Effective use of ibrutinib in the treatment of ABC lymphoma tumours
Dr Louis Staudt - National Cancer Institute, Bethesda, USA
Can you tell us more about ibrutinib?
Ibrutinib is an exciting drug that is one of the so-called targeted agents, it targets a kinase, Bruton’s tyrosine kinase, that is a key enzyme within normal B-cells and also malignant B-cells, malignant lymphoma cells. It links a cell surface receptor, the B-cell receptor to downstream signalling pathways that promote both the survival and the proliferation of the cells. So this drug, ibrutinib, then inactivates this kinase very potently, it actually attaches permanently to the kinase and inactivates it. So it gives it great specificity and great pharmacodynamic properties in patients.
So that’s the differential specificity of cancer cells?
Yes, it might be expected to have some effects on normal B-lymphocytes. In fact, in patients treated so far it has had very little and none that have caused any problems.
What relevance does ibrutinib have to the NF-kappaB pathway?
The one pathway that is downstream, so to speak, in the signalling from the B-cell receptor is the NF-kappaB pathway which has been known for a couple of decades now as being a powerful anti-death pathway. So a pro-survival effect for the cancer cells and we observed that this one type of diffuse lymphoma that we call the activated B-cell like, ABC, is characteristically expressing an active form of this pathway such that if you somehow interfere with that NF-kappaB you then kill the cells. One of the ways to interfere with that is by interfering with upstream signalling that sort of converges on this downstream NF-kappaB pathway and that would be with, for example, B-cell receptor signalling and the use of ibrutinib to inhibit.
Could you tell us more about your case reports?
Our second patient on our phase I trial had this form of lymphoma that we predicted should respond to ibrutinib and she went into a complete remission then kept taking the drug, no discernible side effects, and she keeps coming back to see us and being rescanned and 3½ years later still has no disease and is taking the pill once a day by mouth with no side effects.
Didn’t your multicentre stud show a huge benefit to survival?
The important take-home from that trial is that we were able to molecularly characterise subtypes of lymphoma, the ABC subtype and something called the GCB subtype, and it was only the ABC subtype tumours that were responding because those are the ones that have activity of this pathway that ibrutinib targets. So in that we had a 40% response rate in the ABC subtype and we believe we prolonged their overall survival from 3 months on average to a little over 10 months on average but there seemed to be no effect on the other GCB subtype. So it means that further development of the drug will have to be in trials that selectively accrue patients with this molecular subtype of diffuse lymphoma, ABC.
So combinations with ibrutinib are key to this process?
The one thing that is important about ibrutinib is how safe it is. So most patients have no side effects, the ones that have been reported are grade 1 and 2 toxicities, so we predicted that it should combine very well in the clinic with other drugs. We’ve been working very heavily on several, one that is a little further along is a drug called lenalidomide, which is already approved for other cancers, and we found the mechanistic basis of why that should synergise quite nicely with ibrutinib and hope to start those clinical trials soon for the combination.
What should doctors take from this?
What I would pull out is that in these lymphomas it is not the addiction they have to this B-cell receptor signalling is not to a particular mutation they have but to a signalling through the receptor that is somehow non-genetic. In fact, we have evidence that I presented that it is an actual antigen that is released by the tumour cells themselves that stimulates the receptor. I think this is important because other cancers that ibrutinib has been approved for now, in chronic lymphocytic leukaemia and mantle cell lymphoma, there is circumstantial evidence also that such a non-genetic form of B-cell receptor signalling is in play. So it may be a general mechanism for B-cells tumours becoming addicted to this form of B-cell receptor signalling.
What looks clinically promising at the moment?
The first thing is to acknowledge that diffuse large B-cell lymphoma is not one disease and we are actively working on methods to clinically discern the subtypes such that it would make no sense from our phase II trial data to treat a patient with a GCB subtype of lymphoma with ibrutinib. So very soon you should be able to order a test to discern the two subtypes of lymphoma and that will tell you which patients are likely to be benefitted by ibrutinib.
How close is knowledge of functional and structural genomics to being practically applied?
In a way everything I’ve described came out of a genomic investigation. So we took an unbiased look at what makes these cancer cells tick. So we did a genetic screen asking for which genes maintain the survival of these cancer cells and out of that screen came various components within the B-cell receptor pathway, within a pathway downstream of another signalling adapter and these then focussed our attention on where to go therapeutically. Had we not done the genomics we would have been poking around in the dark for years and years but the genomic methods allow us to look at the entire genome at once to find the most relevant targets, ones that the cancer cells are most addicted to.
What would be your take-home message for oncologists?
Be encouraged that we have very active new drugs that have virtually no side effects for the patients, just a completely different experience from standard chemotherapy that can make, in some cases, the tumours that are very large, resistant to other therapies, completely disappear either for some length of time, many months, or in a few cases for years.