Rapid Readout: Pirtobrutinib, A Highly Selective, Noncovalent (Reversible) BTK Inhibitor In Previously Treated CLL/SLL: Updated Results From The Phase 1/2 BRUIN Study

Anthony Mato, MD, discusses data from the following presentation:

• Updated results from the phase 1/2 BRUIN study of the noncovalent BTK inhibitor (BTKi) pirtobrutinib in patients with previously treated chronic lymphocytic leukemia/small lymphocytic lymphoma [CLL/SLL]. (Mato AR, et al. ASH 2021; December 11-14, 2021)
  • Covalent BTKi have low oral bioavailability and short half-life, which may lead to suboptimal BTK target coverage in rapidly proliferating tumors with high BTK protein turnover such as accelerating CLL/SLL, ultimately manifesting as acquired resistance in some patients. To address these limitations, pirtobrutinib, a highly selective, noncovalent BTKi, was developed. Preliminary results from the phase 1/2 BRUIN study showed that pirtobrutinib was well tolerated and demonstrated promising efficacy in patients with CLL/SLL regardless of prior therapy, number of prior lines of therapy, or BTK C481 mutation status.
  • This abstract discusses updated results from the phase 1/2 BRUIN study of pirtobrutinib in patients with previously treated CLL/SLL.
  • BRUIN is a phase 1/2 multicenter study (NCT03740529) of oral pirtobrutinib monotherapy in patients with advanced B-cell malignancies who have received >2 prior therapies. Pirtobrutinib was dose escalated in a standard 3+3 design in 28-day cycles.
  • The primary objective for phase 1 was to determine the recommended phase 2 dose (RP2D), and the primary objective of phase 2 was overall response rate (ORR). Secondary objectives included duration of response, progression-free survival (PFS), overall survival, safety and tolerability, and pharmacokinetics. Efficacy evaluable patients included all dosed patients who underwent their first response evaluation or discontinued therapy. Safety was assessed in all patients (CLL/SLL and non-Hodgkin lymphoma).
  • Eighty nine patients (43%) had BTK C481 mutations; 51 (28%) and 64 patients (37%) had 17p deletions and TP53 mutations, respectively.
  • Efficacy results:
    • The efficacy population consisted of 252 patients with CLL/SLL.
    • The ORR was 68% (95% CI 62-74) among the 252 efficacy-evaluable patients with 137 partial responses (54%), 32 partial responses with lymphocytosis (13%), and 62 with stable disease (25%).
    • Responses deepened over time with an ORR of 73% among the patients with at least 12 months follow-up.
    • ORR was similar in patients who discontinued prior BTKi due to progression (68%), or adverse events or other reasons (70%). ORR was 75% in patients with TP53 mutations or 17p deletions.
    • At a median follow-up of 9.4 months for all BTKi pretreated patients, median PFS was not estimable (95% CI: 17.0 months-not estimable). In patients who received prior BTKi and BCL2 inhibitor therapy, median PFS was 18 months (95% CI: 10.7 months-not estimable).
    • PFS was similar in patients with CLL/SLL with BTK C481 mutations and wild-type who progressed on a prior BTK inhibitor.
  • Safety results:
    • No dose-limiting toxicities were reported, and maximum tolerated dose was not reached.
    • 96% of patients received ≥1 pirtobrutinib dose at or above RP2D of 200 mg daily.
    • 1% (n=6) of patients permanently discontinued due to treatment-related adverse events.
    • Fatigue (23%), diarrhea (19%), and neutropenia (18%) were the most frequent treatment-emergent adverse events seen in >10% of patients. The most common adverse event of grade ≥3 was neutropenia (8%).
    • Treatment-related hemorrhage and hypertension occurred in 8% and 7% of patients, respectively.
  • Pirtobrutinib demonstrates promising efficacy and safety in patients with CLL/SLL previously treated with BTK inhibitors.
    • Efficacy was independent of BTK C481 mutation status, the reason for prior BTKi discontinuation (progression versus intolerance), or other classes of prior therapy received (including covalent BTK inhibitors, BCL2 inhibitors, and PI3K-delta inhibitors).
    • Favorable safety and tolerability are consistent with the design of pirtobrutinib as a highly selective and noncovalent reversible BTK inhibitor.