ASCO 2010|May 15, 2011 9:28 pm

Melanoma Oral Abstracts 2010

For a variety of reasons, I only made it to the Melanoma oral abstract session today. The immunotherapy session in the morning was an update with little new info (for somebody who goes to all these meetings), and the oncogene session conflicted with a research meeting I had to attend. I was going to do a Top Ten poster list before tomorrow am but the internet access in the hotel is pretty marginal so that won’t happen unfortunately.

Today’s Melanoma oral abstract session was very well attended and was in a huge room. As you can see from the Twitter stream in the right hand column, I and my co-tweeters (or is it fellow Twits?) Dr. Omid Hamid from John Wayne Cancer Institute and Dr. Richard Carvajal from Memorial Sloan Kettering Cancer Center posted many live comments during the session.

Below, I have appended some of my comments and impressions from the presentations in italics.

E4697: Phase III cooperative group study of yeast-derived granulocyte macrophage colony-stimulating factor (GM-CSF) versus placebo as adjuvant treatment of patients with completely resected stage III-IV melanoma.

The updated data for this trial was all negative. There were no significant results except for a very small subgroup of patients with Stage IV melanoma. Everybody was pretty negative. I wrote a note in the margin, “the end of GM-CSF”. Post-session, I spoke to Lynn Spitler MD who basically invented the GMCSF regimen for melanoma. She raised important concerns about the statistical design of the trial and how it would be wrong to reach globally negative conclusions. Unfortunately at this point overwhelming sentiment is against her feelings. We shall see.

Randomized phase III trial comparing postoperative adjuvant ganglioside GM2-KLH/QS-21 vaccination versus observation in stage II (T3-T4N0M0) melanoma: Final results of study EORTC 18961

Another negative trial. There is the suggestion that the vaccine is not only no better than observation but could actually be worse. There is some question as to the statistical validity of any firm conclusions that it is worse but clearly if it’s not worse (ie the vaccine is more likely to cause recurrence and death than doing nothing) it’s pointing in that direction consistently. Two for two on negative studies, less than two hours after the multitude of positive news on the ipi trial, including its online publication.

Interleukin-21 (IL-21) activity in patients (pts) with metastatic melanoma (MM).

This is a Phase II study of a new agent, IL-21, that is proposed to work by enhancing the immune system’s ability to recall and attack tumor cells.No additional comments or info from presentation other than their next step was reported as a randomized Phase II trial comparing IL-21 to DTIC.

First report of a randomized phase II trial of multi-epitope vaccination with melanoma peptides for cytotoxic T cells and helper T cells in patients with metastatic melanoma: An Eastern Cooperative Oncology Group Study (E1602).

Craig Slingluff is a very bright guy who I first met when we were presenting back to back at a scientific meeting when the world was young, in 1993 or so. He has doggedly pursued multiple vaccination strategies for melanoma. Unfortunately, this trial does not show clinical benefit for any of the strategies. Knowing Craig, he will revise his strategies again and I hope he hits on a more successful one.

Re-induction with ipilimumab, gp100 peptide vaccine, or a combination of both from a phase III, randomized, double-blind, multicenter study of previously treated patients with unresectable stage III or IV melanoma.

This study, boiled down, examines whether patients who initially respond to the very trendy anti-CTLA-4 antibody ipilimumab (jargon by the melanoma people, “Ippy”) but then progress are able to respond again if re-treated with ipilimumab. Generally, if you progress after treatment with a cancer drug, the same drug is unlikely to be effective. However, immunotherapy is possibly different. This study is interesting, albeit with small numbers of patients (32 total), because about 2/3 of patients were still able to respond to ipilimumab on a second “induction” (7/32 CR+PR, 10/32 SD). No new comments. The abstract and the presentation were consistent. This presentation was certainly more intensively listened too in light of the earlier press frenzy about the parent Ph3 randomized trial, to be presented Sunday afternoon at the Plenary session of ASCO.

