BTK Inhibitors Take Center Stage in B-Cell Lymphomas

Thirteen years ago, the K-Pop band BTS launched on to the music scene in South Korea, becoming the country’s best-selling artist with >40 million albums sold by 2023. At about the same time BTS was disrupting the music charts, Bruton tyrosine kinase inhibitors (BTKis) joined the B-cell malignancy armamentarium taking aim at chronic lymphocytic leukemia (CLL), small lymphocytic lymphoma (SLL), and mantle cell lymphoma (MCL).

Those FDA-approved covalent BTKis are ibrutinib, zanubrutinib, and acalabrutinib, all ready for action in both relapsed/refractory (RR) and/or treatment-naïve settings in various B-cell lymphoma subtypes.

"However, most patients receiving covalent BTKi eventually experience treatment failure due the development of resistance or intolerance," explained Chan Y. Cheah, MD, MBBS, and Katherine L. Lewis, BMMS, both of Sir Charles Gairdner Hospital in Nedlands, Australia, in a 2021 Journal of Personalized Medicine review.

On the other hand, "non-covalent BTKi have key differences in their structure and mechanism of action, offering important potential strategies to improve patient outcomes due to improved tolerability and retaining efficacy when covalent BTKi have failed," they noted. The FDA recently approved pirtobrutinib in MCL. Other non-covalent agents that have been tested, or in development, are fenebrutinib, vecabrutinib, and nemtabrutinib/MK-1026.

Covalent BTKi

Currently approved BTKis have different characteristics and pharmacological properties even though they are in the same drug class, explained Matt Shirley, PhD, of Springer Nature in Aukland, in a 2022 Targeted Oncology review. These include the mode of binding, binding site, half life, and metabolism. Prior to January 2023, covalent BTK inhibitors dominated the class and all were irreversible, acting "through the formation of a covalent bond with a cysteine residue (Cys-481) within the BTK active site, resulting in potent and sustained inhibition of BTK enzymatic activity," he said.

Ibrutinib is a first-in-class BTKi that was initially FDA approved for previously treated CLL. Since then, the agent has racked up nearly a dozen FDA approvals, including as therapy for CLL with a deletion in chromosome 17 (17p deletion); as front-line treatment for CLL; and in combination with rituximab for treatment-naïve CLL/SLL or obinutuzumab in the first-line setting. Various trials that made the case for ibrutinib in these myriad settings included RESONATE and its eight-year follow-up data, and the E1912 study.

Zanubrutinib won FDA approval in CLL/SLL in 2023, based on the SEQUOIA study, which pitted the agent against bendamustine-rituximab, and in ALPINE where it went up against ibrutinib.

Finally, acalabrutinib nabbed its approval in CLL/SLL thanks to ELEVATE-TN and ASCEND, while tirabrutinib and orelabrutinib are in trials.

In MCL, relevant trials include:

• Ibrutinib: PCYC-1104, SPARK, RAY.
• Zanubrutinib: Phase II trial relapsed/refractory (RR) disease.
• Acalabrutinib: ACE-LY-004; ongoing CARAMEL; ongoing trial as add-on to chemotherapy.
• Tirabrutinib: Long-term follow-up study; Phase I Japanese study.
• Orelabrutinib: Phase I/II trial; FDA breakthrough therapy in RR.

Of course, these agents would not be worthy of the spotlight if they didn’t offer meaningful outcomes. For instance, in RESONATE, the six-month progression-free survival (PFS) was 88% and the seven-year overall survival (OS) was 78% with ibrutinib. In SEQUOIA, median PFS was not reached at about 26 months of follow-up with zanubrutinib. In ELEVATE-TN, again, median investigator-assessed PFS was not reached in patients who got acalabrutinib.

But adverse events (AEs) were an issue, most notably atrial fibrillation (AFib), hypertension (HTN), and hemorrhage. In RESONATE, grade ≥3 AFib occurred in 3% of ibrutinib-treated patients, while in ELEVATE-TN, grade ≥3 HTN happened in 2%, as did grade ≥3 bleeding events, with acalabrutinib.

