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Combination Regimens Targeting Multiple Kinases: Fruitful Avenue of CLL Research?

By: Celeste L. Dixon
Posted: Monday, April 27, 2020

In the first known study of the second-generation BTK inhibitor tirabrutinib alone and in combination with either the PI3Kδ inhibitor idelalisib or the STK inhibitor entospletinib, early results regarding the safety, tolerability, and efficacy were promising in 53 adult patients with relapsed or refractory chronic lymphocytic leukemia (CLL). The phase 1b dose-escalation and dose-expansion study, conducted by Alexey V. Danilov, MD, PhD, of City of Hope National Medical Center, and colleagues, “paves the way for further investigations of concurrent targeting of multiple kinases within the BCR signaling pathway as part of…regimens poised to prolong and deepen responses and prevent emergence of resistance in CLL,” the authors wrote in Clinical Cancer Research.

Treatment with single-agent BCR pathway inhibitors infrequently (< 10%) result in complete responses, noted the team, and “persistent low-level residual disease allows the development of resistance, which can be difficult to treat.” Complete responses were scarce in this trial as well—7%, 7%, and 10% in patients receiving tirabrutinib (n = 29), tirabrutinib/idelalisib (n = 14), and tirabrutinib/entospletinib (n = 10), respectively—but the objective response rates in the cohorts were more encouraging at 83%, 93%, and 100%, respectively.

Further, the median duration of response in the tirabrutinib, tirabrutinib/idelalisib, and tirabrutinib/entosplentinib groups were not reached, 27 months, and not reached; the progression-free survival lengths were not reached, 32 months, and not reached, respectively. No maximum tolerated dose was identified, and treatment discontinuation due to adverse events was uncommon (13%), Dr. Danilov and colleagues stated.

“A potential approach to further deepen responses is to add an anti-CD20 regimen [to] the current combinations,” proposed the authors. In fact, they revealed, phase II studies of tirabrutinib/idelalisib with or without obinutuzumab and tirabrutinib/entosplentinib with or without obinutuzumab in patients with relapsed or refractory CLL are underway.

Disclosure: For full disclosures of the study authors, visit aacrjournals.org.



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