Michael Wang on the Reversible BTK Inhibitor for Previously Treated MCL

The FDA recently granted accelerated approval to pirtobrutinib (Jaypirca), a reversible Bruton’s tyrosine kinase (BTK) inhibitor, for the treatment of relapsed or refractory mantle cell lymphoma (MCL) after at least two prior lines of systemic therapy, including a BTK inhibitor.

In this exclusive MedPage Today video, Michael Wang, MD, of the University of Texas MD Anderson Cancer Center in Houston, highlights the results of the BRUIN study, which led to the approval, and the impact the drug will have on the future treatment of BTK-resistant patients.

Following is a transcript of his remarks:

The Bruton’s tyrosine kinase (BTK) inhibitors have revolutionized the therapy for B-cell lymphomas. So far, three covalent irreversible BTK inhibitors have been approved by FDA, including ibrutinib [Imbruvica] approved in 2013, acalabrutinib [Calquence] approved in 2017, and zanubrutinib [Brukinsa] approved in 2019 for relapsed/refractory mantle cell lymphoma.

Because all three agents bind in the same fashion on the same side of the BTK protein, the ATP binding side, if the mantle cell lymphoma tumor becomes resistant to one, then the other two also will be resistant, because they adapt to the same side, the same way of binding, covalent irreversible.

At ASH [the American Society of Hematology annual meeting], I presented the updated results of the BRUIN study on the mantle cell lymphoma patients. Among 90 patients included in this analysis, the pivotal analysis required by FDA, the response rate has improved to 58% in patients with a prior BTK inhibitor exposure. However, in about less than 20 of the patients who never received the BTK inhibitor exposure, or who never received the BTK inhibitors, the response rate was high, at 85%.

This is a true meaningful progress because, first of all, the mechanism is that the pirtobrutinib is a non-covalent reversible BTK inhibitor. So it binds to the BTK protein, also the ATP side, but in a different fashion. It allows constant association and dissociation of the drug with the protein BTK. Therefore, it has a constant equilibrium of inhibition-targeted occupation.

So even in patients with prior BTK inhibitors not working anymore, the pirtobrutinib could still provide a response rate of 58%. This is truly meaningful because even if prior BTKs don’t work anymore, we can still treat the patient with a BTK inhibitor that’s an oral therapy.

The side effects are very acceptable, with diarrhea, fatigue, and infections, and really to a lesser degree. Surprisingly, among, so far, over 600 patients, the atrial fibrillation rate is only about 2%. And this 2% corresponds to the background atrial fibrillation rate in this normal population.

This is an emerging different panel for toxicity compared with the BTK inhibitors. Of course, we need more time and more cases to further consolidate this early observation.