Jennifer Woyach, MD, Highlights Novel CLL Therapies Presented at ASH 2023

Dr. Woyach, of the Ohio State University, joined Chadi Nabhan, MD, MBA, FACP, host of The HemOnc Pulse, for an interview on novel therapies in chronic lymphocytic leukemia (CLL) at the 65th American Society of Hematology (ASH) Annual Meeting & Exposition.

Dr. Woyach first discussed pirtobrutinib, a highly selective, oral, noncovalent Bruton's tyrosine kinase (BTK) inhibitor, which was granted accelerated approval in CLL due to the results of the BRUIN trial presented at ASH. Among 280 patients who had been treated with a covalent BTK inhibitor previously, progression-free survival was 19.4 months and overall survival was 80%.

Drs. Woyach and Nabhan discussed whether the type of prior therapy would achieve the same response and if pirtobrutinib should be used as frontline therapy.

“There are studies that are investigating it in the frontline setting,” Dr. Woyach said. “I think the biggest hesitation that many of us have to moving [pirtobrutinib] to the frontline is the resistance mutation…the concern is that these mutations likely will make a patient unable to respond well to a covalent BTK inhibitor. Unless we have some strong clinical evidence that you can sequence them in either direction, it seems like the most scientifically rational way to do it is as a covalent and then a noncovalent.”

Dr. Woyach’s second presentation at ASH looked at LP168, a novel dual covalent and noncovalent BTK inhibitor. In a phase I trial, 45 patients (37 patients with CLL) were treated with LP168. The overall response rate was over 70%, and LP168 demonstrated a favorable safety profile.

“One of the really neat things about this drug is that if BTK is wild type, the drug can bind covalently to C41 on BTK just like ibrutinib, acalabrutinib, and zanubrutinib bind,” she said. “And if C41 is mutated, it can bind reversibly. It binds away from the T474 site, suggesting with the laboratory data that it's going to be effective even in the presence of those T474 mutations that we see with pirtobrutinib.”