Pirtobrutinib produces high response rates in heavily pretreated CLL, SLL
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Key takeaways:
- Researchers reported an ORR of 73.3% with the noncovalent (reversible) BTK inhibitor among patients who progressed on a covalent BTK inhibitor.
- Patients who received pirtobrutinib had median PFS of 19.6 months.
Pirtobrutinib appeared effective among a cohort of heavily pretreated patients with chronic lymphocytic leukemia or small lymphocytic lymphoma, according to study results published in The New England Journal of Medicine.
The most common treatment-associated adverse events among the patients, who had experienced disease progression on a covalent Bruton tyrosine kinase (BTK) inhibitor, included infections, bleeding and neutropenia.
Rationale and methodology
New treatment options are needed for patients with CLL or small lymphocytic lymphoma (SLL), who often have poor outcomes after failure on covalent BTK inhibitors, according to Anthony R. Mato, MD, MSCE, associate member and director of the Chronic Lymphocytic Leukemia Program at Memorial Sloan Kettering Cancer Center, and colleagues.
The highly selective, noncovalent BTK inhibitor pirtobrutinib (Jaypirca, Eli Lilly & Co.) has been designed to reestablish BTK inhibition. FDA approved the agent for treatment of patients with relapsed or refractory mantle cell lymphoma following two lines of systemic therapy, including a BTK inhibitor, researchers wrote.
The phase 1/phase 2 BRUIN trial evaluated pirtobrutinib among 317 patients with CLL or SLL, of whom 247 (median age, 69 years; 68% men) had previously received a BTK inhibitor. Patients received a median three previous lines of therapy and 40.5% also received a B-cell lymphoma 2 inhibitor.
Overall response by independent review served as the primary endpoint. Secondary endpoints included PFS and safety.
At the time of data-cutoff, 87.4% patients received at least one dose of pirtobrutinib at the recommended phase 2 dose of 200 mg once daily.
Median duration of treatment was 16.5 months.
Findings
Efficacy results among those who previously received a BTK inhibitor showed median PFS of 19.6 months (95% CI, 16.9-22.1) and an ORR of 73.3% (95% CI, 67.3-78.7) with pirtobrutinib. The ORR increased to 82.2% (95% CI, 76.8-86.7) when including those who achieved a partial response with lymphocytosis.
Common adverse events among all 317 patients who received pirtobrutinib included infection in 71%, bleeding in 42.6% and neutropenia in 32.5%. Other adverse events common with BTK inhibitors occurred less frequently, such as hypertension (14.2%), atrial fibrillation or flutter (3.8%) and major hemorrhage (2.2%).
Discontinuation of pirtobrutinib due to a treatment-associated adverse event occurred among only 2.8% of patients.
Study limitations included the lack of an active control group and the near absence of prospective data for other modern therapies after use of BTK inhibitors, which limits direct comparisons with other available therapies.
Implications
The findings indicate that CLL and SLL tumors maintain nearly universal dependence on B-cell receptor signaling mediated by BTK, despite previous exposure to a covalent inhibitor, the researchers wrote.
“Sequential use of a covalent BTK inhibitor followed by pirtobrutinib may therefore meaningfully extend the total period of clinical benefit of targeting this critical pathway dependency,” they wrote.
Perspective
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Brian Hill, MD, PhD
Treatment of CLL has been revolutionized by the introduction of highly effective orally available agents, including BTK inhibitors. These agents irreversibly bind to the active site (C481) of the kinase, inhibiting downstream signaling.
After prolonged exposure, treatment resistance to these agents — such as ibrutinib (Imbruvica; Janssen, Pharmacyclics), acalabrutinib (Calquence; AstraZeneca) and zanubrutinib (Brukinsa; BeiGene) — can emerge, frequently in the form of point mutations in BTK.
Pirtobrutinib is a noncovalent BTK inhibitor that binds reversibly to the hydrophobic site in BTK that is distinct from C481. As shown in this study, pirtobrutinib is highly active in patients with relapsed/refractory CLL previously treated with covalent inhibitors, including both those patients who discontinued due to intolerance as well as patients who developed treatment resistance including those with BTK mutations in C481. Adverse effects generally were manageable and were noteworthy for low rates of atrial fibrillation.
Looking forward, pirtobrutinib is a welcome addition to the ever-growing armamentarium against CLL that is already benefiting patients and likely to expand.
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