In a 2021 Frontiers in Oncology review, Susan M. O’Brien, MD, of the University of California Irvine, and co-authors, noted that "[d]ata suggest that BTK inhibitors increase the risk of bleeding by impairing collagen-induced platelet activation, akin to the effects of aspirin. Inhibition of Src-kinases is suggested to be associated with bleeding. Acalabrutinib has less inhibitory potential with respect to Src-family kinases compared with that seen with ibrutinib…in our experience, the risk for a major bleeding event is equal for both acalabrutinib and ibrutinib."

As for AFib, David Milan, MD, of the Leducq Foundation in Boston, and co-authors reported that ibrutinib-mediated AFib was most likely attributable to inhibition of C-Terminal Src Kinase (Csk). In their animal model study, they found that "[c]ardiac-specific Csk knockout in mice led to increased [AFib]," and that "four weeks of ibrutinib resulted in "inducible [AFib]…This effect was reproduced in mice lacking [BTK], but not in mice treated with 4 weeks of acalabrutinib," they wrote in Circulation in 2022.

For HTN, Daniel Addison, MD, of The Ohio State University Wexner Medical Center in Columbus, and co-authors, explained in a 2019 Blood article that [development of new or worsened HTN after ibrutinib initiation associates with a more than twofold increased risk of other cardiac events," and that among patients with B-cell malignancies who did not have preceding HTN, being on the agent resulted in >17% developed high-grade HTN (BP >160/100 mm Hg).

Non-Covalent BTKi

Cheah and Lewis explained that "[n]on-covalent BTKi exert their inhibition of BTK by different mechanisms to covalent BTKi. They do not act by binding to the C481 site on BTK, and therefore offer a potential alternative therapeutic option to patients with B-cell malignancies than covalent BTKi, including those who have developed acquired resistance due to BTK C481 mutations following prior therapy with a covalent BTKi."

So far, the big success story among non-covalent BTKis has been for pirtobrutinib. It was tested in the phase I/II BRUIN trial in patients with RR CLL/SLL that did not response to a covalent BTKi, and treatment led to a PFS of 19.6 months. Notably, the incidences of AFib, major hemorrhage, and HTN were low as compared with covalent BTKi.

In MCL, pirobrutinib is for patients with relapsed/refractory (RR) MCL who have gotten at least two lines of systemic therapy, including a covalent BTKi. Again, in the phase I/II BRUIN trial, the overall response rate came in at 52% and there were no instances of grade 3 AFib, although there was one case of hemorrhage.

Two other agents failed to find their starring roles in B-cell malignancies: "Fenebrutinib and vecabrutinib showed acceptable tolerability in phase I studies, but were withdrawn from development…Vecabrutinib was withdrawn due to insufficient evidence of activity limiting its advancement to a phase II study " explained Jennifer R. Brown, MD, PhD, and Inhye Ahn, MD, both of Dana-Farber Cancer Center in Boston, in a 2021 Frontiers in Immunology review.

Newcomers nemtabrutinib/MK-1026 and CG-806 may be able to fill the role vacated by those agents. Nemtabrutinib/MK-1026, which is a noncovalent, competitive inhibitor of both wild type and C4815 mutations, of note since acquired BTKi resistance is commonly associated with BTK C4815 mutations.

Nemtabrutinib/MK-1026 is auditioning in a dose-escalation phase I/II trial of pre-treated patients with RR CLL/SLL, with or without a documented BTK mutation on C481.

Another trial of the novel non-covalent BTKi nemtabrutinib/MK-1026— BELLWAVE-003—is an open-label phase II study looking at the safety and efficacy of nemtabrutinib in patients with R/R B-cell malignancies. This tw0-part trial, which was reported at ASCO 2023, includes dose escalation/confirmation in part 1 and cohort expansion in part 2, according to Guilherme Fleury Perini, MD of Hospital Israelita Albert Einstein in Sãn Paulo, Brazil and colleagues. In this ongoing trial, the primary endpoints for part 1 are safety and tolerability and for part 2 the primary endpoint is objective response rate.

