ASCO 2011|June 5, 2011 10:46 pm

ASCO Melanoma Oral Abstract Session


ASCO Melanoma Oral Abstracts 2011

For the second year in a row, the oral abstract session for melanoma was overshadowed by the presence of two important, iconic, melanoma treatment studies in the ASCO plenary session.

I have two general observations about this new (and hopefully now commonplace) situation. First, that our expectations for research findings in this sometimes relentless disease have been forever changed: the bar has been raised by the results with Ipilimumab and now Vemurafenib. Second, interest level in melanoma by non-specialist physicians, biotech and Pharma companies has never been higher. The crowds at melanoma talks seems unprecedented, and all sessions at ASCO have been moved to much larger venues, Also, the “graveyard of melanoma” that we had seen grow over the years (Maxim, Synta, Genta, others) no longer scares Pharma, as company after company are suddenly entering the field with new drugs and protocols. This bodes well for future advances and improved outcomes for melanoma patients.

On to the oral abstract session…

The first presented paper was a population based study of the prevalence and outcomes of the Melanocortin-1 Receptor. The chosen specific expression was termed RHC. This gene’s product is involved with protection and repair of skin DNA from UV induced sun damage and RHC patients tend to have red hair, fair skin, multiple freckles, etc. Expression of the RHC mutation was associated with increased risk of melanoma, apparently worse with extensive sun exposure and sun bed use. However as a population based study employing questionnaires these are far from hard numbers, Treatment strategies? No specific targeted agents in sight. It makes me think of the South Park episodes where all the redheads (“gingers”) got together to complain about their social plight.

The second presentation was the ECOG 1697 final report. This study was begun over a decade ago, looking at adjuvant therapy for stage II or early stage III disease. Unfortunately, the inclusion and exclusion criteria were modified a few times over the years, making the groups a little muddied. It compared one month, aka induction, interferon-alfa-2b (Intron-A) to observation. The trial was stopped for futility last year. That means that the statisticians determined from the results to date that the study was negative and could not become positive regardless of results in the future, hence “futile”. Another strike against short term induction interferon therapy without maintenance. In fact, recent approval for Sylatron (see below) was based on up to 5 years of maintenance therapy, and the data suggests in some ways that continued therapy was beneficial in delaying recurrence.

The next presentation was from the Italian Melanoma Group or Consortium. They also investigated adjuvant interferon, modifying the dose so that it was higher or more “intense” during a time frame when the risk of early recurrence is possibly increased. The study was also negative, as the newer regimen did not significantly improve RFS (although trending, which is interesting but ultimately not enough) or OS.

The next report was an update of EORTC (European equivalent of ECOG) trial 18991, which provided the data leading to the approval of Sylatron in the USA earlier this spring. The median followup for the data is now 7.6 years; it was half that when presented to the FDA. The results basically remain the same: in the overall intent-to-treat group, relapse free survival remains positive, and this was the primary endpoint chosen by the FDA. Overall survival is negative. As before, the results appear “driven”, or almost entirely the result of, the patients with microscopic nodal disease, who were diagnosed through sentinel node biopsy. To a lesser extent, primary melanoma ulceration is also very significant, as this may be associated with increased sensitivity to interferon therapy. In fact, patients with ulceration and micro-nodal disease showed huge benefits. This last part was once again a controversial point, since apparently the ECOG Intron data from years past do not support this conclusion. Regardless, EORTC is sticking to its guns and is initiating a new trial, designated 18081, randomizing patients with ulcerated primary melanoma and microscopic sentinel node involvement to Sylatron or observation.

The next paper was from an Israeli group looking at treatment for metastatic melanoma with interleukin-2 (IL-2) and tumor infiltrating lymphocytes or TILs. They hypothesized that “young” TILs, made more quickly through an abbreviated, less-screened method, work better than standard TILs. Small numbers, many possible confounding variables, impossible to analyze in the big picture. Virtually nobody in the USA, outside of the NCI, work with TILs, which are labor and cost intensive and do not definitely improve outcomes over IL-2 alone.

The next presentation was to my mind the highlight of the session, a Phase I study of Ipilimumab and Bevacizumab, (Ipi and Bev to the jargon challenged or Yervoy and Avastin for the trade-name aficionados). This combination was suggested by some microscopic findings in pts treated with Ipi where there was evidence of vascular inflammation, a hallmark of Bev therapy. Of 22 pts treated, a typical number for a Phase I study, 1 had a CR, 6 a PR, and 7 SD, for a “clinical benefit” rate of 14/22, 63.6%. This is quite impressive. In addition there were some unique microscopic findings on biopsy suggesting that the proposed synergy between the agents is real. An obvious candidate for further studies!

The last three studies were all regarding the emerging clinical importance of specific BRAF genetic mutations in melanoma patients and the growing number of targeted drugs that attack that mutated pathway.

The first of this group was a study looking at BRAF mutation incidence as a function of age and body mass index, ie relative obesity. Interestingly, the frequency of BRAF mutations decreases with age, so that older patients almost never have the mutation. The type of mutation also changes in frequency, where v600k becomes more common than v600e. This mutation change may affect response to therapy, and possibly also eligibility for treatment. Thinner patients are more likely to have the mutation. Ultimately this is all kind of academic, because the tissue will have to be tested first, regardless of age, height, weight, etc.

The second paper was a Phase I study of a new drug from Novartis called RAF265. It is also a BRAF inhibitor but probably is much less selective than Vemurafenib or GSK 436′ the first two major drugs in that class. They had problems identifying a dose due to toxicity. Although there were responses, even in non-mutated or wild-type BRAF patients, the toxicity was significant and included retinopathy and other retinal problems. Also, responses were not necessarily dose dependent, and the predicted dose from pre-clinical models could not be safely achieved. Will this drug continue in development? So-so.

The last presentation was of the BRIM2 study, the Phase II study of the BRAF inhibitor Vemurafenib. This confirmed the Phase I results that were published last year. The interesting findings in this study were that patients with high LDH were less likely to respond, which was not noted previously. The other results were all consistent with the earlier data, and will ultimately be superseded by the Phase III BRIM-3 study to be presented at the Plenary Session June 5.

On a side note, I have decided to give Vemurafenib a nickname, because it is too long a word to type (or say) often, and its relentlessly positive study results ensure that it will remain a popular topic for the foreseeable future. After much consideration, I am going to call it,

V-Fib

More to follow, on the ASCO plenary session and poster sessions.

Eric D. Whitman, MD
Senior Editor, TheMelanomaCenter.com


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