Pirtobrutinib Shows Durable Responses After Covalent BTKi Treatment in CLL/SLL

Jennifer A. Woyach, MD

Heavily pretreated patients benefited from pirtobrutinib (Jaypirca) for chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL) after prior treatment with a covalent Bruton tyrosine kinase (BTK) inhibitor, according to updated data from the phase 1/2 BRUIN study (NCT03740529) presented at the 2023 ASH Annual Meeting.¹

At a median follow-up of 30 months, pirtobrutinib elicited an objective response rate (ORR) including partial response with lymphocytosis (PR-L), of 81.6% (95% CI, 76.5%-85.9%) in this population (n = 282), including complete response (CR) rate of 1.8%, a nodular partial response (nPR) of 0.7%, a PR of 69.5%, and a PR-L of 9.6%.

The ORR achieved with the agent was approximately 80%, irrespective of prior BCL-2 inhibitor exposure. In the subset of patients who were naive to BCL-2 inhibition (n = 154), the ORR achieved with pirtobrutinib was 83.1% (95% CI, 76.2%-88.7%), which included a CR rate of 3.2%, a nPR rate of 1.3%, a PR of 70.1%, and a PR-L rate of 8.4%. In the group of patients who had prior exposure to BCL-2 inhibitors (n = 128), the agent induced an ORR of 79.7% (95% CI, 71.7%-86.3%), which was comprised of a PR rate of 68.8% and a PR-L rate of 10.9%.

At a median follow-up of 27.5 months, the median progression-free survival (PFS) with pirtobrutinib in patients who previously received covalent BTK inhibitors was 19.4 months (95% CI, 16.6-22.1). At a median follow-up of 27.6 months in the BCL-2 inhibitor–naive group, the median PFS with pirtobrutinib was 23.0 months (95% CI, 19.6-28.4). At a median follow-up of 22.2 months in the BCL-2 inhibitor–exposed group, the median PFS was 15.9 months (95% CI, 13.6-17.5).

At a median follow-up of 29.3 months in the total population of patients who previously received a covalent BTK inhibitor, the median overall survival (OS) was not evaluable (NE; 95% CI, NE-NE). At a median follow-up of 31.6 months and 27.4 months in groups of patients who were naive or exposed to BCL-2 inhibitors, respectively, the median OS was NE (95% CI, NE-NE) and NE (95% CI, 28.4-NE), respectively.

“These results suggest that continuation of BTK pathway inhibition may be an important sequencing approach to consider in the treatment of CLL/SLL,” Jennifer A. Woyach, MD, a hematologist-oncologist, professor in the Division of Hematology at The Ohio State University, and co-leader of the Leukemia Research Program at The Ohio State University Comprehensive Cancer Center, said in a presentation of the data.

Although most patients experience prolonged remission durations with covalent BTK inhibitors, most will eventually discontinue treatment because of disease progression or intolerance with subsequent progression, Woyach said. Regimens containing venetoclax (Venclexta) have often served as the next therapeutic approach in this population.

“However, now, an increasing number are refractory to both covalent BTK inhibitors as well as BCL-2 inhibitors,” Woyach noted. “For this subgroup of patients especially, there has been no standard treatment with documented efficacy.”

Pirtobrutinib is a highly selective noncovalent BTK inhibitor. The agent binds to sites distinct from Cys481, where the covalent inhibitors bind, and appears to stabilize BTK in an inactive closed configuration, Woyach said. “[This] prevents BTK activity and interferes with scaffolding interactions to support kinase-independent BTK signaling,” she added.

The trial, which utilized a 3+3 design, enrolled patients with CLL/SLL or non-Hodgkin lymphoma who were previously treated and had active disease in need of treatment. They were required to be at least 18 years of age and an ECOG performance status of 0 to 2.

In the dose-escalation portion of the trial, pirtobrutinib was evaluated at daily doses ranging from 25 mg to 300 mg, “and allowed for intrapatient dose-escalation,” Woyach noted. The dose-expansion phase evaluated the recommended phase 2 dose of 200 mg once daily.

The key end points of the research were assessing safety/tolerability, identifying the maximum-tolerated dose and recommended phase 2 dose, examining pharmacokinetics, and evaluating efficacy in the form of ORR, duration of response (DOR), PFS, and OS.

A total of 778 patients were included in the trial; of these patients, 166 had mantle cell lymphoma, 317 had CLL/SLL, and 295 had other cancers, which could have included diffuse large B-cell lymphoma, Waldenström macroglobulinemia, follicular lymphoma, marginal zone lymphoma, Richter transformation, B-cell prolymphocytic leukemia, hairy cell leukemia, primary central nervous system lymphoma, and other transformation.

Within the group of patients with CLL/SLL, 35 were naive to BTK inhibitors and 282 previously received covalent BTK inhibitors. Of those who had prior exposure to covalent BTK inhibitors, 154 did not previously receive BCL-2 inhibitors and 128 had.

The median patient age in the BCL-2–naive group was 69 years (range, 36-87) vs 68 years (range, 41-88) in the BCL-2–exposed group. Most patients were male (69% vs 67%). In terms of Rai staging in the naive group, 61% had stage 0 to II disease, 38% had III to IV disease, and 1% had missing information; in the exposed group, these percentages were 41%, 48%, and 10%, respectively. In terms of ECOG performance status in the naive group, 58% had a status of 0, 36% had a status of 1, and 6% had a status of 2; in the exposed group, 43%, 48%, and 9% of patients had a status of 0, 1, and 2, respectively.

