ASCO 2011 Annual Meeting, 3—7 June 2011, Chicago

Ipilimumab improves survival in metastatic melanoma

Professor Jedd Wolchok – Memorial Sloan-Kettering Cancer Center, New York, USA

Last year’s study demonstrated that ipilimumab was the first drug to improve overall survival in patients with metastatic melanoma. That study looked at patients with previously treated metastatic disease and had refractory patients in it. This study was a first line study where patients had no prior therapy for advanced melanoma. It had a bit more of a classical design with dacarbazine, the standard chemotherapy, being given to both groups of patients and then one group received ipilimumab with dacarbazine at a higher dose than was used last year, now we’re using 10mg/kg with the dacarbazine, the other group receiving a blinded placebo.

So a 500 patient trial, about 250 patients in each group, with overall survival being the primary endpoint and overall survival was significantly improved with the use of ipilimumab. A 28% reduction in the risk of death with a highly statistically significant p-value; progression free survival also enhanced with ipilimumab plus dacarbazine compared with dacarbazine. The toxicity profile was interesting; ipilimumab has this set of side effects which are termed immune related adverse events.

Because you’re suppressing the T-cells?

Exactly, so you’re really turning on the T-cells and they can now see and respond to normal body tissues if necessary. So tissue-specific inflammations, specifically in the skin and the gastrointestinal tract, were the most common side effects and they still were in this trial as well. What was interesting was that the severity of these side effects, especially the gastrointestinal events – diarrhoea and colitis – which were a severe problem in the prior study for some patients with some GI perforation even, was not nearly as severe in this study. Perhaps the dacarbazine affected the severity of the side effects.

It might have killed a few lymphocytes.

It might have. Yet there was an enhanced rate of hepatic toxicity, elevations of AST and ALT were more common than predicted in this study so perhaps dacarbazine did have some effect on the skewing of the toxicity profile but patients still did have some of the classical, now, immunotherapy related toxicities.

But then this group of patients hadn’t seen prior chemotherapy, so the pharmacodynamics, pharmacokinetics might have been different. Might they have had more liver disease?

They might have had more liver disease, that’s correct. But the vast majority of the patients responded in terms of the liver function test elevation to the usual management with corticosteroids for ipilimumab, so some of it was due to the drug.

Standard of care now?

I think in the US right now, ipilimumab as monotherapy at 3mg/kg is a standard of care for metastatic melanoma, now proven in the first line setting. The US FDA did give its approval in both settings, actually, without the data from this trial being publically available but this really validates that decision, that it doesn’t really matter that we see efficacy of ipilimumab regardless of prior therapy.

And do you need the dacarbazine?

I would say we don’t have any evidence that you need the dacarbazine. The results of this study show that ipilimumab enhanced survival in the presence of, despite dacarbazine or even dacarbazine could have added to it, we simply don’t know. Because of the possibility that you alluded to, that dacarbazine might have blunted the activity in some way, and because we know that ipilimumab monotherapy is active, outside of a clinical trial I would stick with ipilimumab monotherapy.

And temozolomide? It’s used an awful lot off label in the United States, not used for melanoma elsewhere but clearly active. Some people say it’s just dacarbazine easier to give. Any thoughts about where that might fit in with ipilimumab or sequentially with ipilimumab down the line?

A very, very intriguing question. I have some observations from the phase II ipilimumab programme that patients who were heavily pre-treated with temozolomide and had very low lymphocyte counts as a result, you would actually have expected that perhaps they wouldn’t respond well to ipilimumab but, in fact, those are some of the most dramatic responses that I personally saw. Not only were their tumours well controlled but they had a very vigorous immune reconstitution with restoration of normal lymphocyte counts. So perhaps the lymphopenia induced by temozolomide sets the patient up for a robust homeostatic proliferation when ipilimumab is added. I think sequential therapy with temozolomide and ipilimumab is a very valid question to explore. I know that the MD Anderson actually has a trial of concurrent therapy but perhaps sequential could be even more interesting.

And then of course we’ve got BRAF at this meeting and so we’re overflowing with riches in malignant melanoma management, having had a desert behind us for the last thirty or forty years, quite extraordinary.

Precisely. We’re really in a place that nobody imagined, even a few years ago, to have now two therapies for melanoma that both prolong overall survival, one of them US FDA approved and the other one hopefully soon. This combination of BRAF inhibitor with ipilimumab is really the natural next step for BRAF mutated patients but again the question of scheduling is one that has to be addressed prospectively because who is to know whether inhibiting BRAF in lymphocytes or antigen presenting cells could negatively impact on the activity of ipilimumab. Pre-clinical models done by our group and others would suggest that perhaps it’s not a lot to worry about but we certainly don’t know for sure yet. I think your comments about the role of dacarbazine are very well taken, that dacarbazine with ipilimumab, or with an anti-CTLA4 antibody in mice, was a very potent combination. In humans perhaps the use of chemotherapy with an immunotherapy concurrently just does not have the same kinetics as in a mouse.