Novel BTK, PI3K Inhibitors on Horizon for Relapsed CLL

Targeted Therapies in OncologyApril 2016
Volume 5
Issue 3

With nearly a dozen new PI3K and BTK inhibitors currently in development for patients with relapsed chronic lymphocytic leukemia it is challenging to know which therapies are truly "next-generation" agents and which are "me too" products.

Susan O'Brien, MD

With nearly a dozen 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 the20th AnnualInternational 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 promising efficacy with a superior 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 and a better safety profile compared with ibrutinib (Imbruvica).

“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,1the 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 theTP53-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 next-generation PI3K-delta inhibitor TGR-1202 has a unique molecule 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,2the 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 were no incidences of colitis and only 4% of patients experienced an AST/ALT increase, 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 to 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 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).

“This is an interesting study with both a PI3K inhibitor and a BTK inhibitor for patients with relapsed CLL,” noted O'Brien.

BTK Inhibitors in Development

The early phase BTK inhibitor ONO-4059 demonstrated promising signs of clinical efficacy in 2014; however, further data on this agent have not yet been reported, noted O'Brien. The ORR with ONO-4059 was 84%, including ORRs of 89% in del17p patients and 92% in a refractory population.3

In December 2014, Gilead acquired exclusive rights to ONO-4059 for the treatment of B-cell malignancies and other disease. After the acquisition, Gilead renamed the drug GS-4059 and is now exploring the agent in combination with idelalisib or the SYK inhibitor entospletinib for patients with relapsed B-cell malignancies (NCT02457598).

“Entospletinib is very well tolerated but if you look at the data the response rates are 30% to 40%, so not as effective as BTK or PI3K inhibitors in CLL,” said O'Brien.

The second-generation BTK inhibitor acalabrutinib has shown promising early signs of activity, including pharmacokinetic studies that suggest the agent is five times more potent than ibrutinib. This added strength does not only apply to BTK but also other kinases, including Tec, which is thought to mediate certain AEs.

“One of the potential benefits of this is that if we think some of the toxicity related to ibrutinib is from the binding to these other kinases. What you would hope is that you would have some of these toxicities being much less likely to be seen with acalabrutinib,” said O'Brien. “The other thing that might be potentially very favorable with this drug is that it does not inhibit platelet mediated thrombosis, which we know that ibrutinib does, and is one of the reasons for the bruising.”

In data from a phase I/II 60-patient study,4the ORR with acalabrutinib was 95%. In the del17p population, the ORR was 100%. The median PFS was 14.3 months, with 1 fatal progression and 1 disease progression.

There were no episodes of atrial fibrillation or major bleeding events. Two percent of patients had grade 4 febrile neutropenia, and serious AEs consisted of pneumonia (10%), autoimmune hemolytic anemia (3%), and pyrexia (3%).

Following the early demonstration of efficacy and tolerability, a number of studies were initiated to explored acalabrutinib. The agent is being looked at alone or in combination with obinutuzumab versus chlorambucil and obinutuzumab (NCT02475681). The pivotal study for this agent will compare acalabrutinib directly with ibrutinib for high-risk patients with relapsed CLL (NCT02477696).

“I would encourage you to put your patients on this trial, because one nice thing is that ibrutinib is provided for free,” said O'Brien. “Here, even if they get randomized to the 'control' arm, they are still getting a very good drug for free.”

Acalabrutinib is also being explored in combination with the PD-1 inhibitor pembrolizumab (Keytruda) across CLL, multiple myeloma, and other hematologic malignancies (NCT02362035). The agent is also being explored as monotherapy across CLL treatment settings (NCT02337829).

Another early phase BTK inhibitor in development, BGB-3111, has shown early signs of activity and tolerability. In a phase I study of 14 patients with CLL,5the response rate was 93%. The AEs were similar to expectations, including bruising, petechiae, and contusion.

“In every BTK trial, some of these people were 75 or 80 years old, we all know when you get older your skin thins. Every patient has bruising. How much is drug-related, remains unclear,” said O'Brien. “These data were presented very early, in fact, there is no data for durability of these responses, and this study is actually still ongoing and this is the only study for this drug right now.”

A great deal of research still needs to be conducted before this new wave of BTK and PI3K inhibitors can be labeled either next-generation or "me too" agents, said O'Brien. A traditional next-generation agent will still be effective after a first-generation therapy has failed, she noted. Some of the benefits of these agents might be better efficacy and less toxicity, but it remains too soon to draw conclusions.


  1. O'Brien S, Patel M, Kahl BS, et al. Duvelisib (IPI-145), a PI3K-δ,γ Inhibitor, Is Clinically Active in Patients with Relapsed/Refractory Chronic Lymphocytic Leukemia. Presented at: the 56th Annual Meeting of the American Society of Hematology; December 6-9, 2014; San Francisco, California. Abstract 3334.
  2. O'Connor OA, Flinn IW, Patel MR, et al. TGR-1202, a Novel Once Daily PI3K-Delta Inhibitor, Demonstrates Clinical Activity with a Favorable Safety Profile in Patients with CLL and B-Cell Lymphoma. Presented at: 57th American Society of Hematology Annual Meeting; Orlando, Florida; December 5-8, 2015. Abstract 4154.
  3. Fegan C, Bagshawe J, Salles G, et al. A Phase I Study of the Oral Btk Inhibitor ONO-4059 in Patients with Relapsed/Refractory and High Risk Chronic Lymphocytic Leukaemia (CLL). Presented at: 19th Congress of the European Hematology Association; Milan, Italy; June 12-15, 2014. Abstract S705
  4. Byrd JC, Harrington B, O’Brien S, et al. Acalabrutinib (ACP-196) in relapsed chronic lymphocytic leukemia [published online December 7, 2015].N Engl J Med. doi:10.1056/NEJMoa1509981.
  5. Tam C, Grigg AP, Opat S, et al. The BTK Inhibitor, Bgb-3111, Is Safe, Tolerable, and Highly Active in Patients with Relapsed/ Refractory B-Cell Malignancies: Initial Report of a Phase 1 First-in-Human Trial. Presented at: 57th American Society of Hematology Annual Meeting; Orlando, Florida; December 5-8, 2015. Abstract 832.
Related Videos
Yi-Bin Chen, MD, an expert on GVHD
Yi-Bin Chen, MD, an expert on GVHD
A panel of 3 experts on GVHD
A panel of 3 experts on GVHD
Andrew Kuykendall, MD, an expert on polycythemia vera
Andrew Kuykendall, MD, an expert on polycythemia vera
Andrew Kuykendall, MD, an expert on polycythemia vera
Andrew Kuykendall, MD, an expert on polycythemia vera
Related Content