2011 ASH Annual Meeting, December 10-13, San Diego, USA
Clinical trial data on treatment of chronic lymphocytic leukaemia with PCI32765
Dr Susan O’Brien – MD Anderson Cancer Center, Houston, USA
It’s a very interesting drug, PCI32765 and the concept behind this drug, and there are some other different drugs in clinical trials with the same concept, is that if you ligate the B cell receptor, that provides a very strong survival and proliferative signal to the cell, both in normal B cell as well as the malignant B cell like CLL so that there are a number of downstream enzymes that conduct that message to the nucleus. If you could interfere or inhibit one of them then that might be a very beneficial thing because then you stop that signal from going to the nucleus. So there are a number of different enzymes in that pathway that could be targeted. This one targets Bruton’s tyrosine kinase or Btk and the clinical relevance of that is that people born with mutations in that gene actually have a syndrome called X-linked agammaglobulnemia, so clearly a relevant target. PCI32765 is an oral agent, it’s an irreversible binder of Btk and the study I’m presenting is in relapsed refractory patients with CLL using one of two dose levels, either 420mg orally once a day or later on in the trial, after an amendment to look at a higher dose, 840mg. Follow-up is slightly different for the 420mg, it’s about a year now, for the 840 it’s about nine months. What’s very interesting with all of these drugs that interfere with B cell receptor signalling is you see a very different pattern of response than you would see with chemotherapy or monoclonal antibodies, namely that when the patients take the drug they get a very rapid reduction in lymph node mass very quickly but at the same time the lymphocyte count goes up. So at least initially there appears to be a compartment shift but over time it appears to come down. So one of the questions when these drugs were being presented early on was how many patients will it come down and how long will it take or will it stay up etc? So what’s interesting now is that this data was presented at ASH last year, then at ASCO Lugano and at ASH this year and what we’ve seen is if you looked at what we’re calling the nodal response, meaning a patient has a 50% reduction lymph node mass, it’s about 80-90% even at the first evaluation point. But because the lymphocyte count initially is high, we don’t call them partial remitters. So, for example, at ASH last year we had a nigh nodal response rate but about 25% partial remissions, meaning the lymphocyte count had to have decreased by 50%. When this data was presented at ASCO Lugano that 25% had gone up to 48% and this presentation here it’s about 70% and that’s in a very refractory population.
The other thing that’s very exciting is this drug has very little toxicity, the most common side effect is diarrhoea which is usually mild, often self-limited, and very important in the treatment of CLL and very exciting is that it’s not myelosuppressive because these are patients who are often cytopenic from the disease, the prior therapy, they’re immunosuppressed so the biggest risk of treating a CLL patient is generally myelosuppression and infection. So to have a highly effective agent that doesn’t cause any myelosuppression is very, very exciting and is very different from all the other treatments that we have for this disease.
How does the efficacy compare?
Right now there are no tyrosine kinase inhibitors approved for CLL, these are the first batch. There is another drug in clinical trials, CAL-101, that targets a different enzyme in the pathway, it targets PI3K-delta and that drug is not being updated here, the results, but has also shown a very high nodal response rate of about 80-90% and also is an oral, fairly well tolerated drug.
Are there any developments you would like to highlight?
I think the B cell receptor inhibitors are the hottest things in CLL right now for all the reasons that we just discussed – the high efficacy, the low toxicity, the lack of myelosuppression. And I think the feeling among people who treat CLL and are participating in these trials is that these drugs really may change the paradigm for treatment of CLL in the long run.
I think there are some interesting presentations at ASH involving monoclonal antibodies, two of them attached to a toxin. So there are two different trials being presented using two different drugs but the common theme is that they both target CD22 which is highly expressed in most patients with ALL. In one trial this is conjugated to pseudomonas exotoxin, so in other words you have binding of the antibody, internalisation and then release of the toxin into the cell. That’s being done in paediatrics, Alan Wayne is presenting that and that’s in a phase I so they have not reached an MTD yet. Even without reaching an MTD, in a very refractory paediatric population they have a response rate of about 30%. What you have to keep in mind is that ALL is not like CLL, people don’t respond and live for a long time then relapse and respond, this could be a really lethal disease if people relapse.
Another trial using the anti-CB22 is inotuzumab where our group is presenting that. That’s bound to calicheamicin, so the toxin is different, and that’s actually the toxin that was part of Mylotarg. If you remember Mylotarg was originally used for AML because the antibody there was targeting CD33 which is a myeloid antigen. So here we’re targeting CD22 with calicheamicin and we’ve also shown in a fairly refractory population now a response rate of 57% which is an extremely high response rate to a single agent.
The third antibody based treatment that’s also being presented here that looks very exciting, and this has been to some extent presented before, is the blinatumomab or the BiTE antibody. And the key there is that that’s an antibody that actually binds two antigen binding, so it binds to CD19, targeting malignant B cells, but then it binds to CD3 at the same time, getting the T cells. When that happens the T cells are activated and you’re directing the immune system actually to kill off the malignant cell. And there has actually been some data that was published this year in Lancet using that antibody but in the setting of MRD positivity because we know in ALL that if patients do not become MRD negative, minimal residual disease, or they have MRD reoccurring that inevitably will lead to relapse. So, in other words, trying to come in early before the patient has a frank clinical relapse, they showed a very high efficacy and that was what was published. What’s new and what’s being presented here is the trial looking at the same antibody, blinatumomab, in full-blown relapses and also showing with a small n, I think it will probably be a bigger number at the presentation but right now we only have the abstract, this small number, maybe about a dozen patients, showing a very high response rate in patients with full-blown relapse. So I think that’s an exciting theme in ALL are some of these novel antibody conjugates.
Blinatumomab is actually in a pivotal trial in Europe in MRD positivity that will potentially lead to European approval, that trial is already up and on-going, and the pivotal trial here in the United States is going to be a phase II trial in relapsed ALL, which is just about to open.