Inhibiting the B cell receptor (BCR) signaling pathway by blocking BTK first with ibrutinib and now with acalabrutinib has dramatically improved survival for chronic lymphocytic leukemia patients. CLL cells are “addicted” to BCR signaling and when it’s turned off by a BTK inhibitor, the cancer has no purpose in life and dies off.
Both of these drugs block BTK by covalently or “irreversibly” binding to it at the C481S site. However, patients can become resistant to these medications when the cancer cells mutate at that binding site so the drugs can no longer bind and therefore can no longer block BCR signaling. This can lead to relapses.
ARQ 531 is a new BTK inhibitor that binds reversibly to BTK and also binds at a different binding site.
Dr. Deborah Stephens leads the CLL program at the Huntsman’s Cancer Institute in Salt Lake City and was one of this trial’s investigators. I caught up with her at ASH 2019 in Orlando to discuss her research.
This phase 1 trial was designed primarily to find the correct dose (dose escalation trial) and to check for side effects. For more on trial phases, see this simple explanatory link.
Takeaways:
- Of the total of 40 patients that enrolled we will focus on the 26 patients with CLL and the 6 with Richter’s Syndrome (RS).
- BTK-C481S mutation was documented in 22/26 (85%) CLL patients meaning these patients would stop responding to the approved 2 BTK inhibitors, ibrutinib and acalabrutinib.
- Nausea and diarrhea were the most common side effects.
- One patient had a severe rash that limited the dose.
- 65 mg a day was found to be the dose that will be used in future trials.
- 7 patients with CLL responded including some who had the C481S mutation.
- Knowing that patients do well when BTK is blocked, finding new ways to keep it blocked makes good sense and this different reversible binding is a way that is being explored with a few different experimental drugs including:
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- SNS 062 (vecabrutinib)
- ARQ 531
- LOXO 305
- And for an entirely new approach in this ASH 2019 interview, ASH 2019: “ Wiestner Discusses a New Approach to Stopping Bruton’s Tyrosine Kinase (BTK)”, we learn about a novel drug that doesn’t just block BTK but destroys it.
- Saving the best for last: 3 of 6 Richter’s Syndrome (RS) patients also responded to ARQ 531 which is remarkable.
Conclusions:
Phase 1 trials are designed to find the best dose and make sure the drug is safe. They are ostensibly not designed to check for the activity of the drug but make no mistake the researchers and the pharmaceutical companies want to see some indication that the new molecule is active against the cancer being studied.
Now that we know that ARQ 531 has yet to show any major safety signals and now that we have a recommended dose, larger phase 2 trials can begin to check how well it actually works.
In the meantime, we have to settle for the tantalizing results from very small numbers that ARQ 531 can work for some CLL patients that have progressed on ibrutinib and has stopped disease progression in a few patients with the difficult to treat fast moving Richter’s Syndrome. All very early, but very promising.
Here is my brief interview from ASH 2019 in Orlando with Dr. Stephens:
Here is link to the ASH 2019 abstract: Final Results of Phase 1, Dose Escalation Study Evaluating ARQ 531 in Patients with Relapsed or Refractory B-Cell Lymphoid Malignancies.
Stay strong. We are all in this together.
Brian
Brian Koffman MDCM (retired) MS Ed
Co-Founder, Executive VP and Chief Medical Officer
CLL Society, Inc.
