Investigational BTK Inhibitor Demonstrates Long-Term Safety and Efficacy in CLL

Author’s Perspective

Co-author Martin J.S. Dyer, PhD, of the University of Leicester in the United Kingdom: “This report describes the first long-term outcome data with a selective Bruton tyrosine kinase (BTK) inhibitor in patients with chronic lymphocytic leukemia (CLL). These data show maintained efficacy of ONO/GS-4059 with no new safety concerns in CLL and will encourage future clinical development of this and other selective BTK inhibitors alone and in combination with other precision medicines.”

Since its approval for the treatment of chronic lymphocytic leukemia (CLL) in 2016, ibrutinib, a Bruton tyrosine kinase (BTK) inhibitor, has increased the rates of durable remission and survival.  However, up to 20 percent of patients discontinue ibrutinib because of unacceptable toxicities. In a Letter to the Editor published in Blood, researchers shared 3-year follow-up data from a phase I trial of patients treated with an investigational BTK inhibitor, ONO/GS-4059, being evaluated as a possible alternative to ibrutinib in this patient population.

Results from the phase I trial showed a high response rate in evaluable CLL patients (96%; n=24/25), according to Harriet S. Walter, MD, of the Ernest and Helen Scott Haematological Research Institute at the University of Leicester in the United Kingdom, and co-authors.

Ninety patients with relapsed/refractory B-cell malignancies including CLL were enrolled in the ongoing ONO/GS-4059 POE001 phase I clinical study between September 2012 and January 2015. The 28 patients with CLL included in the trial were treated with ONO/GS-4059 20 mg to 600 mg once daily or 300 mg twice daily and next generation sequencing data from peripheral blood samples were available in 27 patients.

These patients were heavily pretreated, having received a median of four prior therapies (range = 2-9 therapies).

At data cutoff (June 8, 2016), the median time on study was 32.5 months. Eleven patients (39.3%) had discontinued treatment because of death (n=3), disease progression (n=4), adverse events (AEs; n=3), and sponsor decision due to extended drug interruption (n=1).

A maximum tolerated dose (MTD) was not identified, and patients remaining on study were receiving ONO/GS-4059 at doses ranging from 40 mg to 600 mg once daily or 300 mg twice daily.

The median progression-free survival (PFS) was 38.5 months and the median overall survival was 44.9 months.

Patients with high-risk CLL genetics appeared to respond to ONO/GS-4059 treatment “with minimal toxicity,” the authors wrote. Seven of 21 patients with unmutated IGHV gene segments discontinued treatment, and three of 10 patients with TP53 mutation discontinued.

“Interestingly, all CLL mutational subgroups responded well to ONO/GS-4059, [and] toxicities appeared to be much less [with ONO/GS-4059] than those observed with ibrutinib, although formal demonstration of this point awaits head-to-head studies,” Martin J.S. Dyer, PhD, a study co-author, told ASH Clinical News.

The most common AEs were bruising (35.7%), neutropenia (35.7%), and anemia (32.1%), and “extended follow-up did not reveal new safety or toxicity concerns,” according to Dr. Walter and co-authors. One grade 3 bleeding event occurred in a patient not receiving anticoagulation therapy. Twelve patients (42.9%) had grade ≥3 infection. No cases of Richter’s transformation were reported.

The study is limited by its small patient population. In addition, “the lack of a [defined] MTD with ONO/GS-4059 hinders identification of a dose to take into phase II combination studies,” Dr. Dyer told ASH Clinical News.

Source: Walter HS, Jayne S, Rule SA, et al. Long-term follow-up of patients with CLL treated with the selective Bruton’s tyrosine kinase inhibitor ONO/GS-4059. Blood. 2017 April 4. [Epub ahead of print]