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Dr. Lindsey Roeker of MSKCC, NYC, NY presented results at 2021 European Hematology Association Virtual Congress, (EHA 2021).
The tightly covalently binding BTK inhibitors (BTKi) such as ibrutinib and acalabrutinib have improved outcome in chronic lymphocytic leukemia or CLL by blocking BTK and thus, turning off the B-cell receptor (BCR) signaling that the cancer cells need for their survival. But the development of resistance and discontinuation for adverse events can lead to treatment failure. Moreover, pharmacological liabilities of these agents such as low oral bioavailability (how much of. the drug taken by mouth can be absorbed and used by the body or a short half-life can lead to suboptimal BTK target coverage. This could ultimately result in acquired resistance in some patients (pts). To address these limitations, pirtobrutinib (LOXO-305), a highly selective, non-covalent BTKi that inhibits both wild type (WT) where the binding site for the BTK inhibitor is unchanged or in its “wild form” or “wild type”, and where there is C481-mutated BTK, the mutation of the binding sites that leads to ibrutinib and acalabrutinib no longer being able to covalently (irreversibly) bind and block BTK and therefore not turning of the BCR signaling and ultimately, not controlling the cancer.
BRUIN is a multicenter phase 1/2 trial for patients with advanced B-cell malignancies who have received >2 prior therapies including CLL/SLL.
- 170 CLL/SLL patients were treated on 7 dose levels (25-300mg daily or QD). The dose chosen for future trials was 200 mg QD.
- Median age was 69 (range 36-84) years.
- Median number of prior lines of therapies was three.
- 86% had received a prior BTKi, and 67% an anti-CD20 antibody, chemotherapy, and BTKi. 21% had received a PI3K inhibitor and 34% venetoclax.
- At enrollment, high risk features such as de(17p) were present in 25% (20/81), TP53 mutation in 30% (27/91), and unmutated IGHV in 88% (71/81).
- Common adverse events were fatigue (20%), diarrhea (17%), and contusion (13%).
- At the cutoff date, 150 CLL/SLL pts remained on therapy and 139 were efficacy evaluable (121 BTKi-treated). Median follow-up was 6 months (range 0.6-17.8+) for efficacy evaluable pts.
- The overall response rate (ORR) was 63% with 69 patient remissions (PRs), and 45 stable disease (SDs), 1 progressive disease (PD), and 5 discontinued prior to first response assessment.
- Responses deepened over time; among pts with at least 10 months of follow-up (n=29), the ORR was 86%. ORR was not influenced by the reason for prior BTKi discontinuation (i.e. progression vs intolerance), or other classes of prior therapy received (including a covalent BTK and a BCL2 inhibitor).
- Of the 88 pts who responded, all except 5 remain on therapy (4 progressed, and 1 achieved a PR and electively discontinued). The longest followed responding patient continues on treatment for 17.8+ months.
Pirtobrutinib (Loxo-305) was well tolerated and is an effective option for hard-to-treat patients who have failed other BTK inhibitors such as ibrutinib, or acalabrutinib, and/or venetoclax. Larger studies will be needed to sort out where it will eventually fit into the treatment paradigm, but I have no doubts it will be an important treatment option for CLL patients in the future.
Here is the link to the actual EHA abstract.
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Stay strong. We are all in this together.
Brian Koffman MDCM (retired) MS Ed
Co-Founder, Executive VP and Chief Medical Officer
CLL Society, Inc.