BGB-3111 Response Rate Nears 100% in CLL/SLL

Constantine S. Tam, MBBS

Treatment with the BTK inhibitor BGB-3111 had an objective response rate (ORR) of 96% for patients with chronic lymphocytic leukemia (CLL) and small lymphocytic leukemia (SLL), according to findings from a phase I study presented at the 2016 ASH Annual Meeting.

The ORR with BGB-3111 consisted entirely of partial responses (PRs; 67%) and PRs with lymphocytosis (28%). There were no complete responses at the time of the analysis. In those with high-risk molecular characteristics (del17p and/or del11q; n = 17), the ORR was 100%. Additionally, treatment with the agent was well tolerated, despite higher selectivity of targets thought to induce greater adverse events (AEs), such as TEC.

"No patients had progressive disease or Richter transformation to date. With limited follow-up, efficacy appears independent of molecular risk features," said lead investigator Constantine S. Tam, MBBS, Peter MacCallum Cancer Centre, Melbourne, Australia. “Late-stage clinical trials will reveal whether BGB-3111’s excellent tolerability and high target occupancy will translate into improvements in disease control, rates of drug resistance, and rates of treatment-limiting adverse events.”

BGB-3111 has similar BTK selectivity as the already approved agent ibrutinib (Imbruvica); however, the agent is more selective for EGFR, ITK, JAK3, HER2, and TEC. In plasma studies conducted on peripheral blood and lymph nodes, the optimal dose, based on BTK occupancy, was defined 160 mg twice daily (P = .002).

"We think this drug is differentiated by being a highly selective and orally bioavailable BTK inhibitor. BGB-3111 achieves high plasma concentrations and complete BTK occupancy not only in the blood but across all tissue compartments," said Tam. "This is probably the best BTK inhibition that we can get with drug therapy."

In the phase I dose escalation study, 66 patients with CLL/SLL received BGB-3111 at escalating doses starting at 40 mg daily to 160 mg twice daily. The analysis included 46 patients with at least 12 week of follow-up. The median duration of follow-up in the study was 8.6 months.

The median age of patients in the trial was 67 years (range, 24-79) and the majority of patients had an ECOG performance status of 1 (59%). The median number of prior therapies was 2 (range, 1-6) and 27% were refractory to their last prior therapy. Nine patients were treatment-naive. Molecular risk factors included 17p deletions/TP53 mutations (18%), 11q deletion (35%), and IGHV unmutated (75%).

The most common all-grade adverse events (AEs) were contusion/petechiae/purpura (48%), upper respiratory tract infection (33%), fatigue (28%), cough (20%), diarrhea (20%), headache (20%), muscle spasms (17%), nausea (15%), arthralgia (13%), dizziness (11%), constipation (11%), neutropenia (11%), and rash (11%).

Grade ≥3 AEs were experienced by 35% of patients, with 22% having serious AEs. Toxicity led to treatment discontinuation for just 1 patient (grade 2 pleural effusion). The most common grade 3/4 AEs were neutropenia (9%), contusion/petechiae/purpura (2%), serious hemorrhage (2%), and atrial fibrillation (2%). AEs related to BGB-3111 were neutropenia (n = 3), atrial fibrillation (n = 1), and purpura (n = 1).

"By the time we conducted this trial, we were highly aware of the risk of bruising and bleeding with these inhibitors. Patients were questioned at every visit about bruising and bleeding," said Tam. "Despite the high exposure and BTK occupancy, there was only one AE-related treatment discontinuation to date.”

BGB-3111 is currently under exploration in 3 phase I clinical trials. These studies are focused on establishing the safety and efficacy of the agent for patients with B-cell lymphoid malignancies as a single agent and in combinations. The agent is being combined with obinutuzumab (NCT02569476) and BGB-A317, an early-stage PD-1 inhibitor (NCT02795182). Further studies are planned to compared the agent directly with ibrutinib, Tam concluded.

Tam CS, Opat S, Cull G, et al. Twice Daily Dosing with the Highly Specific BTK Inhibitor, Bgb-3111, Achieves Complete and Continuous BTK Occupancy in Lymph Nodes, and Is Associated with Durable Responses in Patients (pts) with Chronic Lymphocytic Leukemia (CLL)/Small Lymphocytic Lymphoma (SLL). Presented at: 58th ASH Annual Meeting and Exposition; San Diego, California; December 2-6, 2016. Abstract 642.

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BGB-3111 induced at least a 50% reduction in tumor size in the lymph nodes for almost all patients, with 8 having a 100% reduction in lymphadenopathy. One patient had stable disease, with a 40% reduction in tumor size. At the time of the analysis, all patients remained alive and progression-free with marked improvements in hemoglobin and platelet counts for patients who were thrombocytopenic (n = 13) and anemic (n = 4).