yervoy, pending additional studies which are imminent. Or the multitude of studies in follow-up, including for Abraxane, Oncovex, Vical gene therapy, etc., that may yet yield positive results, garner FDA approval, and force recalculation of everybody’s treatment design.

Coloring all this is physician bias: the conviction by smart people who are used to being right that they have the best answer based on experience, knowledge, statistical expertise, etc., etc. I am guilty of the same thing; I am a disbeliever in IL2 and believe Yervoy is always a better choice. But I may be wrong…

The bottom line is, there is no consensus. And there is no “hard” data to support any choice. Many physicians are seemingly daily changing their minds about the answers to these questions. Hopefully, with time more answers will be carved out of the uncertainty.

Eric Whitman, MD

Senior Editor,

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