Recent Success in CLL Spurs Development of New Agents

Susan O'Brien, MD

Recent success with novel agents for chronic lymphocytic leukemia (CLL) has spurred development of more treatments in the same therapeutic classes; however, definitive advantages over the originals have yet to be established, Susan O’Brien, MD, said in a presentation at the 2016 Society of Hematologic Oncology annual meeting.

Focusing primarily on the therapeutic categories of PI3K and BTK inhibitors, O’Brien, associate director for clinical science at the Chao Comprehensive Cancer Center, acknowledged efforts to build on existing success but said the hoped-for progress and advances await definitive data.

“Are they really next-generation therapies or just ‘me too’ agents?” asked O’Brien. “Importantly, will a patient who is resistant to ibrutinib [Imbruvica] respond to any of the other BTK inhibitors?”

“Will they have greater efficacy and/or less toxicity? There is some early data to suggest that, but it is very early data,” she added. “That remains to be seen.”

Since the introduction of idelalisib (Zydelig) as the first approved PI3K inhibitor, potential competitors have emerged in the form of duvelisib (IPI-145), and TGR-1202. Similarly, the success of ibrutinib has followers in the BTK-inhibitor category that currently include ONO-4059, acalabrutinib (ACP-196), and BGB-3111.

Duvelisib targets the delta and gamma isoforms of PI3K, which are preferentially expressed by leukocytes and have mostly non-overlapping roles in B-cell, T-cell, and myeloid-cell function.

In a 55-patient study, treatment with duvelisib resulted in an overall response rate of 57%, including 1 complete response. Among patients with TP53 mutations or 17p deletion, the response rate was 48%, including the only complete response. Median progression-free survival (PFS) was 15.7 months for all doses studied, but was not reached at the pivotal-trial dose of 25 mg twice daily.

At the 25-mg dose, two-thirds of patients remained progression-free at 12 months and 59% at 24 months, said O’Brien.

“In many of the trials that we discuss, the PR-Ls (partial responses with lymphocytosis) are counted in the overall response rate. That was not done in this trial. Although the response rates in this trial are inferior to those with ibrutinib or idelalisib, if you added in the PR-Ls, you would be in the same ballpark in terms of response.”

The most frequently reported serious adverse events (AEs) were pneumonia in 15 patients, febrile neutropenia in 8, and diarrhea and fatigue in 3 patients each. Overall, 19 patients discontinued treatment because of AEs, 7 because of pneumonia, and 2 each because of diarrhea and stomatitis. All other discontinuations involved a single episode of an AE.

“In terms of adverse events, it’s in sort of the same spectrum as what you see with idelalisib,” said O’Brien. “However, my impression is that the incidence of these toxicities, particularly transaminitis and colitis, is lower than with idelalisib, although the numbers of patients are smaller and the duration of follow-up is shorter than with idelalisib.”

A first-in-human study of AMG-319 (a selective PI3K-delta inhibitor) involved 30 patients, who received doses ranging from 25 to 400 mg once daily. The agent was well tolerated, and antitumor activity was observed across all dose levels.

The study did not establish a maximum-tolerated dose up to 400 mg. Notable side effects consisted of late-occurring, reversible grade ≥3 colitis and 1 case of grade 2 QT-interval prolongation without associated sequelae.

TGR-1202 is a next-generation PI3K-delta inhibitor, which has a unique chemical structure that contributes to favorable pharmacokinetics permitting once-daily dosing. The agent also has an absence of hepatic toxicity, which distinguishes it from other PI3K-delta inhibitors, said O’Brien.

In a study involving 63 patients with CLL and various forms of non-Hodgkin lymphoma, TGR-1202 has demonstrated the greatest activity in CLL, achieving reductions in disease burden ranging from 35%-40% to 100%. No patient with CLL exhibited disease progression during treatment with the agent. The CLL subgroup had a median PFS of 23.98 months. Patients with NHL had a median PFS of 27.3 months.

Acalabrutinib has potency against BTK that is more than 5 times greater than that of ibrutinib. In a phase I/II study involving 61 patients with relapsed CLL, the agent achieved an overall response rate of 95%, including 100% in patients with 17p deletion. Responses were observed across the spectrum of doses evaluated, ranging from 100 to 400 mg daily, as well as a group that received 100 mg twice daily.

After a median follow-up of 14.3 months, there were no episodes of atrial fibrillation or major bleeding. PFS was very favorable, said O’Brien, as all but 2 patients remained progression-free.

BGB-3111 is another BTK inhibitor that has demonstrated near-complete BTK occupancy in peripheral blood mononuclear cells, as well as good occupancy in lymph nodes. Some evidence has suggested that a factor limiting response to ibrutinib is bulky nodes, said O’Brien.

BGB-3111 was designed with the objective of offering better safety as compared with ibrutinib. In a phase I first-in-human trial involving patients with relapsed or refractory B-cell malignancies, the only grade 3/4 AE was neutropenia, occurring in 15% of patients. The most common AEs, irrespective of grade, were petechiae/contusion/bruising (33%), upper respiratory tract infection (28%), constipation (23%), diarrhea (21%), cough (21%), and rash (15%).

BGB-3111 demonstrated encouraging activity in the trial, achieving objective responses in 29 of 39 patients with various hematologic malignancies, including 13 of 14 patients with relapsed CLL.

With respect to BTK inhibitors, ONO-4059 was evaluated in a phase I trial involving 25 patients with relapsed or refractory CLL. Overall, 21 of 25 (84%) patients achieved objective responses, including 2 complete responses. The overall response rate included 8 of 9 patients with 17p deletion and 11 of 12 patients with treatment-refractory disease. No additional data have been reported since the rights to the agent were acquired by Gilead Sciences, said O’Brien.