Pirtobrutinib Elicits Responses in Heavily Pretreated Patients With CLL, SLL

Pirtobrutinib Elicits Responses in Heavily Pretreated Patients With CLL, SLL

Pirtobrutinib (Jaypirca) demonstrated efficacy in a population of heavily pretreated patients with chronic lymphocytic leukemia (CLL) and small lymphocytic lymphoma (SLL), many of whom had undergone prior treatment with a BTK inhibitor, according to findings from the phase 1/2 BRUIN trial (NCT03740529), which were published in the New England Journal of Medicine.¹

The overall response rate (ORR) associated with pirtobrutinib (n = 247) was 73.3% (95% CI, 67.3%-78.7%), this included 4 complete responses (1.6%), 1 nodular partial response (0.4%) and 176 partial responses (71.3%). When including partial response with lymphocytosis, the ORR was 82.2% (95% CI, 76.8%-86.7%). At a median follow-up of 19.4 months, patients achieved a median progression-free survival (PFS) of 19.6 months (95% CI, 16.9-22.1).

Most patients experienced a decreased in their target lesion size (96.9%; n = 216 of 223), independent of the reason for previous treatment discontinuation. Of note, the treatment was associated with a high rate of infection (71.0%). Bleeding (42.6%) and neutropenia (32.5%) were also common adverse events (AEs).

“Pirtobrutinib showed efficacy in patients with heavily pretreated CLL or SLL who had had disease progression during previous treatment with a covalent BTK inhibitor,” Anthony R. Mato, MD, a hematologic oncologist, and director of the CLL Program at Memorial Sloan Kettering Cancer Center, and co-investigators, wrote in the study. “These findings indicate that reestablishing BTK inhibition with pirtobrutinib is a potential therapeutic option regardless of whether previous covalent BTK inhibitor therapy is discontinued owing to disease progression, toxic effects, or other reasons.”

According to the study authors, in many countries, targeted therapies such as BTK inhibitors and BCL2 inhibitors have become the standard care for patients with CLL and SLL.^2,3 However, because covalent BTK inhibitors are not curative, and because all approved covalent BTK inhibitors share the same mechanism of action, they are not effective when used in sequence for patients whose disease has developed a resistance to one of the agents. Consequently, following failure with BTK inhibition, patients face a poor prognosis.^1,4

For patients with BTK inhibitor resistance, venetoclax (Venclexta) is an agent that has shown efficacy, and is associated with a response rate range of 65% to 85% in this population. However, venetoclax is also associated with a rapid tumor lysis syndrome, and if it occurs, it can require careful dose escalation and inpatient monitoring. Moreover, among patients with BTK resistance who are heavily pretreated, the median time to subsequent treatment failure or death is less than 6 months with sequential venetoclax.⁴

To that end, the BRUIN trial sought to evaluate pirtobrutinib among pretreated patients. Pirtobrutinib is a highly selective, noncovalent BTK inhibitor intended to reactivate BTK inhibitor in this patient population.¹

The trial was conducted across 49 cancer centers in 10 different countries (Australia, France, Italy, Japan, Poland, South Korea, Sweden, Switzerland, United Kingdom, and United States). In the phase 1 portion of the trial, patients received pirtobrutinib monotherapy at doses ranging from 25 mg to 300 mg once daily in 28-day cycles. For those in the phase 2 portion, the administered dose was 200 mg once daily. Patients continued treatment until they experienced disease progression or unacceptable AEs.

Patients were enrolled between March 21, 2019, and July 29, 2022. The trial enrolled a total of 773 patients with B-cell cancers, 317 of whom had relapsed or refractory CLL/SLL. Among those 317 patients, 247 had received a BTK inhibitor. The median number of previous lines of therapy was 3 (range, 1-11). One hundred of these 247 patients had also been pretreated with a BCL2 inhibitor, such as venetoclax. Patients with controlled atrial fibrillation, and concomitant anticoagulant (excluding warfarin) and antiplatelet agents were allowed to enroll.

The trial’s primary end point was ORR. Secondary end points included ORR factoring in partial response with lymphocytosis, PFS, overall survival (OS), safety, and biomarker analysis.

