Micrograph showing CLL
Long-term follow-up of a phase 1 study suggests the BTK inhibitor ONO/GS-4059 can stave off progression in patients with relapsed or refractory chronic lymphocytic leukemia (CLL).
Roughly 60% of the patients studied were progression-free and still taking ONO/GS-4059 at last follow-up, with the longest time on treatment exceeding 3 years.
In addition, researchers said the extended follow-up revealed no new safety concerns, and the maximum tolerated dose of ONO/GS-4059 has not been reached.
Martin Dyer, DPhil, of the University of Leicester in the UK, and his colleagues reported these results in Blood.
The research was funded by Gilead Sciences, Inc., and ONO Pharmaceuticals helped with data analysis.
The study enrolled 90 patients with relapsed or refractory B-cell malignancies, 28 of whom had CLL. Dr Dyer and his colleagues reported follow-up results in CLL patients only.
The patients’ median number of prior treatments was 4 (range, 2-9), and 11 patients were refractory to their last line of therapy. None had received prior treatment with a BTK inhibitor.
The patients received ONO/GS-4059 at varying doses, from 20 mg once daily (QD) to 600 mg QD and a twice-daily (BID) regimen of 300 mg. Six patients were also taking anticoagulant therapy while on study.
Patients were allowed to continue treatment with ONO/GS-4059 if they responded to the drug or maintained stable disease.
Initially, 25 patients were evaluable for response, and 24 of them responded to ONO/GS-4059, for an overall response rate of 96%.
At last follow-up on June 8, 2016, 17 patients were still receiving ONO/GS-4059, and all had a very good partial response.
Dr Dyer said the responses have been similar to those seen with other irreversible BTK inhibitors. Most have involved rapid and almost complete resolution of lymph node masses and rapid improvement in hematological indexes.
“It is clear . . . that the major responses occur rapidly, within the first 3 months of drug, and that, thereafter, improvement occurs at a much slower rate,” Dr Dyer said. “It will be of interest, I think, to look at the remaining patients on study to assess whether responses deepen with time on drug.”
The duration of treatment for these patients ranged from 302 days to 1160 days at last follow-up. They were receiving ONO/GS-4059 at doses ranging from 40 mg QD to 600 mg QD or 300 mg BID, and no maximum tolerated dose had been identified.
Eleven patients (39.3%) discontinued ONO/GS-4059 due to death (n=3), disease progression (n=4), adverse events (AEs, n=3), and sponsor decision due to extended drug interruption (n=1). One of the patients included in the AE group also had concurrent disease progression.
The median progression-free survival was 38.5 months, and the median overall survival was 44.9 months. The median time on study was 32.5 months.
The most common treatment-emergent AEs were bruising (35.7%), neutropenia (35.7%), anemia (32.1%), nasopharyngitis (32.1%), fall (32.1%), cough (28.6%), arthralgia (28.6%), and basal cell carcinoma (28.6%).
The most common grade 3/4 AEs included neutropenia (25%), thrombocytopenia (14.3%), lower respiratory tract infection (14.3%), and anemia (10.7%).
“Our long-term follow-up shows maintained efficacy without toxicity,” Dr Dyer said. “This study is the first report of long-term follow-up of a selective BTK inhibitor, and it is excellent news for patients. We are now doing studies of ONO/GS-4059 in combination with other precision medicines to assess whether these results can be enhanced in patients with CLL and other B-cell malignancies.”
