Non-Covalent BTK Inhibitor Yields High Response Rate in Pretreated CLL

The non-covalent or reversible Bruton tyrosine kinase (BTK) inhibitor pirtobrutinib (Jaypirca) demonstrated promising efficacy in patients with chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL) previously exposed to BTK inhibition, the phase I/II BRUIN study showed.

Among 247 patients who had previously received a covalent BTK inhibitor, 73.3% (95% CI 67.3-78.7) achieved an overall response with pirtobrutinib, including four complete responses, reported Jennifer Woyach, MD, of the Ohio University Comprehensive Cancer Center in Columbus, and colleagues.

Moreover, when a partial response with lymphocytosis was included in the analysis, the overall response rate (ORR) was 82.2% (95% CI 76.8-86.7), they noted in the New England Journal of Medicine.

In a subgroup of 100 patients who had previously received both a BTK inhibitor (mostly ibrutinib [Imbruvica] and acalabrutinib [Calquence]) and a BCL2 inhibitor (such as venetoclax [Venclexta]), the ORR was 70%, and 79% when partial response with lymphocytosis was included.

“These findings indicate that reestablishing BTK inhibition with pirtobrutinib is a potential therapeutic option regardless of whether previous covalent BTK inhibitor therapy is discontinued owing to disease progression, toxic effects, or other reasons,” Woyach and team concluded.

In the overall efficacy cohort, median progression-free survival (PFS) was 19.6 months at a median follow-up of 19.4 months, while the median PFS was 16.8 months in the subgroup who had previously received both a BTK inhibitor and a BCL2 inhibitor, and 22.1 months among those who had received a BTK inhibitor but not a BCL2 inhibitor.

PFS results were consistent across various subgroups, including patients with poor prognostic markers and those with heavily pretreated disease.

At a median follow-up of 22.6 months, the 12-month overall survival (OS) rate was 86% among the patients who had previously received a BTK inhibitor, and the 18-month OS rate was 80.5%.

While BTK inhibitors have improved outcomes for patients with CLL or SLL, the authors pointed out that they are not curative and have common resistance mechanisms, and “therefore are not effective when used in sequence in the context of drug resistance to another member of the drug class.”

Pirtobrutinib inhibits both wild-type and C481-mutant BTK (the most common mutation associated with resistance to covalent BTK inhibitors) and was recently approved for the treatment of relapsed or refractory mantle cell lymphoma.

Among a safety cohort of 317 patients treated with pirtobrutinib, the most common adverse events (AEs) were infections (71% of patients), bleeding (42.6%), and neutropenia (32.5%). The most frequently reported grade ≥3 AEs were infections (28.1%) and neutropenia (26.8%), and the most frequently reported grade ≥3 treatment-related AE (TRAE) was neutropenia (14.8%).

TRAEs led to dose reductions in 15 patients and permanent discontinuation of pirtobrutinib in nine patients.

Atrial fibrillation, major hemorrhage, and hypertension occurred in 3.8%, 2.2%, and 14.2% of patients — rates that Woyach and team described as “encouraging as compared with other agents in the BTK inhibitor class.”

Looking at the future of BTK inhibitors in CLL, Arnon P. Kater, MD, PhD, of the University of Amsterdam in the Netherlands, and Barbara Eichhorst, MD, of the University of Cologne in Germany, noted in an accompanying editorial that a number of other non-covalent BTK inhibitors are being developed, but it remains to be seen how effective they will be in treating tumors with resistance mutations.

Considering that the results of this study support the safety of pirtobrutinib, Kater and Eichhorst suggested that it may be a candidate for new combination therapies, such as with bispecific T-cell-engaging antibodies.

This approach, they said, “would be expected to overcome the acquired T-cell dysfunction that occurs in CLL and hampers T-cell-directed therapies.”

The phase I/II BRUIN trial was conducted at 49 sites across 10 countries. A total of 773 patients with B-cell cancers were enrolled in the trial from March 2019 through July 2022, 317 of whom had relapsed or refractory CLL or SLL. Of these patients, 247 had previously received at least one BTK inhibitor and were treated with pirtobrutinib and included in the efficacy cohort.

Median age in the efficacy cohort was 69 years, 68% were men, and the median number of previous therapies was three. Almost all of the patients had CLL (99.6%). Most patients had discontinued previous BTK inhibitor therapy owing to disease progression (76.9%), with the remainder discontinuing treatment due to toxic effects or other reasons.

Woyach and colleagues noted that the lack of an active control group and the lack of prospective data for other modern therapies after the use of BTK inhibitors both limited direct comparisons with other available therapies.

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