The median age of participants was 69 years (range, 36-88). For 76.9% (n = 190) of patients who had discontinued BTK inhibitor therapy, disease progression was the driving cause. AEs necessitated treatment discontinuation for the remaining patients.

High-risk molecular features were common in this patient population. For those with available data 46.6% (n = 90 of 193) of patients had a del(17p) or TP53 mutation, 42% (n = 24 of 57) had a complex karyotype, and 84.8% (n = 168 of 198) had unmutated IGHV.

Among patients who had received both a BTK inhibitor and a BCL2 inhibitor (n = 100), the ORR was 70.0% (95% CI, 60.0%-78.8%). Including a partial response with lymphocytosis, the ORR was 79.0% (95% CI, 69.7%-86.5%).

Response rates, including partial response rates, were consistent across most predefined subgroups. Patients with PLCG2 mutations achieved a lower ORR at 56% (95% CI, 31-79).

In the subset of patients who had received both BTK inhibitor therapy and a BCL2 inhibitor, the median PFS was 16.8 months (95% CI, 13.2-18.7) and, among those who had been pretreated with a BTK inhibitor but not a BCL2 inhibitor, the median PFS was 22.1 months (95% CI, 19.6-27.4). In an analysis of patients who had received all 5 classes of available CLL/SLL therapy—BTK inhibitor, BCL2 inhibitor, PI3K inhibitors, chemotherapy, and anti-CD20 antibodies—the median PFS was 13.8 months (95% CI, 10.3-not estimated). Patients with del(17p) or TP53 mutations had an estimated median PFS of 16.9 months and patients with unmutated IGHV had an estimated median PFS of 18.7 months.

At a median follow-up of 22.6 months, the 12-month OS rate was 86% (95% CI, 81.0%-89.8%) of among those who received prior BTK inhibitor therapy the 18-month OS rate was 80.5% (95% CI, 74.8%-85.0%).

Regarding safety, infections and neutropenia were the most reported grade 3 or worse AEs (28.1% vs 26.8%, respectively). Neutropenia was the most frequently reported treatment-related AE of grade 3 or worse severity (14.8%).

The rate of infection was notably higher among patients with CLL/SLL (71.0%) than with other B-cell cancers (55.6%).

Sixteen patients died for reasons other than disease progression on the study. Reasons included COVID-19 and COVID-19–related pneumonia (n = 8), pneumonia or fungal pneumonia (n = 2) shock or septic shock (n = 2), and other causes (n = 4). The percentage of patients who had to reduce their dose of pirtobrutinib because of an AE was 4.7% (n = 15) and 2.8% (n = 9) needed to permanently discontinue treatment because of an AE.

The study authors acknowledged that the lack of the active control group in their study was a limitation. Moreover, because patients with CLL or SLL often received BTK inhibitors for a long duration of time, the long-term safety of pirtobrutinib needs to be evaluated. They concluded by noting that pirtobrutinib is under investigation in several ongoing clinical trials, including 4 phase 3 randomized clinical trials (NCT05023980, NCT05254743, NCT04666038, and NCT04965493), which are evaluating the agent in patients with CLL/SLL.

Editor’s Note: This research was funded by Loxo Oncology.

References

1. Mato AR, Woyach JA, Brown JR, et al. Pirtobrutinib after a covalent BTK inhibitor in chronic lymphocytic leukemia.N Engl J Med. 2023;389(1):33-44.doi:10.1056/NEJMoa2300696
2. Byrd JC, Furman RR, Coutre SE, et al. Targeting BTK with ibrutinib in relapsed chronic lymphocytic leukemia. N Engl J Med. 2013;369(1):32-42. doi:10.1056/NEJMoa1215637
3. O’Brien S, Furman RR, Coutre SE, et al. Ibrutinib as initial therapy for elderly patients with chronic lymphocytic leukaemia or small lymphocytic lymphoma: an open-label, multicentre, phase 1b/2 trial. Lancet Oncol. 2014;15(1):48-58. doi:10.1016/S1470-2045(13)70513-8
4. Lew TE, Lin VS, Cliff ER, et al. Outcomes of patients with CLL sequentially resistant to both BCL2 and BTK inhibition. Blood Adv. 2021;5(20):4054-4058. doi:10.1182/bloodadvances.2021005083