Pirtobrutinib Demonstrates Encouraging Efficacy, Favorable Safety in Previously Treated CLL/SLL

Anthony Mato, MD, MSCE

Pirtobrutinib (LOXO-305) continued to produce promising responses in heavily pretreated patients with chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL), irrespective of BTK C481 mutation status, reason for prior BTK inhibitor discontinuation, or other classes of previous therapy received.¹

Updated data from the phase 1/2 BRUIN study (NCT03740529), presented during the 2022 EHA Congress, showed that pirtobrutinib elicited an overall response rate (ORR) of 68% (95% CI, 62%-74%) in BTK-pretreated patients with CLL/SLL who were efficacy evaluable (n = 252). Among those who responded to treatment, 1% achieved a complete response (CR), 54% experienced a partial response (PR), 13% had a PR with rebound lymphocytosis (PR-L), and 25% had stable disease.

“The ORR was consistent across all of the subgroup analyses. It was consistent in patients who had longer-term follow-up, in [those] who had a TP53 aberration, as well as in [those] who had both a BTK and a PLCγ2mutation,” lead study author Anthony Mato, MD, MSCE, hematologist oncologist and director of the CLL Program at Memorial Sloan Kettering Cancer Center, said during an oral presentation on the data.

“Responses were also consistent regardless of the prior therapy. You can see that it was consistent for the double-exposed population, but even in the so-called pentavalent-refractory patient population,” Mato added. “[In] patients who had a BTK inhibitor, venetoclax [Venclexta], a CD20 [monoclonal antibody], chemoimmunotherapy, and a PI3K inhibitor, the response was maintained. The responses were also consistent regardless of the reason of discontinuation of the prior covalent BTK inhibitor, be it progression of disease or toxicity.”

The highly potent and selective non-covalent BTK inhibitor, pirtobrutinib, comprises nanomolar potency against wild-type and C481-mutant BTK in cell and enzyme assays, with greater than 300-fold selectivity for BTK compared with 370 other kinases. Because of reversible binding mode, BTK inhibition is not affected by an intrinsic rate of BTK turnover, and the agent’s pharmacologic properties allow for sustained BTK inhibition throughout the dosing interval.

BRUIN enrolled those with previously treated CLL or other B-cell non-Hodgkin lymphoma who had active disease requiring treatment, and who were at least 18 years of age with an ECOG performance status of 0 to 2.

A total of 296 patients with CLL or SLL comprised the safety population of the trial; 35 had not received prior BTK inhibition. The efficacy population was comprised of 252 patients with BTK-pretreated CLL or SLL.

The key end points of the trial were to determine the maximum tolerated dose (MTD) and recommended phase 2 dose (RP2D) of the agent, as well as to examine pirtobrutinib’s safety/tolerability, pharmacokinetics, and efficacy as it relates to ORR and duration of response.

Among 261 patients with BTK-pretreated CLL or SLL, the median age was 69 years (range, 36-88); 68% were male, 53% had an ECOG performance status of 0, 40% had a status of 1, and 7% had a status of 2.

Regarding mutation status, 57% had BTK C481 wild-type disease, 43% had BTK C481-mutant disease, and 16% had PLCγ2-mutant disease. Eighty-four percent of patients were IGHV unmutated, and 25% had 11q deletion. Moreover, 37% of patients harbored a TP53 mutation, 28% had a 17p deletion, 36% had 17p deletion or a TP53 mutation, and 27% had both.

Patients had received a median of 3 prior lines of systemic therapy (range, 1-11). All patients previously received a BTK inhibitor, 88% received a prior CD20 antibody, 79% had prior chemotherapy, 41% previously received a BCL-2 inhibitor, 20% received a prior PI3K inhibitor, and 6% had prior CAR T-cell therapy. Six patients previously underwent stem cell transplant (SCT); 5 received allogeneic SCT, and 1 received autologous SCT.

Seventy-five percent of patients discontinued their prior BTK inhibitor because of disease progression, and 25% did so because of toxicity or another unspecified reason.

Additional data showed that the median PFS with pirtobrutinib in pretreated patients who received a median of 3 prior lines of therapy with at least 1 BTK inhibitor was not estimable (NE; 95% CI, 17.0-NE). In pretreated patients who received a median of 5 prior lines of therapy with at least 1 BTK inhibitor and 1 BCL-2 inhibitor, the median PFS was 18 months (95% CI, 10.7-NE).

At a median follow-up of 9.4 months (range, 0.3-27.4), 74% of 261 BTK-pretreated patients were still receiving pirtobrutinib at the time of the data cutoff, which was July 16, 2021.

“Responses appeared to deepen over time. The ORR with pirtobrutinib was 68% for the entire cohort; however, for the 119 patients who had greater than or equal to 12 months of follow-up, the ORR increased to 73%,” Mato noted.

Ninety-six percent of patients received at least 1 dose of pirtobrutinib at, or above, the RP2D of 200 mg daily. The most common treatment-related adverse effects (TRAEs) reported with pirtobrutinib included fatigue (any-grade, 9%; grade 3/4, 1%), diarrhea (any-grade, 8%; grade 3/4, <1%), neutropenia (any-grade, 10%; grade 3/4, 8%), and contusion (any-grade, 12%).

TRAEs of special interest included bruising (any-grade, 15%), rash (any-grade, 5%; grade 3/4, <1%), arthralgia (any-grade, 3%), hemorrhage (any-grade, 2%; grade 3/4, <1%), hypertension (any-grade, 2%; all-grade, <1%), and atrial fibrillation/flutter (any-grade, <1%).

Notably, no dose-limiting toxicities were reported, and the MTD was not reached. Six patients permanently discontinued treatment with pirtobrutinib because of TRAEs.

“The favorable safety and tolerability are consistent with the design of pirtobrutinib as a highly selective and noncovalent reversible BTK inhibitor,” Mato concluded.

References

1. Mato AR, Pagel JM, Coombs CC, et al. Pirtobrutinib, a highly selective, non-covalent (reversible) BTK inhibitor in previously treated CLL/SLL: updated results from the phase 1/2 BRUIN study. Presented at: 2022 EHA Congress; June 9-12, 2022; Vienna, Austria. Abstract S147. https://bit.ly/3O1tQAg