Bruton tyrosine kinase (BTK) inhibitors, such as ibrutinib, have transformed the treatment of chronic lymphocytic leukemia (CLL). Over time, the cancer can acquire mutations in the BTK pathway. This in turn can cause patients to relapse or become resistant to their current medications. Scientists are trying to expand their toolkit of treatment options by targeting BTK in different ways.
At the annual meeting of the American Society of Hematology (ASH) 2019, our own Dr. Brian Koffman interviewed Dr. Anthony Mato, Director of the CLL Program at Memorial Sloan Kettering Cancer Center. They discussed preliminary results from a clinical trial of a new BTK inhibitor, LOXO-305.
This is a phase 1/2 clinical trial of LOXO-305 in 28 patients with advanced B-cell malignancies, such as CLL and mantle cell lymphoma (MCL), who had failed to respond to or were unable to tolerate at least two prior therapies. Phase 1/2 clinical trials test the safety, side effects, and best dose of a new treatment.
Takeaways:
- LOXO-305 is a selective, reversible (non-covalent) BTK inhibitor. This means that it binds specifically to BTK, but it binds at a different site and in a different way than irreversible (covalent) BTK inhibitors, such as ibrutinib or acalabrutinib.
- Targeting a different site on BTK could be useful for patients who have developed mutations at the C481 binding site on BTK, which prevents ibrutinib from binding.
- In this clinical trial, the majority of patients had previously been treated with a BTK inhibitor and were resistant; 25% of patients had a known resistance mutation.
- Among patients who could be evaluated, 77% responded to treatment.
- All patients, who are responding, continue on the study drug. It is still early with eight months being the longest monitored time period for the drug.
- Thus far, most adverse events have been mild or moderate and easily managed.
- The clinical trial is ongoing. The investigators would like to expand the number of patients in the trial.
Conclusions:
The success of BTK inhibitors, such as ibrutinib, has demonstrated that blocking the BTK pathway is a very effective strategy for treating CLL. However, CLL is smart and can mutate to try to escape treatment.
Patients are likely to need multiple treatment strategies over time. Drugs that block the BTK pathway, through new and different mechanisms, could provide much needed options for patients who are refractory or resistant to currently available medications.
The preliminary results of this clinical trial of LOXO-305 are promising, and we look forward to seeing the final results in the future.
Please enjoy this brief interview with Dr. Mato from December 2019 at ASH in Orlando, Florida.
You can read the actual ASH abstract here: Results from a First-in-Human, Proof-of Concept Phase 1 Trial in Pretreated B-Cell Malignancies for LOXO-305, a Next-Generation, Highly Selective, Non-Covalent BTK Inhibitor
Take care of yourself first.
Ann Liu, PhD