CG-806 is also in an early-phase trial in CLL/SLL (estimated study completion date March 2024), with data from the phase Ia/b portion were presented at the 2020 European Hematology Association meeting. The oral FLT3/BTK cluster selective kinase inhibitor was well-tolerated at multiple doses with no dose-limiting toxicities or serious AEs, according to the developer.

In a 2022 Blood and Lymphatic Cancer: Targets and Therapy review, Shuo Ma, MD, PhD, and Frédérique St-Pierre, MD, both of Northwestern University in Chicago, said that more "data will be necessary to confirm long-term efficacy and safety, however there is good initial evidence that novel non-covalent agents may represent an important therapeutic option in patients who develop resistance to covalent BTK inhibitors."

Cheah and Lewis reported relationships with, and/or support from, Roche, Janssen, MSD, Gilead, Ascentage Pharma, Beigene, AstraZeneca, Loxo/Lilly, TG therapeuticsm, Celgene, AbbVie, TG Therapeutics.

O’Brien reported relationships with, and/or support from, Amgen, Astellas, Celgene, GlaxoSmithKline, Janssen Oncology, Aptose Biosciences, Vaniam Group, AbbVie Alexion, Kite Pharma, Regeneron, Acerta Pharma, Gilead, Pharmacyclics, TG Therapeutics, Pfizer, and Sunesis. Co-authors reported relationships with, and/or support from, multiple entities.

Brown reported relationships with, and/or support from, the National Cancer Institute, AbbVie, Acerta, Astra-Zeneca, Beigene, Catapult, Dynamo Therapeutics, Eli Lilly, Genentech/Roche, Juno/Celgene/Bristol Myers Squibb, Kite, Loxo, MEI Pharma, Nextcea, Novartis, Pfizer, Pharmacyclics, Rigel, Sunesis, TG Therapeutics, Gilead, Loxo, SPARC, Verastem, and Invectys. Ahn reported support from an American Society of Hematology Scholar Award.

Ma reported relationships with AbbVie, AstraZeneca, BeiGene, Janssen, Juno, Loxo, Pharmacyclics, TG Therapeutics, and Genentech. St-Pierre reported no relationships relevant to the contents of this paper to disclose.

BELLWAVE-003 was sponsored by Merck, Sharp & Doehme Corp, a subsidiary of Merck & Co., Inc.

Perini reported honoraria from Abbvie, AstraZeneca, Janssen, MSD, Roche and Takeda; consulting or advisory payments from Abbvie, AstraZeneca, Janssen, MSD, Roche, and Takeda; speakers bureau fees from Abbvie, AstraZeneca, Janssend, MSD, and Roche. He also received research funding from AstraZeneca, Janssen, Kartos Therapeutics and MSD, and travel expenses from Abbvie, AstraZeneca, Janssen, MSD, and Roche.

Lewis KL, Cheah CY "Non-covalent BTK inhibitors—The new BTKids on the block for B-cell malignancies" J Pers Med 2021; 11: 764 DOI: 10.3390/jpm11080764.

O’Brien SM, et al "Monitoring and managing BTK inhibitor treatment-related adverse events in clinical practice" Front Oncol 2021; 11: 720704 DOI: 10.3389/fonc.2021.720704.

Ahn IE, Brown JR "Targeting Bruton’s tyrosine kinase in CLL" Front Immunol 2023; DOI: 10.3389/fimmu.2021.687458.

St-Pierre F, Ma S "Use of BTK inhibitors in chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL): A practical guidance" Blood Lymphat Cancer 2022; 12: 81-98 DOI: 10.2147/BLCTT.S326627.

Perini GF, et al "BELLWAVE-003: A phase 2 dose escalation, confirmation, and cohort expansion study of nemtabrutinib in hematologic malignancies." Journal of Clinical Oncology 2023; 41:16_suppl.