Oncology

Chronic Lymphocytic Leukemia

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Noncovalent BTK Inhibitors: What Should Their Future Role Be in Chronic Lymphocytic Leukemia?

patient care perspectives by Susan O’Brien, MD

Overview

Noncovalent BTK inhibitors (eg, pirtobrutinib) have generated promising data in the later-line treatment of chronic lymphocytic leukemia (CLL). Pivotal registration trials of pirtobrutinib as frontline therapy are ongoing.

Expert Commentary

Susan O’Brien, MD

Professor
Division of Hematology/Oncology
Department of Medicine
University of California, Irvine
Irvine, CA

“Since, as of now, pirtobrutinib has not been used in the frontline setting, we do not know what mutations might occur without prior exposure to a covalent BTK inhibitor. But there will be a population that can be studied in regard to this question, since pivotal registration trials of pirtobrutinib as frontline therapy are ongoing.”

Susan O’Brien, MD

Of the noncovalent BTK inhibitors that are currently in development, the most exciting is pirtobrutinib, not only because of promising clinical data but also because it is the furthest along in development. Pirtobrutinib has little of the toxicity that we associate with the covalent BTK inhibitors. For example, in a safety profile that was generated from a database of all patients with B-cell cancers who were treated with pirtobrutinib, representing more than 700 patients, the rate of atrial fibrillation was similar to the background rate in patients with CLL. The improved safety profile of pirtobrutinib makes it attractive to consider before covalent BTK inhibitors; however, we would need a substantial amount of additional data before considering that approach.

We know from the BRUIN trial that patients can go from receiving a covalent BTK inhibitor to a noncovalent BTK inhibitor, and they benefit from that treatment. However, we do not know if the reverse is true, so I would be very cautious. An analysis found that patients in BRUIN who became resistant to pirtobrutinib developed BTK mutations, some of which could also render resistance to covalent BTK inhibitors. However, it is important to point out that all of those patients had already been exposed to covalent BTK inhibitors. Since, as of now, pirtobrutinib has not been used in the frontline setting, we do not know what mutations might occur without prior exposure to a covalent BTK inhibitor. But there will be a population that can be studied in regard to this question, since pivotal registration trials of pirtobrutinib as frontline therapy are ongoing. If someone is resistant to pirtobrutinib and covalent BTK inhibitors, presumably we could go to venetoclax. But losing the efficacy of covalent BTK inhibitors would be no small thing. If you look at the RESONATE-2 trial, the 7-year progression-free survival rate with frontline ibrutinib was 59%. So, these patients benefit for a really long time.

There are 2 ongoing trials that are evaluating pirtobrutinib in the frontline setting. The BRUIN CLL-313 trial is comparing pirtobrutinib with bendamustine plus rituximab in untreated patients with CLL/small lymphocytic lymphoma, and the BRUIN CLL-314 trial includes a mixture of patients with previously untreated and relapsed CLL/small lymphocytic lymphoma and will directly compare pirtobrutinib with ibrutinib. With the head-to-head comparisons, pirtobrutinib and other noncovalent BTK inhibitors may eventually receive US Food and Drug Administration approval for use in frontline settings. Would I then want to use a noncovalent BTK inhibitor before I use a covalent BTK inhibitor in previously untreated patients? With the limited current data that are available, my answer to that question is no.

References

Barr PM, Owen C, Robak T, et al. Up to 8-year follow-up from RESONATE-2: first line ibrutinib treatment for patients with chronic lymphocytic leukemia. Blood Adv. 2022;6(11):3440-3450. doi:10.1182/bloodadvances.2021006434

ClinicalTrials.gov. A study of pirtobrutinib (LOXO-305) versus bendamustine plus rituximab (BR) in untreated patients with chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma (SLL) (BRUIN CLL-313). Updated July 11, 2023. Accessed September 19, 2023. https://classic.clinicaltrials.gov/ct2/show/NCT05023980

ClinicalTrials.gov. A study of pirtobrutinib (LOXO-305) versus ibrutinib in participants with chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma (SLL) (BRUIN-CLL-314). Updated July 11, 2023. Accessed September 19, 2023. https://classic.clinicaltrials.gov/ct2/show/NCT05254743

Jurczak W, Dartigeas C, Coscia M, et al. BRUIN CLL-313: a phase 3 open-label, randomized study of pirtobrutinib vs bendamustine+rituximab in untreated patients with chronic lymphocytic leukemia/small lymphocytic lymphoma (trial in progress) [abstract PB1862]. Abstract presented at: 2022 European Hematology Association Congress; June 9-17, 2022; Vienna, Austria.

Mato AR, Woyach JA, Brown JR, et al. Efficacy of pirtobrutinib in covalent BTK-inhibitor pre-treated relapsed/refractory CLL/SLL: additional patients and extended follow-up from the phase 1/2 BRUIN study [abstract 961]. Abstract presented at: 64th American Society of Hematology Annual Meeting and Exposition; December 10-13, 2022; New Orleans, LA.

Mato AR, Woyach JA, Brown JR, et al. Pirtobrutinib after a covalent BTK inhibitor in chronic lymphocytic leukemia. N Engl J Med. 2023;389(1):33-44. doi:10.1056/NEJMoa2300696

Nakhoda S, Vistarop A, Wang YL. Resistance to Bruton tyrosine kinase inhibition in chronic lymphocytic leukaemia and non-Hodgkin lymphoma. Br J Haematol. 2023;200(2):137-149. doi:10.1111/bjh.18418

Wang E, Mi X, Thompson MC, et al. Mechanisms of resistance to noncovalent Bruton’s tyrosine kinase inhibitors. N Engl J Med. 2022;386(8):735-743. doi:10.1056/NEJMoa2114110

Woyach JA, Coombs CC, Lewis KL, et al. BRUIN CLL-314: a phase 3, open-label, randomized study of pirtobrutinib versus ibrutinib in patients with chronic lymphocytic leukemia/small lymphocytic lymphoma [abstract TPS7584]. Abstract presented at: 2023 American Society of Clinical Oncology Annual Meeting; June 2-6, 2023; Chicago, IL.

Susan O’Brien, MD

Professor
Division of Hematology/Oncology
Department of Medicine
University of California, Irvine
Irvine, CA

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