I want to set the stage by saying that there is an unmet medical need in myeloma and the unmet medical need is that really we have limited, what I call, blockbuster agents in myeloma, meaning agents as a single agent that have significant activity in the relapsed and refractory setting. What we have is IMiDs, you may know of some of these drugs. The IMiDs are thalidomide, lenalidomide, otherwise known as Revlimid, or pomalidomide, otherwise known as Pomalyst; those are the IMiDs that are blockbuster drugs. And then we have the proteasome inhibitors: bortezomib or Velcade or Kyprolis or carfilzomib. With those two blockbuster classes we have really advanced the overall survival for patients with myeloma. We’ve changed it from potentially a 3 year survival that hopefully now is more like a 7-10 year survival so that’s great.
I’m going to talk to you about a more heavily pre-treated patient population and in these patients the Mayo Clinic, Keith’s colleagues and myself, have published extensively on this. The average survival really is about 9 months in the patient population I’m going to talk about. I’m going to tell you that these CD38 antibodies I think are blockbuster drugs. These are real drugs. We should be in here talking about CD38 because it’s an important component to myeloma therapy.
Now, as Maria said, the way these antibodies work, they bind to the surface of the cell and they hold up a flag. They’re naked antibodies, all they’re doing is holding up this flag. It’s different than what you heard about with brentuximab that takes a toxic payload to the drug, this is just putting a flag on the cell and saying, ‘Immune system, come and get me.’ It’s worked very well with drugs like rituximab in lymphoma and so in myeloma we’re, I think, way behind. We’re ten years behind lymphoma with the use of these antibodies but we finally have some that actually work.
Now, in our study we combined it with lenalidomide and lenalidomide, I told you, has a lot of anti-myeloma affect but one way it has anti-myeloma affect is that it actually stimulates the immune system. So it tells the immune system, ‘Hey, go look for these flags.’ So the reason we put this combination together is we thought that the antibody itself would work better if we combine it with lenalidomide, an immuno-stimulatory drug. Now, I don’t have the data to show you here but we’ve used these anti-CD38 antibodies as a single agent in a similar population and found an overall response rate of about 30-32% and that’s the background for the study.
So this study is a phase I study. The goals of a phase I study are actually to look at toxicities - is the combination safe? This included adults with relapse and refractory myeloma; they had to have at least two prior therapies and prior autologous transplant was fine. There was actually no upper limit on the number of therapies so, in fact, this ended up being a very heavily pre-treated population. Before they start they just had to have adequate bone marrow reserve.
I hope you guys can all see the colour of these slides. In any event, the way we did this study is we did a standard what’s called a 3 3 design. You put three patients on the lowest cohort, the lowest cohort was the SAR drug at 3mg/kg given every other week with standard doses of lenalidomide and dexamethasone. You enrol three, if they do fine then you go up to the next cohort. So we went from 3mg/kg of SAR every other week to 6mg to 10mg every other week and in fact it was very well tolerated. In the combination there were no unexpected toxicities. These antibodies tend to be very well tolerated drugs, there is an incidence of infusion reactions and I think I have a slide about that in a second. Now, once you get to what was our top dose, the 10mg/kg, and it was safe then we enrol what’s called an expansion cohort, more patients, to see if we can get some preliminary evidence about efficacy.
So here’s the patient population. I’ll show you that overall they were a heavily pre-treated population. Now we divide myeloma therapy into regimens, meaning they got this double therapy and this triple therapy and also lines of therapy. The difference between regimens and lines is you may get one regimen as induction and knock the myeloma down and then a transplant to further knock the myeloma down and then maintenance to further knock it down. That’s three regimens but it’s only one line of therapy. Line of therapy means it’s gone down and then they’ve relapsed and then they’ve got another line of therapy to make it go down again. So on average they had four lines of therapy. So in the ASPIRE trial it was 1-3 lines of therapy, so it was a much less heavily pre-treated population.
Now, if we look at the characteristics of the therapies these people received prior, more than 90% received prior lenalidomide, more than 90% received prior bortezomib, about a third of the patients had prior pomalidomide and almost 50% had prior carfilzomib. So many of these patients were what we consider double refractory or refractory to our most potent blockbuster drugs. In fact, in terms of the IMiDs you can see in the red box 84% of the patients were relapsed and refractory to their last IMiD containing regimen.
So I told you that the SAR drug is very well tolerated, the only side effects really seen were infusion reactions. These occur about a third of the time, they’re mostly mild grade1 and 2, meaning the person gets a little rash or gets a little itch or gets stuffy nose. We only had to actually stop the infusion in very few, 3% of the overall infusions throughout the whole study did we have to stop the infusion and then restart the infusion. Then after the second cycle of therapy there are no infusion reactions. So it happens in the first couple of cycles and then it’s really not a toxicity that we see long term.
What about the responses? If we look at the overall response rate in the 31 patients that were treated the overall response rate was 58% with a clinical benefit rate, meaning adding the minor responses, of 65%. If we look at just the patients that had just the 10mg/kg dosing, 24 of the patients, this was basically the highest dose of the antibody, we see basically an overall response rate of 63%, double what we saw as a single agent, and a clinical benefit rate of 67%. We did have two stringent CRs in this patient population.
Now, here’s the waterfall plot. I don’t know if you guys are used to seeing waterfall plots, this is the waterfall plot. Below the line means they’d had a reduction in their M protein. This is a dramatic waterfall plot, you can see that the majority of these patients had some response. Again, 84% of these patients were refractory to IMiD based therapy so if we just gave them lenalidomide these should all be above the line. So this combination was very active. Now, if we look at progression free survival in this small cohort of patients the progression free survival is about 6.2 months.
So I’m going to simply conclude by saying that this combination was well tolerated, there were no unexpected toxicities. In my mind it had a fairly dramatic response with two-thirds of the patients having a response even though they were refractory to our other blockbuster agents. Lastly, I do think these anti-CD38 antibodies are the next blockbuster class of agents. These are the next agents that are really going to show some benefit to myeloma patients and the next five years is going to be really fun moving them from the refractory setting to the less refractory setting to the front line setting. It’s going to be great.