Novel BTK, PI3K Inhibitors on Horizon for Relapsed CLL

Silas Inman @silasinman
Published: Saturday, Mar 19, 2016

Susan M. O’Brien, MD

Susan M. O’Brien, MD

With the onslaught of new PI3K and BTK inhibitors currently in development for patients with relapsed chronic lymphocytic leukemia (CLL), it is challenging to know which therapies are truly “next-generation” agents and which are “me too” products, according to a presentation by Susan O'Brien, MD, at the 20th Annual International Congress on Hematologic Malignancies.

Despite this ongoing hurdle, a number of therapies stand out from the pack, by offering higher efficacy or toxicity advantages. In the PI3K class, TGR-1202 has shown early signs of efficacy with a better toxicity profile compared with idelalisib (Zydelig). Additionally, the BTK inhibitor acalabrutinib (ACP-196) has shown promising early signs of activity along with impressive pharmacokinetic data.

“This is really an exploding field in CLL and B-lymphoid malignancies. There are multiple PI3K and BTK inhibitor agents in clinical trials,” said O'Brien, associate director, Clinical Science Medical Director of the Sue and Ralph Stern Center for Cancer Clinical Trials and Research, Chao Family Comprehensive Cancer Center, University of California at Irvine. “I think the big question is, are they really next-generation? There are a lot of trials now looking at those who failed BTK or PI3K inhibitors. It's interesting times.”

Novel PI3K Inhibitors

The PI3K inhibitor that is furthest along in development is duvelisib (IPI-145), explained O'Brien. Although this agent targets both PI3K delta and gamma, at the current dose under development, it primarily inhibits just the delta isoform, she noted.

In a phase I study,1 the objective response rate (ORR) with duvelisib was 57% at 25-mg twice daily. This response rate did not include partial responses (PR) with lymphocytosis, which are common with the B-cell signaling inhibitors, noted O'Brien. Once these are added, the ORR was closer to 80%, she explained.

The progression-free survival (PFS) was not reached with the 25 mg twice-daily dose of duvelisib versus 15.7 months across all doses in pretreated patients with CLL. The 24-month PFS rate at the 25 mg dose was 59%. Similar data were demonstrated in the TP53-mutated and del17p groups.

Across the study, duvelisib showed a similar toxicity profile to the already FDA-approved PI3K inhibitor idelalisib (Zydelig), said O'Brien. Across all doses, pneumonia occurred in 15 patients, with 7 discontinuing therapy as a result.

A number of studies continue to assess duvelisib in various combinations, including ofatumumab (NCT02004522), fludarabine, cyclophosphamide and rituximab (NCT02158091), and with obinutuzumab (NCT02292225) for patients with relapsed CLL. The study comparing the drug with ofatumumab is meant to support an FDA approval and is expected to complete later in 2016, according to O'Brien.

Compared with duvelisib and idelalisib, the PI3K-delta inhibitor TGR-1202 has a unique molecular structure that provides the agent with a differentiated safety profile, notably the absence of hepatic toxicity, noted O'Brien.

In a dose escalation study of 17 patients with CLL,2 the response rate in the lymph nodes with TGR-1202 was 94%. The ORR was 59%, which consisted entirely of partial responses. The median PFS with the PI3K inhibitor was 24 months.

Interestingly, with TGR-1202 there was no incidence of colitis and only 4% of patients experience AST/ALT increases, half of which were grade 3/4 events. Seven percent of patients discontinued due to adverse events (AEs). The presumed thinking is that colitis is an on-target effect of PI3K inhibition; however, these results would call this theory into question, O'Brien said.

“Discontinuations are rare, and if you look at the transaminase elevation that appears to be much less,” she said. “This looks to be very interesting, and I say stay tuned, to see what happens and see how this adjusts our thinking with the PI3K inhibitor toxicity profile.”

TGR-1202 is being explored in a number of clinical trials for patients with CLL, including in combination with ibrutinib (Imbruvica) in the relapsed setting (NCT02268851). Additionally, the combination of TGR-1202 and the CD20 inhibitor ublituximab is being compared with obinutuzumab and chlorambucil in the relapsed and frontline setting (NCT02612311). TGR-1202 plus ublituximab is also being looked at with or without ibrutinib (NCT02006485).

“There is a design for a pivotal trial, but it has not yet been announced,” O'Brien added.

Another agent in development, ACP-319 (previously AMG-319), targets the delta isoform and has shown similar findings as idelalisib. Data from this study were last presented at the 2013 ASH Annual Meeting. Acerta Pharma recently acquired the agent, and an ongoing phase I study is currently exploring ACP-319 in combination with acalabrutinib for patients with CLL (NCT02157324).

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Cancer Summaries and Commentaries™: Update from Atlanta: Advances in the Treatment of Chronic Lymphocytic LeukemiaFeb 28, 20190.5
Community Practice Connections™: 2nd Annual International Congress on Immunotherapies in Cancer™: Focus on Practice-Changing ApplicationFeb 28, 20192.0
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