The median number of prior lines of systemic treatment received in the naive and exposed groups were 3 (range, 1-9) and 5 (range, 1-11), respectively. Patients in these groups previously received an anti-CD20 antibody (83% vs 97%), chemotherapy (74% vs 89%), PI3K inhibitor (11% vs 42%), CAR T-cell therapy (1% vs 12%), and allogeneic stem cell transplant (1% vs 5%). In the naive group, patients discontinued prior BTK inhibitors because of disease progression, at 71% and 28%, respectively; in the exposed group, these percentages were 84% and 16%, respectively.

“Eight percent of patients had mutations in BCL-2, 39% had C481 mutations in BTK, and 7% had mutations in PLCG2,” Woyach said. “When we look at our subgroups of BCL-2 inhibitor–naïve and –exposed patients, as expected, those patients who had previously been exposed appear to be a slightly higher-risk group of patients—with a median of 5 prior therapies, 12% of those patients having received CAR T-cell therapy, and 5% an allogeneic stem cell transplant. Seventeen percent of patients previously treated with a BCL-2 inhibitor had a BCL-2 mutation.”

The ORR achieved with pirtobrutinib did not significantly vary based on age (<75 years, 81.1%; ≥75 years, 90.6%), performance status (0, 80.9%; 1, 83.9%; 2, 100.0%), Rai stage (0 to II, 80.9%; III to IV, 86.2%), number of prior therapies (≤3, 83.0%; >3, 83.3%), or reason for prior BTK inhibitor discontinuation (disease progression, 80.0%; toxicity/other, 90.7%).

“Within the BCL-2–naive cohort, there’s a trend toward a lower response rate for patients with PLCG2 mutations; this is biologically expected although the number of patients in this group is very small. No other features affect response rate within this cohort,” Woyach said. “Within the BCL-2–exposed patients, again, we’re looking at small subsets of patients, but there’s a trend toward a lower response rate for patients with PLCG2 mutations, as well as a trend toward lower response rates for IGHV-mutated patients, and higher response rates for those high-risk patients with deletion (11q) and those with TP53 alterations.”

Additional efficacy data showed in all patients who previously received covalent BTK inhibitors, the PFS rate at 6 months was 84.9%; at 12 months, 18 months, and 24 months, these rates were 67.4%, 52.8%, and 38.6%, respectively. The OS rates in this population was 92.9%, 85.6%, 79.8%, and 73.2%, respectively, at these time points.

In the BCL-2–naive group, the PFS rates at 6 months, 12 months, 18 months, and 24 months were 87.1%, 72.8%, 62.5%, and 48.3%, respectively. The OS rates in these groups were 95.4%, 90.0%, 87.3%, and 83.1%, respectively. In the BCL-2–exposed group, the 6-, 12-, 18-, and 24-month PFS rates were 82.2%, 60.7%, 39.6%, and 24.3%, respectively. The OS rates were 89.%, 80.2%, 70.7%, and 60.6%, respectively.

“Looking at our BCL-2–naive vs –exposed cohorts, we see [a] 24-month OS [rate] of 83.1% for the BCL-2 inhibitor–naive patients compared to a 60.6% 24-month OS [rate] for the BCL-2 inhibitor–exposed patients, demonstrating the availability of effective subsequent treatment options for the BCL-2 inhibitor–naive patients,” Woyach noted.

Pirtobrutinib was found to be well tolerated. The median time on pirtobrutinib for the total population exposed to prior BTK inhibitors was 18.7 months; in the naive and exposed groups, the median time on treatment was 24.3 months and 15.3 months, respectively.

In all patients (n = 282), treatment-related adverse effects (TRAEs) included fatigue (any grade, 3.5%; grade ≥3, 0%), neutropenia (19.5%; 15.2%), diarrhea (7.8%; 0%), cough (1.8%; 0%), contusion (17.4%; 0%), COVID-19 (0.7%; 0%), dyspnea (0.7%; 0.4%), nausea (3.5%; 0%), and abdominal pain (2.1%; 0.4%). TRAEs of interest included infections (any grade, 12.8%; grade ≥3, 4.3%), bruising (19.1%; 0%), rash (5.7%; 0.4%), arthralgia (4.3%; 0%), hemorrhage (4.6%; 1.1%), hypertension (3.5%; 0.4%), and atrial fibrillation or flutter (1.4%; 0.7%).

TRAEs led to dose reductions for 3.9% of patients (BCL-2 naive, n = 9; BCL-2 exposed, n = 2) and discontinuation for 2.5% of patients (BCL-2 naive, n = 4; BCL-2 exposed, n = 3).

On December 1, 2023, the FDA granted accelerated approval to pirtobrutinib for the treatment of adult patients with CLL or SLL who previously received at least 2 lines of therapy, including a BTK inhibitor and a BCL-2 inhibitor.² The decision was supported by ORR and DOR data from BRUIN.

_References

_{1. Woyach JA, Brown JR, Ghia P, et al. Pirtobrutinib in post-cBTKi CLL/SLL: ~30 months follow-up and subgroup analysis with/without prior BCL2i from the phase 1/2 BRUIN study. Ann Oncol. 2023;142(suppl 1):325. doi:10.1182/blood-2023-185852}

_{2. Jaypirca (pirtobrutinib) now approved by US FDA for the treatment of adult patients with chronic lymphocytic leukemia or small lymphocytic lymphoma who have received at least two lines of therapy, including a BTK inhibitor and a BCL-2 inhibitor. News release. Eli Lilly and Company. December 1, 2023. Accessed December 9, 2023. https://investor.lilly.com/news-releases/news-release-details/jaypircar-pirtobrutinib-now-approved-us-fda-treatment-adult}