Dr Weber, you’ve been presenting here on nivolumab. Now this is something called an anti-PD1, tell me what it’s doing and what category of patients you were looking at.
This was a trial in patients with metastatic melanoma who had failed or progressed after prior ipilimumab therapy or if they had what we call the BRAF V600 mutation, which is about 40-45% of the patients. They had to have failed both a BRAF inhibitor, alone or in combination, and the ipilimumab, which is an immune treatment.
Now what’s the relevance of PD1 because you’re affecting that?
PD1 is what we call a checkpoint protein. It turns out that the immune system has many brakes and it has many accelerators. There are at least eight of these brakes or checkpoints that exist to dampen the immune response which, as you can imagine, would be important. In any immune response you want to have a yin and a yang, you want to be able to limit it but you also want to promote it. It turns out in chronic stimulation of the immune system like cancer, viral infections, HIV, the immune cells contain a very high quantity of this checkpoint protein called PD1. When they do and they interact with their ligand, which is the substance that binds this PD1 receptor on the immune cell, it shuts off the immune response, it acts as a brake. It turns out that it’s probably one of the most potent brakes that exists in the cancer bearing state.
Nivolumab can reverse that and take off the brake.
That’s exactly correct. So nivolumab blocks the interaction between the PDL1 and the PD1 and it releases the immune system or rejuvenates it, so to speak.
So can you tell me what you did with the study?
In this study it was the first randomised study that has been presented in which patients who had, as I stated, already progressed after receiving the checkpoint protein inhibitor ipilimumab or if they had the BRAF mutation, both the BRAF inhibitor and ipilimumab, they were randomly allocated to receive the checkpoint protein inhibitory antibody nivolumab or what we call investigator choice chemotherapy.
So that’s a high bar you’ve set because they’re already getting state of the art therapy, therapy which is head and shoulders above what it was just a few years ago?
That is correct. Although you could look at it either way. In the scenario of having failed prior first line or even second line therapy, there’s no approved drug that we know benefits patients. So even a modest response rate would have been significant in that population.
But did you get a modest response rate?
We got more than a modest response rate. The results of this trial showed that when you did an imbalanced randomisation, so two patients got nivolumab for every one that got the chemotherapy, there is a 32% response rate, which is a very impressive response rate, in the nivolumab, the immunotherapy group, versus 11% for the chemotherapy group. 11% is what you would have expected by historical experience; 32% amazingly virtually completely matches what we’ve seen in the early phase studies of nivolumab.
What about the durability of those responses?
The responses looked very durable. As I showed earlier, if you look at what we call the swim plot, which is a plot on a horizontal access of the duration of response of each patient, every patient, there were 38 responders of 120 patients that got nivolumab in this study, in this analysis of response. 36 of them continue in response or continue to maintain their response over time with follow-up that ranges anywhere from 7-12 months already.
Any idea of how this might translate into overall survival?
No-one can predict but the survival data which is the co-primary endpoint to the study, remember initially, early on, it’s response which is the current analysis. Obviously you know your response rate early on in a trial, just 120 patients were planned to complete six months of treatment and then you assess response; that’s easy. You have to wait for a certain number of events to occur before you can tote up whether the survival is better on the experimental arm than the control. We’ll probably have those numbers in a couple of months and then we’ll make the assessment.
You’re taking off the brakes of the immune system, that could be good but it could also be bad. What about adverse events?
Interestingly, the adverse events completely favoured the nivolumab arm. With chemotherapy we often see myelosuppression, neutropenia, nausea, vomiting, fatigue. 31% of the patients on the chemotherapy choice arm had significant grade 3/4 adverse events; only 9% in the nivolumab arm. So, as those of us who work with the drug know, it’s a very well tolerated drug; it’s easy to give and the side effects in all cases that were of the high grade, the grade 3/4 side effects, were all completely reversible. There were no treatment related deaths on either arm in this study, by the way, so patients did very well.
So what are the clinical implications?
The implications of this first randomised phase III study of a checkpoint protein inhibitor against PD1 are that chemotherapy, as a second or third line therapy in melanoma, should go the way of the dodo. I don’t think anymore, even in the EU, the US, that chemotherapy like dacarbazine or carboplatinum and Taxol should be the reference arm of a front line or second line study. It should go away and, as I mentioned, I almost never use chemotherapy any more.
In the overall context, where does this leave therapy for, first of all metastatic melanoma and perhaps other stages of the disease?
It gives you now multiple new options. We have pembrolizumab that was approved on the basis in the US of just a phase I/II study. Hopefully nivolumab will eventually gain registration with the FDA on the basis of this randomised phase III study. It just gives you more tools in the tool box to treat patients with metastatic disease and, given the toxicity profile I mentioned, it’s the perfect adjuvant treatment and there will be three adjuvant studies of PD1 antibodies coming up in the next 6-12 months.
Give me some ballpark idea of just how much the prospects for treating melanoma have improved recently with this.
As with, for example, colorectal cancer, ten years ago your survival was 12 months then you added two drugs together, it was 16 months, now it’s 20-30 months. I think we’re going to be in the realm of colorectal cancer very quickly with median survivals in the range of 20-30 months very soon. When you look at the upcoming trials which combine ipilimumab and nivolumab together, I think you’re looking at some very impressive median survivals. So things are a lot better for melanoma patients today; when I see a newly diagnosed patient with melanoma I say, “Well, I have good news and I have bad news. The bad news is you have metastatic disease, the good news is we now have many more options to prolong your life.”
So if you were to summarise in just a few seconds what doctors should remember coming out of your talk here today, what would that be?
That is that PD1 blockade is here to stay; nivolumab seems to be a very effective agent in metastatic melanoma and, to quote that famous philosopher Frank Sinatra, the best is yet to come.