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Pirtobrutinib Delays Progression in CLL Already Treated With a BTK Inhibitor

— But no overall survival benefit seen in confirmatory trial

MedpageToday

SAN DIEGO -- Pirtobrutinib (Jaypirca) delayed disease progression versus other available options in patients with chronic lymphocytic leukemia (CLL) who had previously received a covalent Bruton's tyrosine kinase (BTK) inhibitor, a phase III study showed.

Median progression-free survival (PFS) reached 14 months with pirtobrutinib, an oral non-covalent BTK inhibitor, as compared with 8.7 months with investigator's choice of idelalisib (Zydelig) plus rituximab (Rituxan) or bendamustine (Bendeka, Treanda) plus rituximab (HR 0.54, 95% CI 0.39-0.75, P=0.0002), reported Jeff Sharman, MD, of Willamette Valley Cancer Institute and Research Center and U.S. Oncology Research in Eugene, Oregon.

Though the trial met its primary endpoint of PFS, no significant difference in overall survival (OS) was observed (HR 1.09, 95% CI 0.68-1.75), with the analysis "confounded by over three-quarters of subjects who crossed over to subsequent pirtobrutinib from investigator's choice," he said during a presentation at the American Society of Hematology annual meeting.

"In this high-risk population with relapsed and refractory disease and extensive prior therapy, pirtobrutinib demonstrated superior PFS and low rates of treatment discontinuation," Sharman said in his conclusion. "Patients were able to delay next therapy or death for a median of approximately 2 years, or 2.5 years among venetoclax [Venclexta]-naive subjects. Pirtobrutinib is an effective, well-tolerated agent among patients with difficult-to-treat disease and provides a clinically meaningful way to sustain BTK inhibition."

He pointed out that the study, BRUIN CLL-321, is the first phase III trial assessing the safety and efficacy among a population of patients who had all received prior treatment with a covalent BTK inhibitor such as ibrutinib (Imbruvica) or acalabrutinib (Calquence). "Long-term outcomes among patients previously treated with first- and second-generation covalent BTK inhibitors are poor and represent an underappreciated unmet medical need," said Sharman.

A highly selective, reversible BTK inhibitor, pirtobrutinib was designed to re-establish BTK inhibition. The drug late last year received accelerated approval from the FDA in CLL based on findings from the phase I/II BRUIN trial, which demonstrated deep responses with the drug, including in patients previously treated with a covalent BTK inhibitor.

"The safety profile of pirtobrutinib is really unimpeachable," Jennifer Brown, MD, PhD, of the Dana-Farber Cancer Institute in Boston, told 鶹ý via email.

"It is definitely better tolerated than our other BTK inhibitors and really our other drugs as well, which I think underscores the issue that variations in OS that are not statistically significant should not be overinterpreted by anyone -- particularly in studies with a lot of crossover, where you end up comparing patients on the same drug to each other at longer timepoints!" added Brown, who was not involved in the study.

Sharman presented sensitivity analyses with adjustment for crossover that demonstrated numerically improved OS for patients treated with pirtobrutinib, with HRs ranging from 0.77 to 0.89.

BRUIN CLL-321 serves as the confirmatory trial to support pirtobrutinib's full FDA approval, but the agency in recent times has pushed to remove some drugs' indications in cases where confirmatory trials have shown mixed signals when it comes to OS.

The international phase III trial randomized 238 adults with previously treated CLL or small lymphocytic lymphoma to either oral monotherapy with pirtobrutinib or investigator's choice of idelalisib-rituximab or bendamustine-rituximab. Patients were mostly enrolled from Europe and North America and to a lesser degree Asia and Australia.

Participants had a median age of 66-68 years, 70% were men, and over 90% had CLL histology. Most (≥90%) had an Eastern Cooperative Oncology Group (ECOG) performance status of 0-1, but patients with an ECOG score of 2 could enroll as well.

The study population had poor-prognosis disease, with 54% harboring 17p deletions and/or TP53 mutations, and over 60% with complex karyotype. They had been heavily pretreated as well, with a third having received at least four prior lines of therapy, including a BCL2 inhibitor in about 50%.

The primary endpoint was PFS as assessed by an independent review committee. The PFS benefit with pirtobrutinib was consistent against both idelalisib-rituximab and bendamustine-rituximab and among clinical subgroups, including age, sex, ECOG status, number of prior therapies, and reason for BTK inhibitor discontinuation (e.g., progression or toxicity). Similarly, said Sharman, a consistent benefit was demonstrated among the various molecular subgroups, including by TP53 mutational status, complex karyotype, and IGHV status.

Secondary endpoints showed that pirtobrutinib's PFS was consistent when assessed by investigators and also led to improvements in event-free survival (14.1 vs 7.6 months; HR 0.39, 95% CI 0.28-0.53) and time to next treatment or death (24 vs 10.9 months; HR 0.37, 95% CI 0.25-0.52).

Venetoclax-naive patients had a median time to next treatment or death of 29.5 months with pirtobrutinib versus 12.5 months with investigator's choice (HR 0.36, 95% CI 0.21-0.61), while median times among venetoclax-exposed patients were 20 and 8.7 months, respectively (HR 0.37, 95% CI 0.23-0.60).

Treatment-related grade ≥3 adverse events (AEs) were less frequent with pirtobrutinib (57.7%) than with investigator's choice (73.4%), despite longer treatment exposure with the non-covalent BTK inhibitor (15.1 months vs 7.1 months with idelalisib-rituximab and 4.7 months with bendamustine-rituximab).

Treatment discontinuation due to AEs occurred in 5.2% of the pirtobrutinib arm and 21.1% of the investigator's choice arm.

Grade ≥3 AEs of interest with pirtobrutinib included infections (29.3%), neutropenia (20.7%), anemia (11.2%), thrombocytopenia (7.8%), bleeding (3.4%), hypertension (2.6%), and atrial fibrillation (1.7%). "Notably, subjects with atrial arrhythmias were not excluded from participation and cumulative event rates remain low," said Sharman.

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    Ian Ingram is Managing Editor at 鶹ý and helps cover oncology for the site.

Disclosures

The study was funded by Eli Lilly.

Sharman disclosed relationships with AbbVie, Eli Lilly, BeiGene, AstraZeneca, Bristol Myers Squibb, Genentech, Merck, Genmab, ADC Therapeutics, TG Therapeutics, and Pharmacyclics.

Brown disclosed ties to Acerta/AstraZeneca, Pharmacyclics, Grifols Therapeutics, Gilead, Pfizer, Numab Therapeutics, Merck, Loxo/Lilly, iOnctura, Kite, InnoCare Pharma, Genentech/Roche, MEI Pharma, TG Therapeutics, UpToDate, Bristol Myers Squibb, BeiGene, Alloplex Biotherapeutics, AbbVie, Seymour, Genor Bio, and Janssen.

Primary Source

American Society of Hematology

Sharman JP "BRUIN CLL-321: Randomized phase III trial of pirtobrutinib versus idelalisib plus rituximab (IdelaR) or bendamustine plus rituximab (BR) in BTK inhibitor pretreated chronic lymphocytic leukemia/small lymphocytic lymphoma" ASH 2024; Abstract 886.