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Professor John Seymour of Peter MacCallum Cancer Centre in Melbourne, Australia describes two new BTK inhibitors beyond ibrutinib in our short interview at the 2016 Annual Meeting of the American Society of Hematology held in San Diego. New research was presented on two new molecules that are still in clinical trials.
Take Away Points
- Acalabrutinib in early data appears to have similar efficacy compared to ibrutinib and may be tolerated in some patients who needed to discontinue ibrutinib due to side effects. In laboratory testing it does seem to hit fewer targets than ibrutinib and that may explain why it holds the promise of fewer adverse events.
- There is surprising very early data that acalabrutinib might even be effective for some patients with Richter’s transformation, a gaping unmet need in CLL.
- BGB-3111 is an even newer BTK inhibitor that has shown in lymph node biopsies to strongly and completely bind to BTK blocking its activity. This is important because the lymph nodes are the site where much of the action occurs in CLL.
Here is a link to the UK’s Peter Hillmen’s research: Acalabrutinib Monotherapy in Patients with Richter Transformation where we learn that there was on overall response rate of 38% with 3 patients having a complete response (CR) in this difficult to treat population with aggressive transformed disease.
From Ohio State comes Dr. Farrukh Awan’s abstract: Acalabrutinib Monotherapy in Patients with Ibrutinib Intolerance. His team found that 73% of patients who came off ibrutinib due to intolerance were able to tolerate acalabrutinib and were still on the drug at a median follow-up of 9.5 months. The main reason for stopping the drug was disease progression. While there were side effects including atrial fibrillation, just as there is with ibrutinib, there were no major bleeds and most patients could stay on the trial.
Finally, from Melbourne, Dr. Constantine Tan presented the research: Twice Daily Dosing with the Highly Specific BTK Inhibitor, Bgb-3111, Achieves Complete and Continuous BTK Occupancy in Lymph Nodes, and Is Associated with Durable Responses in Patients (pts) with Chronic Lymphocytic Leukemia (CLL)/Small Lymphocytic Lymphoma (SLL).
He found that BGB-3111 occupancy rate of BTK receptors in lymph nodes averaged 99.5% and the early clinical response rate was 90%. Whether the high rate of blocking the BTK in the nodes with the twice-daily dosing results into better patient outcomes is yet to be determined, but it is certainly exciting research.
Here is my interview with Dr. Seymour where he references the three linked abstracts included above. You can read the transcript here, or watch the video below:
Dr. Brian Koffman: Hi, Dr. Brian Koffman. I’m a family doctor and a CLL patient and I’m here at the last day of the American Society of Hematology Meeting 2016 in San Diego, as the Medical Director of The CLL Society.
Dr. John Seymour: John Seymour. I’m a hematologist, been here at the meeting looking at new data in CLL.
BK: Dr. Seymour you’ve spent the last several years looking at CLL and doing some research in that area and we know that the BTK inhibition has been a breakthrough in CLL. We’ve spent a lot of time talking about Ibrutinib here, but there’s some new molecules that you’re interested in, that you saw some new data. Can you explain that at a patient-friendly level?
JS: Yes. While ibrutinib was designed to inhibit BTK and it does that well, it also inhibits another group of molecules other than BTK. So there was data presented here on molecules that are perhaps more potent at inhibiting BTK, and certainly more selective, cleaner in hitting the designed target, and less of the undesired targets. One that John Byrd first presented last year at this meeting, acalabrutinib, or ACP196 was its previous name, so additional data is being presented here. It appears that that drug can be dosed at higher doses with good safety. Perhaps that higher dose gives stronger blockade of BTK. Information was presented that that drug was very effective in patients who were intolerant of ibrutinib – who had side effects, perhaps related to the off-target effects of ibrutinib. But also, some I think intriguing, I wouldn’t say yet definitive, but intriguing data that in some patients where their disease had progressed, and even progressed to Richter Syndrome so it transformed into a more aggressive diffused large B cell lymphoma, that acalabrutinib was able to be active against a proportion of those transformed disease. Clearly, it’s an effective drug. It appears that it’s probably a safer drug and it has the possibility that it may have effectiveness against some forms of CLL or transformed CLL that are resistant to ibrutinib. None of this is a direct head-to-head comparison. None of it is randomized, so it’s still preliminary data. But it looks very promising for the development of that drug as another option for patients who have safety issues with ibrutinib and potentially – and this remains unproven – as a more effective option than ibrutinib.
The other drug that is earlier in its development is one by a company called BeiGene, the drug is called BGB-3111. Again, early data, it’s somewhat similar to acalabrutinib because of a cleaner target profile. It’s able to be dosed at a level that is proven on biopsy. This was an interesting component where lymph nodes had samples taken proving that the BTK was fully occupied and inhibited with this drug. And with about 50 patients with CLL, very good effectiveness. But again, early follow-up and one of the things we’ve seen with ibrutinib is that the true picture of effectiveness, we need longer follow-up. So with both of these drugs it’s still relatively early, but clearly its emerging that there will be a range of options hitting this important target, BTK.
BK: And with that last study you were talking about, I mean I think it was really good information to look at lymph nodes because that’s where the action is. Our CLL doesn’t proliferate in the blood stream – it proliferates in the nodes and in the marrow. So actually, looking at that and seeing yes, that is being blocked in the lymph nodes is, I think, a powerful piece of information.
JS: Yes, I agree with you on that. Scientifically, and guiding us how to optimally use these drugs, that was a key element of that trial. I think it’s given us good information about optimal dosing levels of these drugs. Also, both acalabrutinib AND BGB-3111 are dosed twice daily because there is some emerging information that all the while ibrutinib irreversibly blocks BTK that is present, there is some new synthesis (production) of new protein over a 12 or 24hour period and perhaps once daily dosing of ibrutinib allows re-emergence of some BTK activity. So, the twice daily dosing, the higher levels, and the confirmation of penetration into tissue sites, were key elements I think with these newer drugs.
BK: I’m eagerly waiting to see their development from a patient’s perspective and having more options on the table, is always good. Dr. Seymour thanks so much.
Enjoy the video:
This is all very encouraging. I can’t wait to see how the data develops.
My only caveat is that all drugs look good when they are new. We will need to wait and have larger data sets before we can pass judgment, but the early signs are certainly encouraging.
The more choices and the more competition, the better for us all.
Professor John Seymour is the director of Cancer Medicine at MacCallum Cancer Centre in Melbourne, Australia and a member of many scientific committees including the Victorian Government Consultative Council on Human Research Ethics, Scientific Advisory Committees for the International Workshop on NHL, International Conference on Malignant Lymphoma, and Board of Directors of the International Extranodal Lymphoma Study Group.
Dr. Brian Koffman, a well-known doctor, educator and clinical professor turned patient has dedicated himself to teaching and helping the CLL community since his diagnosis in 2005. He serves as the medical director of the CLL Society Inc.
Originally published in The CLL Tribune Q1 2017.