N Engl J Med 2023 Jul 6
Pirtobrutinib after a Covalent BTK Inhibitor in Chronic Lymphocytic Leukemia.
Abstract
Background
Patients with chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL) have poor outcomes after the failure of covalent Bruton's tyrosine kinase (BTK) inhibitor treatment, and new therapeutic options are needed. Pirtobrutinib, a highly selective, noncovalent (reversible) BTK inhibitor, was designed to reestablish BTK inhibition.
Methods
We conducted a phase 1-2 trial in which patients with relapsed or refractory B-cell cancers received pirtobrutinib. Here, we report efficacy results among patients with CLL or SLL who had previously received a BTK inhibitor as well as safety results among all the patients with CLL or SLL. The primary end point was an overall response (partial response or better) as assessed by independent review. Secondary end points included progression-free survival and safety.
Results
A total of 317 patients with CLL or SLL received pirtobrutinib, including 247 who had previously received a BTK inhibitor. Among these 247 patients, the median number of previous lines of therapy was 3 (range, 1 to 11), and 100 patients (40.5%) had also received a B-cell lymphoma 2 (BCL2) inhibitor such as venetoclax. The percentage of patients with an overall response to pirtobrutinib was 73.3% (95% confidence interval [CI], 67.3 to 78.7), and the percentage was 82.2% (95% CI, 76.8 to 86.7) when partial response with lymphocytosis was included. The median progression-free survival was 19.6 months (95% CI, 16.9 to 22.1). Among all 317 patients with CLL or SLL who received pirtobrutinib, the most common adverse events were infections (in 71.0%), bleeding (in 42.6%), and neutropenia (in 32.5%). At a median duration of treatment of 16.5 months (range, 0.2 to 39.9), some adverse events that are typically associated with BTK inhibitors occurred relatively infrequently, including hypertension (in 14.2% of patients), atrial fibrillation or flutter (in 3.8%), and major hemorrhage (in 2.2%). Only 9 of 317 patients (2.8%) discontinued pirtobrutinib owing to a treatment-related adverse event.
Conclusions
In this trial, pirtobrutinib showed efficacy in patients with heavily pretreated CLL or SLL who had received a covalent BTK inhibitor. The most common adverse events were infections, bleeding, and neutropenia. (Funded by Loxo Oncology; BRUIN ClinicalTrials.gov number, NCT03740529.).
Related Questions
Does tolerance of prior BTKi therapy or specific agent used (e.g., ibrutinib, acalabrutinib) influence your starting dose of pirtobrutinib?
Not really. I generally start pirtobrutinib at the standard dose of 200 mg daily.
How does pirtobrutinib compare to other available therapies for relapsed/refractory CLL after BTK inhibitor treatment, particularly in terms of efficacy and tolerability?
BRUIN trial enrolled patients with a median of 3 prior lines of treatment. The response rate with pirtobrutinib is close to 80%. However, overall PFS is about 1.5-2 years. So, most patients will eventually relapse after pirtobrutinib.It is possible that the use of pirtobrutinib in earlier lines of t...
What post-protocol therapies did patients on the BRUIN trial in CLL receive, and how did these therapies impact outcomes?
The patients with CLL enrolled in the BRUIN study were heavily pre-treated with a median number of 3 prior therapies. All the patients in the BRUIN study had prior exposure to covalent BTK inhibitors and 40% of them also had been treated with a BCL2 inhibitor. As expected for patients offered a phas...
How do CLL patients with downstream treatment-resistant mutations such as PLCG2 respond to pirtobrutinib?
Although BTK/PLCG2 mutations are present in patients with CLL relapsing on covalent BTK inhibitors, more than one-third of them DO NOT harbor such mutations even after high-sensitivity analyses. Additional genetic mechanisms, in particular aberrant activation of the BcR and NF-κB pathways, may be re...
Do complex cytogenetics have any therapeutic or prognostic relevance in CLL?
In this patient, the finding of a TP53 mutation trumps all, including complex karyotype. In the absence of TP53 mutation or deletion of 17p13.1 (the TP53 locus) on FISH, complex karyotype of 5 or greater abnormalities is generally associated with shorter time to treatment and PFS on both chemoimmuno...
How do you approach treatment for a fit patient with unmutated CLL who has progressed after BTKi and venetoclax containing regimens in the first and second line?
Original answer: February 10, 2023 This is a tough situation and we are seeing increasing number of patients who have failed both BTKi and BCL2i. Clinical trial enrollment with non covalent BTKi, or other novel strategies including CAR T cell therapy should be considered. PI3K inhibitors are also ap...