Selective Bruton’s tyrosine kinase inhibitor shows long-term safety, efficacy in CLL

ONO/GS-4059 — a selective Bruton’s tyrosine kinase inhibitor — appeared effective and well tolerated in patients with chronic lymphocytic leukemia, according to 3-year follow-up results published in Blood.

“Our long-term follow-up of previously treated patients shows maintained efficacy without toxicity,” Martin J.S. Dyer, professor of hematology/oncology at University of Leicester, said in a press release. “This study is the first report of long-term follow-up of selective Bruton’s tyrosine kinase [BTK] inhibitors in patients with CLL, and it is excellent news for patients.”

Many patients with CLL have achieved durable remissions with the BTK inhibitor ibrutinib (Imbruvica; Pharmacyclics, Janssen). However, because the kinome of ibrutinib is broad, it can lead to toxicities such as bleeding, arthralgia, diarrhea, hypertension and atrial fibrillation. Selective BTK inhibitors may have comparable efficacy but reduced toxicity as ibrutinib.

Researchers enrolled 90 patients with CLL (n = 28) or non-Hodgkin lymphoma (n = 62) in an international clinical trial from 2012 to 2015. The trial examined the efficacy of ONO/GS-4059 (ONO Pharmaceutical Co. and Gilead) — which targets BTK, a protein essential for the survival and proliferation of tumor cells — in the treatment of CLL and non-Hodgkin lymphoma that is refractory or resistant to chemotherapy.

Patients with response or stable disease continued in a long-term extension study — which included 28 patients with CLL — and received ONO/GS-4059 in doses of 20 mg to 600 mg once daily or 300 mg twice daily.

PFS and OS among patients with CLL served as primary endpoints.

Patients had received a median of four (range, 2-9) prior treatments; five were primarily fludarabine refractory and 11 were refractory to their last line of therapy. One patient received a prior PI3K inhibitor, and none had received prior BTK inhibitors. Six patients received anticoagulant therapy during the study.

As of June 8, 2016, 11 patients had discontinued treatment due to disease progression (n = 4), death (n = 3), adverse events (n = 3) and sponsor decision due to extended drug interruption (n = 1). The 17 patients who remained in the study received doses of ONO/GS-4059 ranging from 40 mg to 600 mg once daily or 300 mg twice daily; researchers did not determine a maximum-tolerated dose.

Patients demonstrated a median PFS of 38.5 months and median OS of 44.9 months.

Researchers initially observed complete or partial response in 24 patients.

Twenty-three patients experienced lymphocytosis — all of which resolved by cycle 6 — and immunoglobulin levels did not change significantly with long-term use of ONO/GS-4059.

The most common adverse events included bruising (35.7%), neutropenia (35.7%) and anemia (32.1%).

No patients experienced Richter’s transformation — an early occurrence in patients receiving ibrutinib.

Ongoing studies of ONO/GS-4059 in combination with other precision medicines will assess whether their results can be enhanced in patients with CLL and other B-cell malignancies.

“Identification of significant differences in toxicity profiles between BTK inhibitors awaits direct comparative studies,” Dyer and colleagues wrote. “However, the tolerability of ONO/GS-4059 may confer advantages, particularly in the context of combination therapies and in ibrutinib-intolerant patients.” – by Chuck Gormley

Disclosure: Gilead Sciences, Inc., funded this study. Dyer reports a consultant role with AbbVie and Roche; research funding from Gilead Sciences and ONO Pharmaceutical, and honoraria from Roche. Please see the full study for a list of all other researchers’ relevant financial disclosures.