Ipilimumab and BRAF inhibitors for advanced melanoma
Dr Lynn Schuchter - University of Pennsylvania, USA
These are important advances in the management of patients with stage 4 melanoma. The ipilimumab combination with GM-CSF builds upon information about single agent ipilimumab and it’s a natural idea to combine immunotherapy. In that study patients receiving pretty high doses of ipilimumab, so not the standard dose, received GM-CSF compared to ipilimumab alone. Then in the small study, it’s a randomised phase II study, but in the small study with preliminary data the combination looked like it may be more successful as measured by overall survival. There wasn’t a difference in response rate or progression free survival but there was a significant improvement in overall survival. Also interesting was that there were fewer immune adverse events in patients that received the combination and there are interesting ideas about why the addition of a cytokine, GM-CSF, to ipilimumab might reduce the side effects. So one of the big concerns with ipilimumab are these serious immune adverse events and if we could figure out a medication that could help prevent some of those side effects, that would be a step forward.
What are your thoughts on dosing?
We don’t know if higher doses of ipilimumab are going to be better than lower doses; certainly there are on-going studies exploring this question of 3mg/kg versus 10mg/kg. This study also looks at the question of maintenance, so maintenance ipilimumab was also a part of this study. So difference in the current standard of care and FDA approval of ipilimumab is that we just use 3mg/kg, we give a total of four doses and there’s no maintenance. So this study raises a couple of questions about is this addition of GM-CSF only relevant in high doses of ipilimumab? Is this a way to augment the response rate and is this a way to improve safety? So I think a really important study but it definitely requires additional follow-up and additional studies to sort out whether this is going to be something that we take into practice going forward.
Is Dr Hodi overselling the medicine here?
No, the whole advances, when we think about three years ago we had really no options with our patients, so to see these advances in immunotherapy at the same time that we’re seeing advances in targeted therapy, I think the golden era is certainly a good description of where we are with patients from advanced melanoma.
What do you make of Dr Sznol’s data?
The PD1 antibody is really exciting and there are two different PD1 antibody studies that are being presented here. So nivolumab is one of them, that’s the BMS. And this study confirmed the high response rate of about 31% and that is very few side effects associated with this treatment. So this is an update on data that have been previously reported but it really shows that PD1 is going to be an important new approach. Tomorrow we’re going to hear about a PD1 antibody from Merck which also looks incredibly exciting; so two different approaches with PD1, both showing really substantial response rates and interesting, really durable responses. So at two years with the nivolumab study, at two years almost half the patients were still enjoying a response. So in this example of the PD1, very active, prolonged duration of response and I think it’s going to have a much better safety profile than ipilimumab.
Do you think this is something that can translate to other diseases?
Yes, there’s no reason that both ipilimumab and PD1 won’t be useful approaches in other solid tumours and so it’s being explored, of course, in lung cancer and other tumours. What we want to understand is biomarkers – are there certain characteristics about the host, the patient, or certain characteristics about the tumour, in particular whether the tumour expresses PDL1, that seems to be an important biomarker for this treatment. But it should be useful in other tumour settings. Melanoma has always been thought of as the tumour that would be responsive to immunotherapies and this approach has been really for more than a hundred years thinking about immunotherapy approaches. Now we’re really seeing treatments that have a significant activity. What’s really remarkable is that we’re not thinking about chemotherapy in first or second line treatment anymore; we’re thinking about immunotherapy and targeted approaches. So to say that chemotherapy doesn’t have a role as first or second line is pretty remarkable.
Going forward, do you think we will step into a more targeted direction or will it be about the immunotherapies?
That’s precisely right. How do we decide if we’re going to start with targeted therapy or immunotherapy depends upon the disease burden, how many symptoms a patient is experiencing from their melanoma. So it’s really key that all patients with melanoma have their tumour determined to see if they have a mutated BRAF and that probably needs to be done earlier and earlier in the course of the disease because we need to know for the planning purposes if this patient has a mutated BRAF. If they don’t then we’re going to go more immediately towards immunotherapy approaches, either approved agents or clinical trials. If they do have a mutated BRAF then we’ll need to decide – do we start with immunotherapy or do we start with targeted therapy? Again the clinical circumstances will really determine what the right sequence is. And of course combining these approaches is an important approach as well.
What should doctors in practice make of this?
They need to say that patients have to have their tumour tested and there are laboratories available and FDA approved tests in order to determine it. So physicians do need to work with their patients in terms of getting these mutation profiles performed. This is sometimes challenging in melanoma, the primary tumour might have been many, many years ago, sometimes even a decade earlier, the amount of tumour may be quite small. We try to avoid doing invasive surgical procedures to harvest tumours to determine the mutation status so it’s cumbersome, often, to sort out if a patient’s tumour has the BRAF mutation. Other tumours like lung cancer, colon cancer, breast cancer, the tumours themselves are much larger and there’s much more DNA available to determine this analysis. Remember, this could be tiny millimetre lesions on the skin, that could be the only tumour that’s in the laboratory to do this testing. So one is the physicians need to know that BRAF is an important target and has to be determined; they need to know that ipilimumab is available to patients but it has unique side effects. So it’s different than chemotherapy, different than targeted therapy. So physicians need to be aware of these immune adverse events and how to manage this toxicity. Then partnering with patients and centres to enrol patients on clinical trials. That really is how we get access to some of these most innovative treatments. So it’s in the past easy to say ‘Order chemotherapy,’ that’s not the way to go for these patients, it requires much more time and planning out these therapies but patients are now living years with stage 1 melanoma so it’s a totally different landscape for these patients.
Is it possible to see a combination of ipilimumab and PD1?
Absolutely and it will be presented at this year’s ASCO. Dr Wolchok will be presenting those data on combining ipilimumab with PD1 and in that study it’s almost a 70% response rate, also durable. Certainly more toxicities, I have to say that investigators and physicians were concerned about combining PD1 and ipilimumab, that’s a very powerful way of shutting down the immune system. These are very preliminary data, a relatively small number of patients treated but really exciting results. So a higher response rate than what we’ve talked about; cautionary about the side effects but certainly manageable, manageable side effects.
How close are we to a cure?
We don’t say that but we do begin to think it and hope it. So when patients are out three years, they haven’t had recurrence of their melanoma, we do begin to entertain could this really be gone. I think with the immunotherapy approaches it’s a reality, with targeted therapies it seems still quite clear that patients develop resistance and then do recur. So we’re much more cautionary about thinking about cure with the targeted therapies but the idea is that we take these into earlier and earlier stages of disease. So I think cure is certainly on the horizon for our patients.