Pirtobrutinib after a Covalent BTK Inhibitor in Chronic Lymphocytic Leukemia. Mato. N Engl J Med. 2023 Jul 6;389(1):33-44
In this phase 1/2 clinical trial, patients with relapsed or refractory B-cell malignancies received pirtobrutinib, a novel noncovalent Bruton tyrosine kinase inhibitor (BTKi). A total of 317 patients with CLL or SLL were treated, including 247 who had previously received a covalent BTK inhibitor. In addition, approximately 40% of patients had also received treatment with venetoclax previously. The median number of prior lines of therapy was 3 in the overall cohort. The overall response rate was 82.2%, and the median progression-free survival was 19.6 months. The most common adverse events were infections, bleeding, and neutropenia. Some of the more common toxicities with BTK inhibitors, such as hypertension, atrial fibrillation, and major hemorrhage, were observed in 14%, 3.8%, and 2.2% patients, respectively. Approximately 3% of patients discontinued pirtobrutinib due to a treatment-related adverse event. These findings established an excellent efficacy and tolerability profile of a novel non covalent Bruton tyrosine kinase inhibitor, pirtobrutinib, and the management of patients with highly relapsed and refractory CLL.
Patients with dual refractory CLL, which is those patients who have had disease progression on both a covalent BTK inhibitor as well as venetoclax, have a particularly dismal outcome with median progression-free survival of less than 24 months with any currently available treatment options. Several new therapeutic options are currently being tested in clinical trials, including novel oral compounds such as non- covalent BTK inhibitors (such as pirtobrutinib and nemtabrutinib), BTK degraders, cellular therapy such as chimeric antigen receptor therapy, and bispecific antibodies. Pirtobrutinib, a novel non-covalent BTK inhibitor, has now shown impressive efficacy in this challenging subgroup of patients with a median progression-free survival approaching 1.5 years. Importantly, there was no difference in the response rate or progression-free survival in patients regardless of the prior treatments received, and regardless of the presence or absence of mutations in BTK/PLCG2. This treatment can also salvage patients who can then potentially proceed with definitive therapy, such as an allogeneic stem cell transplantation, suggesting that it may be used as bridging therapy as well. Although this agent is not yet approved for relapsed CLL, it has been approved by the FDA for relapsed mantle cell lymphoma and is currently listed on the NCCN guidelines for patients with relapsed CLL, particularly those with dual refractory disease. An important aspect of this agent is the remarkably excellent tolerability seen with very few adverse events. Although the follow-up is short at this time, only about 3% of patients stopped treatment due to toxicity, which in a cross-trial comparison basis with other BTK inhibitors appears to be much better tolerated. There are several ongoing clinical trials using pirtobrutinib in earlier settings, including patients with relapsed CLL after one line of therapy, as well as patients with previously untreated CLL.