Pirtobrutinib Shows Impressive Efficacy in Previously Treated CLL/SLL

Catherine C. Coombs, MD

Pirtobrutinib (LOXO-305), showcased promising efficacy signals across dose levels in previously treated patients with chronic lymphocytic leukemia (CLL) and small lymphocytic lymphoma (SLL), according to dose-escalation/-expansion findings from the phase 1/2 BRUIN study (NCT03740529) that were presented during the 2021 SOHO Annual Meeting.¹

Results showed that the overall response rate (ORR) was 62% (95% CI, 53%-71%) in patients with CLL/SLL who previously received a BTK inhibitor (n = 121); this comprised a 47% partial response (PR) rate and a 15% PR rate with lymphocytosis (PR-L). Thirty-four percent of patients had stable disease (SD). In the overall group of patients with CLL/SLL (n = 139), the ORR was 63% (95% CI, 55%-71%); the PR rate was 50%, the PR-L rate was 14%, and the SD rate was 32%.

Data also showed that the ORR with pirtobrutinib increased over time. For patients who had been on treatment for at least 10 months, the ORR increased to 86%.

“Pirtobrutinib demonstrates promising efficacy in patients [with CLL and SLL who have] previously [been] treated with all classes of available therapy, and responses were observed across all dose levels,” lead study author Catherine C. Coombs, MD, assistant professor of medicine in the Division of Hematology, of the University of North Caroline at Chapel Hill, said in a virtual presentation on the data. “Efficacy was independent of BTK C481 mutation status, the reason for prior BTK inhibitor discontinuation—whether progression or intolerance— or other classes of prior therapy received. Pirtobrutinib is well tolerated and exhibits promising efficacy in heavily pretreated [patients with] CLL and SLL.”

Discontinuation with ibrutinib (Imbruvica) remains a significant issue in the treatment paradigm of CLL, Coombs explained, adding that 5-year discontinuation rates with the BTK inhibitor are 41% in the frontline setting² and 54% for those with relapsed/refractory disease.³ In most cases, progressive disease in CLL following covalent BTK inhibitors are BTK C481 mutations, which prevent covalent BTK inhibitors from achieving effective target inhibition.

Pirtobrutinib is a highly potent and selective non-covalent BTK inhibitor currently being tested in B-cell malignancies. It comprises nanomolar potency against wild-type and C481-mutant BTK in cell and enzyme assays, with greater than 300-fold selectivity for BTK vs 370 other kinases. Because of reversible binding mode, BTK inhibition is not impacted by an intrinsic rate of BTK turnover, and its favorable pharmacologic properties allow for sustained BTK inhibition throughout the dosing interval.

In the phase 1/2 BRUIN trial, investigators are enrolling 323 patients with CLL, SLL, mantle cell lymphoma (MCL), Waldenström macroglobulinemia, and other B-cell non-Hodgkin lymphoma to receive pirtobrutinib at daily doses of 25 mg to 300 mg. The phase 1 portion of the trial included 203 patients and the phase 2 portion included 120 patients.

Data presented during the 2021 SOHO Annual Meeting focused on those in the CLL cohort; 170 patients were in the safety population and 139 were in the efficacy population. Assessment of 31 patients is ongoing prior to first restaging.

The phase 1 portion is a 3+3 design with 28-day cycles; intra-patient dose escalation is allowed, and cohort expansions are permitted at safe doses. The phase 2 portion of the trial is enrolling patients to receive the recommended phase 2 dose (RP2D) of pirtobrutinib, which was determined to be 200 mg daily.

To be eligible for enrollment, patients had to be at least 18 years of age, have an ECOG performance status of 0 to 2, have CLL or another B-cell non-Hodgkin lymphoma, have active disease and be in need of therapy, and have received prior treatment.

The key end points of the trial are safety and tolerability, maximum-tolerated dose (MTD), RP2D, and pharmacokinetics, as well as ORR and duration of response (DOR) based on International Workshop on CLL and International Workshop on Waldenström Macroglobulinemia, and Lugano Classification disease criteria.

The median age was 69 years (range, 36-88), and 36% of patients were female. Moreover, 51% of patients had an ECOG performance status of 0. The median number of prior therapies received was 3 (range, 1-11) overall, and was 4 (range, 1-11) in those who were previously treated with a BTK inhibitor.

