Noncovalent BTK Inhibitors in CLL

Transcript:

William Wierda, MD, PhD: Let’s turn to new treatments. One drug that’s furthest along in development is called pirtobrutinib, which Anthony updated at ASH [American Society of Hematology Annual Meeting] 2021. Anthony, can you introduce reversible inhibitors of BTK [Bruton tyrosine kinase] and summarize the update on pirtobrutinib? Then we’ll have Callie discuss nemtabrutinib as another drug within that category of reversible inhibitors.

Anthony Mato, MD, MSCE: As an intro to the topic, these molecules are meant to bind in a noncovalent way to an alternative binding site on BTK to circumvent the main and known mechanism of resistance to covalent inhibitors, which are Cys481 mutations. Pirtobrutinib is a specific noncovalent BTK inhibitor that works as well in wild type preclinically as it did in mutated CLL [chronic lymphocytic leukemia] in models. It looks to be an ideal BTK inhibitor from the perspective of minimal off-target effects and addresses the main unmet need, which is resistance to covalent inhibitors that are utilizing a treat until progression strategy.

The update to the BRUIN study focused on patients who had prior covalent BTK inhibitors, about 252 patients. The take-homes are simple. It’s active. Response rate was 68%. It got better with time. It seemed to be similarly active, no matter how you looked at patients’ prior therapies, high-risk features, and reasons for discontinuation. Remissions were durable. The median PFS [progression-free survival] was not reached with a short follow-up of 9.4 months. In the double-exposed patients, the median PFS was 18 months. The third point I want to make is that it was safe.

Very few AEs [adverse events] occurred at 15% or higher. BTK-associated adverse events were minimal. AFib [atrial fibrillation] was only 2% in more than 600 patients treated on the trial. The major take-home in terms of safety was a discontinuation rate of less than 1% in the population. We know from other covalent BTK inhibitors that the discontinuation rates with similar follow-up can range from 10% to 20%. Overall, it seemed to be safe and effective, and it addressed an unmet need. It’s a promising molecule, and we’ll probably hear a lot more about this in the future.

William Wierda, MD, PhD: Nemtabrutinib, Callie?

Catherine Callaghan Coombs, MD: Nemtabrutinib has had a lot of names. Formerly it was ARQ 531. Now it’s owned by Merck, so it’s MK-1026 or nemtabrutinib. This is another noncovalent BTK inhibitor. Dr Jennifer Woyach presented the results from the single-arm phase 2 trial, which had several expansion cohorts. This trial hasn’t enrolled anywhere near as many patients, and the report from the abstract was that a little over 100 participants had been enrolled, including patients with a variety of B-cell NHLs [non-Hodgkin lymphomas] but also CLL.

They did present efficacy data that show this drug is also efficacious. They quote a response rate of 58% for patients with CLL—22 of 38 patients—who are primarily PR [partial response] or PRL [PR with treatment-induced lymphocytosis]. The 1 difference with this drug is that it appears that grade 3 adverse events are a bit higher: 68% of patients had grade 3 or higher treatment-emergent AEs. There were a few grade 5 events, specifically in 6% of participants, though those were more commonly because of disease progression in 3 of 7 patients that died. This is an interesting compound that appears to be active but not as many patients and maybe not as low of a toxicity profile when doing a cross-trial comparison of the pirtobrutinib data. It will be interesting to follow what happens with more time and patients on this trial.

William Wierda, MD, PhD: Other reversible inhibitors are in development, perhaps not as far along as pirtobrutinib and nemtabrutinib, which we’ll most likely be hearing about.

Transcript edited for clarity.