ASH 2020: Dr. Anthony Mato on LOXO-305 A Next Generation Highly Selective Non-Covalent BTK inhibitor.

In an oral presentation during ASH 2020, Dr. Anthony Mato discussed LOXO-305, a new generation BTKi (Bruton Tyrosine Kinase Inhibitor) that blocks a key step in the B cell receptor (BCR) pathway. In doing so, it blocks pro-survival and “homing” messages to the CLL cells, forcing the cancer cells to leave their protective niches in the lymph nodes and bone marrow, and float out into the blood stream, eventually dying.

Ibrutinib was the first approved BTKi and it revolutionized the treatment of CLL because of its ability to provide a durable response in most patients, including those with high-risk features such as del 17p or TP53.

However, especially in the relapsed and refractory setting, some CLL cells may eventually be able to escape inhibition from ibrutinib and other similar BTKis such as acalabrutinib and zanabrutinib (not approved for CLL at the time of this writing). The most common way this happens is by a mutation in the drug’s binding site at C481 preventing those 1st generation BTKis from irreversibly binding to and blocking BTK, rendering those drugs largely ineffective.

LOXO-305 binds “reversibly” and does not seem to be affected by changes in the C481 binding site. It remains able to turn off BTK when the irreversible binders are no longer effective.

Dr. Mato discusses the CLL data from the BRUIN trial, which is the first in-human trial of LOXO-305 for CLL and NHL (Non-Hodgkin Lymphomas)

• 170 CLL patients were studied.
  • 80% had received ibrutinib or acalabrutinib.
• 200 mg is the daily dose.
• Fatigue, diarrhea, and bruising were the only side effects above 10%.
• < 1% had atrial fibrillation.
• Response rate for all 63%. If one looked at just the patients who were assessed at > 6 months or greater giving the medicine some time to work, the response rate went up to 86%.
• 94% of those who responded are still on drug.
• Patients responded well even they failed multiple other drugs and were running out of options.
• First study of one BTK inhibitor after failing another BKI inhibitor.

Conclusions:

Blocking the BTK pathway works amazing well for CLL patients, so when patients relapse on a first generation BTK inhibitor, there is good sense in trying another drug that uses a different mechanism to block the B cell receptors through BTK inhibition. Early data from the BRUIN trial suggest that LOXO-305 seems is a promising new option with regard to efficacy and tolerability and deserves further study to assess it in larger numbers of patients.

Here is a link to the actual trial on Clinicaltrials.gov that Dr. Mato describes in our ASH interview: A Study of Oral LOXO-305 in Patients With Previously Treated CLL/SLL or NHL.

Please enjoy our interview:

Here is the ASH abstract: LOXO-305, A Next Generation, Highly Selective, Non-Covalent BTK Inhibitor in Previously Treated CLL/SLL: Results from the Phase 1/2 BRUIN Study.

Stay strong.  We are all in this together.

Brian

Brian Koffman MDCM (retired) MS Ed