ASCO 2011, Melanoma|August 6, 2011 7:03 pm

ASCO 2011 Plenary Part 1: Ipilimumab

For the second year in a row, melanoma was a featured part of the ASCO plenary session, filling the last two presentation slots. Last year, it seemed like a novelty, because nobody was sure a melanoma paper had ever made it to Plenary before. This year it seemed almost natural and expected. I heard one of the other melanoma specialists comment afterwards that the melanoma research community would now be the victim of unnatural expectations: next year, must we make enough progress to warrant 3 or even 4 slots at plenary? One can only hope.

Obviously, there has been widespread, “headline”‘ level coverage of the advances in melanoma treatment. In the airport going home, the CNN Headline News story played over a background of people getting sunscreen placed on the beach. I guess it was the only stock footage that might somehow be tied to melanoma.

There are several concise articles that covered the two presented papers, on Ipilimumab (Ipi) and Vemurafenib (VFib for lack of a better nickname). The Wall Street Journal’s lead story the next day was more generic, about the use of genetic testing to treat cancer ‘personally.’ I will summarize the findings too, but my emphasis will be on the lesser appreciated parts of the studies and most of all, how these advances will affect how melanoma is treated, now and looking forward.

First, to summarize the Ipi study. Last year, the presented paper looked at second line therapy, in people with metastatic melanoma who already failed therapy with standard chemotherapy. The current study looked at so-called frontline therapy, given before any other treatment for metastatic melanoma. It randomized patients to receive either the historical standard chemotherapy, DTIC or Dacarbazine, vs. Ipi plus DTIC. After a four dose induction period, patients in both arms were scheduled to receive maintenance therapy with DTIC.

The initial study plan used progression free survival as the primary endpoint. However, results from earlier studies indicated that patients could progress by standard criteria but still ultimately benefit from treatment. Therefore the study design was changed in midstream to use OS (overall survival) as the primary endpoint.

The headline and most important result is that median overall survival (OS) was improved from 9.1 to 11.2 months by the addition of Ipi to DTIC. The Hazard Ratio was 0.72, which can be translated to say that there was a 28% reduction in the risk of death associated with the experimental Ipi treatment (derived by subtracting 0.72 from 1.00 and multiplying by 100). The p-value was < 0.001, meaning that the calculated risk that the result was from random events only was less than 1/10th of 1%, where anything less than 5% is considered statistically significant by convention. This survival advantage was consistent across all patient and prognostic groups. Progression free survival was also improved in the Ipi arm ( HR=0.76, p=0.006). Although the response rate was better in the Ipi/DTIC group this difference did not reach statistical significance, consistent with prior Ipi results.
Most patients in both arms stopped treatment because of disease progression, more so in the DTIC arm (77%). In the Ipi/DTIC arm almost as many patients stopped therapy for toxicity (46% for progression, 36% for toxicity). Few patients stopped DTIC for toxicity, as expected, only 4%.

The toxicity of the treatment was interesting because the side effects recorded were different than those seen in prior Ipi studies, most likely because of unanticipated interactions between the two drugs, Ipi and DTIC. The incidence of diarrhea and colitis was lower than has been typically seen with Ipi treatment. Although the numbers are always fairly low, it also seemed to me that the number of cases of endocrinopathy, involving the thyroid gland or brain among other sites, was also less than expected. Conversely, a significant number of patients had non-infectious hepatitis or inflammation of the liver evidenced by abnormal liver blood tests. This was important because it was the most important cause of dose reduction or treatment cessation, meaning it could have limited the number of Ipi doses.

So the combination may have blocked some of the GI and other typical Ipi side effects from occurring. It also caused liver toxicity not really seen before, which may have reduced patients’ ability to receive Ipi (which could also have minimized the GI and endocrine toxicity on a simple dose-related basis).

Another interesting point is that only about 20% of the patients received any maintenance therapy (96 of 502). Is the benefit from Ipi derived from induction therapy only? Would maintenance Ipi therapy, even in the face of documented disease progression, extend OS even more? Unfortunately these questions cannot be answered in the current study but may become evident in future study results.

I have a couple thoughts about these results. First, I was interested to see how the combo arm did, because if there was spectacular improvement, then perhaps Ipi plus DTIC rather than Ipi alone would become standard therapy. However, the fairly modest 2 month improvement in median overall survival coupled with the overall detrimental side effect profile leads me to agree with Dr. Margolin’s summary commentary that the combination should not be used,

Second, I found the improvement in median overall survival, while statistically significant and real, to be a little disappointing. The second line trial showed a median overall survival of about 10 months, and the frontline trial now has been printed at 11.2 months. Only a five week difference? I realize that this is only a median and hence an average expectation. However, this very slight difference between front and second line therapy could have significant implications for treatment choice for melanoma patients. The benefit of Ipi is the “tail” of the curve, extending out in time. The data suggest to me that this benefit can still be achieved in the second line setting, with perhaps only minimal loss of potential efficacy. I will expand on this in another article specifically looking at treatment choices for metastatic melanoma going forward.

In summary, Ipi has now extended survival in both the front line and second line settings in metastatic melanoma. The FDA approved Ipi for treatment of Stage IV melanoma in March 2011. With the nearly concurrent approval of Vemuranib, patients with melanoma now have two new options for therapy, both of which improve survival. Exciting times indeed!

In a future article, I will put the two approvals into context and discuss the evolving treatment paradigm for metastatic melanoma.

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