ASCO 2013

Nivolumab blocking PD1 in lung cancer and melanoma

Dr Suzanne Topalian - Johns Hopkins Medical Center, Baltimore, USA

Suzanne, thanks for coming to see us at ecancer.tv because this whole question of anti-PD drugs and looking at some of the quite sophisticated processes going on inside cancer cells and how they affect the environment, you’ve been using nivolumab, what were you doing with it and in which setting and why?

What we were reporting on, here at ASCO, is the results of a phase I trial of nivolumab with expansion cohorts. So it’s actually a fairly large trial of about 300 patients with five different kinds of cancer including melanoma, lung cancer, kidney cancer, colorectal and prostate cancer. And the idea of the trial was to block a molecule that we call an immune checkpoint, in this case program death 1, PD1, in order to reactivate immune responses against cancer.

In fact the tumour is holding the body’s immune systems in check.

Exactly right.

And you’re removing that hold.

So it’s along the same lines as what has been discussed before for anti-CTLA4 or ipilimumab which was approved two years ago in the United States for treatment of patients with advanced melanoma. This study goes beyond that to examine patients with other kinds of cancers and what we found were substantial response rates in lung cancer and kidney as well as melanoma.

I’d like to ask you about that but could you tell me about the study, what you did and what sort of patients you had?

These were all patients who had had at least one prior treatment for their cancer but about half of all the patients on the trial had had three or more prior systemic treatments for their cancer. So they were a heavily pre-treated patient population who came on to the study which was designed to test the safety and tolerability of nivolumab. And so early on in the trial, as per standard phase I trials, they were recruited in small groups of patients at increasing dose levels. We did not find a maximum tolerated dose or dose-limiting toxicity. And then at that point additional patients were enrolled to learn more about the safety profile but also to learn something about the efficacy of the drug.

Now at this stage is this all-comers or are there any particular types of patient or characteristics that you can look for that would be more susceptible to inhibition of PD1?

In order to be eligible for this trial you had to have one of the five different kinds of cancers that I mentioned but they were not selected…

So, they weren’t selected for any other marker?

Yes, they were not selected for any other kind of marker. So the purpose of the trial was to learn about the profile of the drug in terms of activity and safety and to explore potential molecular markers that might allow us to select patients most likely to respond.

Now you described the results as quite interesting, quite good, what actually are the data?

Well what we’re reporting on here are not only the objective response rates, meaning a traditional RECIST criteria complete or partial regressions but also the durability of those responses, the fact that those responses can persist even after the drug is discontinued and the patient is simply observed and the fact that those responses are associated with what appears to be favourable overall survivals. Now this was not a randomised study and so really in order to say anything about an overall survival benefit we will need information that’s going to come out of the randomised trials that have already been started. I think we can still learn a lot from this large study that we’re discussing here at ASCO.

One of the thoughts that’s floating to the top in use of checkpoint inhibition is that you could use it as part of a strategy and you can actually add other therapies to it to complete the process. How are you feeling about all of this at the moment?

As a field we think this is the next frontier. On the one hand we’re very encouraged about the fact that we can see the regression of advanced solid tumours with monotherapy with nivolumab and we’re also extremely encouraged that we’re not just seeing this with nivolumab but also the other drugs that are being discussed at the conference from a variety of different companies that either target PD1 or target its major ligand, PDL1. So a very consistent theme is developing that this pathway, the PD1 pathway, is important for cancer. So how do we then go to the next level? We’re helping a certain percentage of patients, we need to help more. Everything that we know from laboratory studies says that combination therapies are going to be the way to go.

Can you incorporate this knowledge into an algorithm that the everyday doctor can use and simply plug in and individualise therapy?

I think that really this needs to be studied in a systematic way based on solid evidence from the laboratory rather than picking and choosing drugs of convenience and so forth.

Are you at the stage where you’ve got enough knowledge to think about having an individualised treatment based on the molecular features you find in the particular pan-cancer effects like checkpoint?

I don’t think we’re there yet so I think we’re on the way, we have some interesting leads but it requires a lot more study and this is what we are doing now in the next generation of clinical trials.

And how would you summarise what doctors should be making of nivolumab and these results you’re quoting here at ASCO?

I think that these are still early results but that there is reason for a lot of optimism that this kind of approach, modulating immune responses against cancer in an outpatient regimen that seems to be fairly well tolerated, this kind of approach is here to stay and the next level now is going to be to increase the efficacy by adding other drugs to the regimen.

Suzanne, thanks for joining us on ecancer.tv.

My pleasure.