ASCO 2010 Annual Meeting, 4—8 June 2010, Chicago
Interview with Professor John Wagstaff (University of Swansea, Wales)
Advances in melanoma treatment
Welcome, thank you very much for taking some time out of your hectic schedule at ASCO. What have you been visiting; what’s been fun?
Well, one of my interests over the years has been melanoma and yesterday afternoon and in the plenary session today there have been some important developments in the field of melanoma. I’ve been interested in melanoma for thirty years, since I was a Fellow in training and it’s really been a pretty depressing business over the years, there have been lots of false dawns but in this meeting there does seem to be some excitement in terms of making progress and that’s with a drug called Ipilimumab which is a drug which really takes the brake off the immune system and allows the body to mount a really strong immune response against melanoma. Ipilimumab is an antibody which causes this brake to be taken off, and in the plenary session this afternoon there’s been the results of a big randomised trial presented looking at this antibody combined with a vaccine and randomised against a vaccine on its own.
Just to put all this in perspective, I think it’s important to think about what the results of treating melanoma are like before this.
This is metastatic melanoma?
This is metastatic melanoma and the best illustration of that is a study that was done a couple of years ago and published in The Journal of Clinical Oncology from Korn and colleagues where they looked back at thirty years of clinical research in melanoma and looked at the survival of patients in clinical trials. What they showed there was that as first line treatment for melanoma, the progression free survival is about two months; the median survival is six months and you have about 20% of patients alive at a year. And in this Ipilimumab trial the median survival in second line treatment, so this is after patients have failed first line chemotherapy, was a median survival of ten months which is longer than you get with first line treatment. And 45% or 46% of patients were alive at a year.
So you’ve doubled the one year survival?
Absolutely. And when you look at the results at two and three years, you’ve got a plateau of about 20% of patients where patients don’t seem to be relapsing any more. So although eight out of ten people don’t benefit from this treatment, two out of ten seem to get really long term benefit from the treatment. Whether they’re cured or not, of course, is going to take a long time for us to work out but I think that that is a significant advance.
It is, and it’s not an anti-cancer antibody, it’s not directed at tumour cells is it?
No, it’s not directed directly at the cancer itself, it’s directed at the immune system.
So it doesn’t depend on mutations happening in the genome?
No, exactly. There is a downside to it is that because you’re taking the brake off the immune system what you tend to do is activate a lot of auto-immunity so there is significant toxicity with this and two-thirds of patients in the trial who received this drug got auto-immune side effects and in a third of them they were actually very severe – grade 3 and 4. And they’re not side effects that a run of the mill oncologist would be very happy with dealing with – people who get very severe colitis, which is very like ulcerative colitis, that requires high dose steroids; they get inflammation of the pituitary gland; hepatitis, so it isn’t a treatment to be taken lightly I think. And once it goes outside of clinical trials, if it gets a license, it’s going to be very difficult for a regular oncologist to be able to manage this drug on their own.
And the non-oncologists will be really in trouble or the patients will be in trouble.
I think that’s absolutely… yes, absolutely.
That’s still a dramatic effect, because I’ve been at oncology longer than you and I can assure you I hadn’t seen anything either that has got close to this.
Yes, the only drug which does produce long term survival in metastatic melanoma is high dose Interleukin-2 but that’s maybe a long term survivorship of about 10 or 15% and that’s the only drug that’s had an impact. And again, because of toxicity issues, that treatment really hasn’t been taken up widely around the world.
You needed to be a bit of an Olympic athlete to be able to qualify for a high dose IL-2. So what’s next then John in that whole series of studies going into first line?
There are first line data available for it now which look very similar to the second line data. The other issue was a paper presented yesterday in the oral session of melanoma where it looks like if you do respond to this treatment and then progress, that if you re-challenge the patient with the drug again that a large proportion of them will respond again. So you can salvage patients who have benefitted with re-challenging the drug. So that’s quite an interesting observation.
And it vindicates your thirty years of immunological research at the bench which you have been at.
Absolutely. I think the negative side of this study is that adding the vaccine into it certainly wasn’t better than just…
That was a ganglioside?
That’s a ganglioside vaccine but that certainly wasn’t better than giving the Ipilimumab on its own and in fact, in terms of disease free survival, it looked as if it was a little bit worse. And that’s completely different than what was found in the animal models where combining the vaccine with an anti-CT04 antibody actually cured mice of melanoma.
That’s mice and we’re treating men and women.
That’s been the case over the last fifty years, I guess.
Anything else that’s caught your eye?
Well, going back to the ASCO from last year, the other interesting area is the BRAF inhibitors which attack a proportion of patients who do have mutations in this oncogene. And the data from the phase I trial that was presented at ASCO last year looked very encouraging with response rates up at around 70%.
If you have the mutation, the BRAF.
If you have the mutation.
If you haven’t, you get zero.
Well yes, but now you’ve got two options if you’ve got the mutation then you can have the BRAF inhibitor; if you haven’t then Ipilimumab is an option for you.
And then a combination of the two, of course, down the line.
Well that was also interesting indeed. But of course those clinical trials are only just beginning really.
John, thank you very much indeed for giving us your time.