Nivolumab produces long-lasting responses in patients with stage IV melanoma
Dr Mario Sznol - Yale Cancer Center, New Haven, USA
What led up to this data?
Nivolumab is a checkpoint inhibitor. Lymphocytes are very important in eliminating tumours and when lymphocytes are activated they express this receptor called PD1. We’ve learned that this receptor when it binds to its ligands actually turns off the T-cell. So if you can block the receptor you can reinvigorate the T-cells, especially within the tumour microenvironment. So we allow the T-cells that are already there to work better and perhaps eliminate the tumour. The data has been around, actually there were some papers that were published several years ago that showed the promise of this therapy. There was an initial phase I trial that was done and published in June of 2010; this study started before then but this was the first multi-dose trial.
How did you investigate this?
The drug was given every two weeks for up to two years. It was a phase I trial so it was a dose escalation from 1-10mg/kg and then after the highest dose was tested there was no maximum tolerated dose found. Another two dose levels were investigated, 0.1 and 0.3mg/kg and the cohorts were expanded at each of those dose levels. So across all dose levels there were 107 melanoma patients that were treated on this trial, a very large sample size.
What activity have you seen with this agent?
Remarkable activity. So out of the 107, 33 responded, had objective responses. That’s a 31% objective response rate which is a very high rate for an agent in previously treated patients. And there were another about 11% of patients that had evidence of activity with either prolonged stable disease or unconventional responses, so quite a lot of activity for this agent. In addition to that the overall survival, median survival of 16.8 months is really quite high compared to historical controls for this population of patients. So my guess is that when this goes to phase III trial, and it is in phase III trials, it will show a meaningful effect on overall survival.
I think the other remarkable thing is that the patients who responded had very long duration of responses. Some of those patients, for example one of mine is out almost 4½ years without relapse.
Did the responses persist after discontinuation of therapy?
In seventeen patients who went off drug for reasons other than progression, twelve of them had responses lasting for more than four months and eight of those, actually, are still responding off of the drug now for some time. So this is not a therapy that in some patients needs to be continued, you can stop the therapy and perhaps the responses will persist for many years.
How is tolerability?
This is one of the best tolerated drugs I’ve given in the clinic. Most patients really can’t tell they’re getting anything. You’ll see a little bit of a rash and other things in some patients, maybe a little bit of fatigue but it’s really well tolerated. About 5% of patients will have one of these tissue related inflammatory events. It can have a dangerous side effect, it can cause pneumonitis, a lung inflammation, and actually there were three deaths in the overall study population because of that. But now that we know how to manage it better and we know to look for it, actually there have been no additional pneumonitis related deaths on the trial and I think we know how to manage this toxicity fairly well.
What is your opinion of ipilimumab’s results?
Again, that’s just another exciting combination for melanoma. It clearly prolongs survival. We don’t know what the best combinations will be. I would point you to an abstract that has been presented by Dr Wolchok combining nivolumab and ipilimumab which really also demonstrated remarkable results. Now that’s not a randomised trial, that’s an early trial, so I think what we’ll see is that combinations of immunotherapy agents are going to give us better activity than the single agents and who knows what the upper limit of activity will be? It’s really very exciting.
In what direction are therapies heading?
I have my biases and I think the immunotherapies are going to end up being better therapies. That’s not to say that targeted therapies don’t have a role, they clearly do. Not everybody will respond to immune therapies but I think the immune therapies have the advantages of giving these very long durable remissions. I think you can cure patients with immune therapies. So if it was my choice in the clinic, and obviously you have to select your patients correctly, I would offer an immunotherapy first before a targeted agent.
What advice do you have for doctors?
Nivolumab is not yet approved. The Leukine is approved but I would really strongly urge them to put patients on clinical trials, number one, because we need more clinical trials to find out the best way to use these agents. But I think you should look into a future where we can treat patients with combinations of immunotherapies and I think we’ll be curing a fair number of those patients.
Cure is a strong word though?
It is and we haven’t proven that yet but that’s what I feel will happen with these agents. If you look at interleukin-2 which is one of the oldest immunotherapy agents, 5% of patients have durable complete remissions that in some cases have lasted beyond ten years. If you look at the ipilimumab single agent data there are patients who are out eight or nine years without any relapse of their disease. Now I can’t say they’re cured but I’m beginning to feel pretty confident those patients aren’t going to have a recurrence of their cancer.