Prior treatment consisted of a BTK inhibitor (86%), chemotherapy (82%), an anti-CD20 antibody (90%), a BCL-2 inhibitor (34%), a PI3K inhibitor (21%), lenalidomide (Revlimid; 8%), allogeneic stem cell transplant (2%), and CAR T-cell therapy (6%). No patients had undergone autologous stem cell transplant. Sixty-seven percent of patients had discontinued a prior BTK inhibitor due to progressive disease.

Most patients (73%) had BTK wild-type disease, compared with those who had BTK C481 mutations (27%) and PLCG2 mutations (4%). Eighty-eight percent of patients had IGHV-unmutated disease, and other patients had 17p deletion (25%), TP53 mutation (30%), both a 17p13 deletion and TP53 mutation (22%), and 11q deletion (19%).

The data cutoff date was September 27, 2020. Additional findings showed that, at a median follow-up of 6 months (range, 0.6-17.8+) for the efficacy-evaluable group, 94% of responding patients continue to receive treatment and are in response. Five responding patients had discontinued due to progressive disease (n = 4) and 1 patient in PR electively withdrew to undergo transplant.

Pharmacokinetic data showed that plasma exposures exceeded BTK IC90 throughout the dosing interval at doses that were at least 100 mg daily. Additionally, plasma exposures were dose dependent and linear.

When examining the safety profile of pirtobrutinib across the entire population, Coombs noted that no dose-limiting toxicities were reported and the MTD was not reached. Five (1.5%) patients had discontinued therapy due to treatment-related adverse effects (TRAEs). 

Any-grade treatment-emergent adverse effects (TEAEs) included contusion (13%), diarrhea (17%), and fatigue (20%); 1 case of grade 3 fatigue was reported. AEs of special interest included bruising (16%), rash (11%), arthralgia (5%), hemorrhage (5%), hypertension (5%), and atrial fibrillation/flutter (<1%).

TRAEs included fatigue (8%), diarrhea (9%), contusion (9%), bruising (12%), rash (6%), arthralgia (2%), hemorrhage (2%), and hypertension (1%).

At the 2021 Pan Pacific Lymphoma Conference, data from the MCL cohort and other non-Hodgkin lymphomas of the phase 1/2 BRUIN study were presented. Here, pirtobrutinib elicited an ORR of 52% (95% CI, 38%-65%) in patients with MCL (n = 56), with a 25% complete response (CR) rate, a 27% PR rate, and a SD rate of 18%.⁴

In those who previously received a BTK inhibitor (n = 52), the ORR with pirtobrutinib was also 52% (95% CI, 38%-66%); the CR, PR, and SD rates were 25%, 27%, and 17%, respectively. In patients who previously underwent stem cell transplant or CAR T-cell therapy, the ORRs with the agent were 64% and 100%, respectively.

References

1. Coombs CC, Pagel JM, Shah NN, et al. Pirtobrutinib (LOXO-305), a next generation, highly selective, non-covalent BTK inhibitor in previously treated CLL/SLL: results from the phase 1/2 BRUIN study. Presented at: 2021 SOHO Annual Meeting; September 8-11, 2021; Virtual. Abstract CLL-039.
2. Burger JA, Barr PM, obak T, et al. Long-term efficacy and safety of first-line ibrutinib treatment for patients with CLL/SLL: 5 years of follow-up from the phase 3 RESONATE-2 study. Leukemia. 2020;34(3):878-798. doi:10.1038/s41375-019-0602-x
3. Woyach JA, Ruppert AM, Guinn D, et al. BTKC481S-mediated resistance to ibrutinib in chronic lymphocytic leukemia. J Clin Oncol. 2017;35(13):1437-1443. doi:10.1200/JCO.2016.70.2282
4. Alencar AJ, Shah NN, Gerson JN, et al. Pirtobrutinib (LOXO-305), a next generation highly selective non-covalent Bruton’s tyrosine kinase inhibitor in previously treated mantle cell lymphoma and other non-Hodgkin lymphomas: results from the phase 1/2 BRUIN study. Presented at: 2021 Pan Pacific Lymphoma Conference; August 9-13, 2021; Big Island, HI. https://bit.ly/3n3XzPl