Final results of E2603: A double-blind, randomized phase III trial comparing carboplatin ©/paclitaxel (P) with or without sorafenib (S) in metastatic melanoma.

This is the final report of a study begun with great excitement due to apparently fantastic Phase II results but ultimately failed to show an improvement. To recap, several Phase I and Phase II studies of taxol, carboplatinum, and sorafenib (now otherwise approved and marketed as Nexavar) showed very impressive results in metastatic melanoma patients, first presented about six years ago. This study compared the combination of all three agents to  taxol/carboplatinum alone. Historically, these two drugs had only rarely been used in melanoma and their efficacy was unknown. Well, now we know: the PFS is about four months, the OS is about 11 months, there is significant toxicity, and the addition of Nexavar didn’t improve or change those results. No new info. This kind of closes the door on Sorafenib in combo with carboplatinum and Taxol, which just 4-5 years ago we were all convinced would now be approved and the standard of care. It leaves open the question of whether taxol/carbo is better than DTIC alone. Also noted was the significant toxicity of the regimen, which was made somewhat better by some dose modifications in the Avastin BEAM trial (which was almost positive last year, presented at the ECMO, the European ASCO). When we now use the taxol/carbo combination, in selected patients, we use the BEAM regimen which is much better tolerated.

A phase III random assignment trial comparing percutaneous hepatic perfusion with melphalan (PHP-mel) to standard of care for patients with hepatic metastases from metastatic ocular or cutaneous melanoma.

Well, this presentation went very well, I thought. The data was even better than the intial press release from April. The hepatic PFS (primary endpoint) was 245 days in the PHP arm and 49 days in the BAC (best alternative care) arm. There was no survival benefit on an intent to treat basis BUT (and this point is currently rattling the cyber sphere) 55% of the 49  BAC patients crossed over to PHP after progressing. Since OS analysis is based on MEDIAN survival of the group, if over 50% of BAC patients end up eventually getting PHP AND benefit similarly from the delayed PHP, then the survival curves should superimpose, as they do. The only way in a crossover trial for the OS curves to NOT superimpose when over 50% crossover would be if the delay in getting PHP resulted in a lesser clinical effect (which clearly was not the case). There was an interesting survival curve they showed comparing the BAC patients divided into whether or not they received PHP at any point. The curves were WIDELY separated, but the analysis was not prespecified and carries no analytic weight statistically. Overall PFS also signficant although less so than hepatic PFS, which is logical. This was 189 days vs 46 days. The response rate data was: 34.1% PR, 52.3% SD. It was noted that NONE of the patients who actually received PHP progressed on initial assessment. There is no question in my mind that this is clinically effective and I was surprised when the discussant, seemingly from left field, pooh-poohed the results and said it was biased, ineffective and not worthy??? The format of the presentations prevented any questioning or commenting of the discussants.

And finally, at the plenary session on Sunday:

A phase III, randomized, double-blind, multicenter study comparing monotherapy with ipilimumab or gp100 peptide vaccine and the combination in patients with previously treated, unresectable stage III or IV melanoma.

The abstract and article are now both available. This treatment shows an OS benefit, from 6.4 months to 10.1 months, which is statistically significant. It was very warmly received by the media and many of the melanoma doctors I spoke to, some of whom of course were on the study. My initial question is whether or not GP-100 vaccine is an appropriate control arm, as many vaccine adjuvants have been shown to adversely affect survival, including the GM2 vaccine presented today. I supporting this thought, I think the OS of 6.4 months in the control arm is lower than I would expect; in today’s melanoma treatment landscape I would expect an OS of about 8 months.

I am going to reserve further comment on the study until I see the full presentation tomorrow afternoon and learn more as well as hear any questions asked. For now, I will let it stand as a very exciting development in melanoma care, since this is the first randomized phase III trial examining ANYTHING to treat Stage IV melanoma that has shown a significant survival benefit.

Eric D. Whitman, MD

Senior Editor


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