KEY TAKEAWAYS
- The BRUIN phase 1/2 study evaluated the safety and tolerability of pirtobrutinib monotherapy in patients with relapsed/refractory B-cell malignancies who had previously been intolerant to a covalent BTK inhibitor.
- Of the 566 study participants, 123 (22%) had discontinued a cBTKi due to reported adverse events such as cardiac disorders, infections, neutropenia, rash, bleeding/hemorrhage, arthralgias/myalgias, and gastrointestinal disorders.
- The median treatment duration with pirtobrutinib for this population was 11 months, with 63% of patients remaining on therapy at the time of data cut-off.
- Treatment-emergent adverse events were manageable, with dose reductions in 8% of patients, primarily due to neutropenia.
Covalent Bruton tyrosine kinase inhibitors (cBTKi) have remarkably improved many B-cell malignancies. Yet, treatment cessation due to intolerance remains a considerable barrier to the efficacy of such treatments. Pirtobrutinib, a highly selective, reversible BTKi, has equal low nanomolar potency against both wild-type and C481-mutant BTK and possesses beneficial oral pharmacology allowing for continuous BTK inhibition throughout the dosing interval regardless of the rate of BTK turnover. In addition, Pirtobrutinib is well-tolerated and has demonstrated promising efficacy in patients with poor prognosis B-cell malignancies after prior therapy, including cBTKi.
This analysis sought to evaluate the safety and tolerability of pirtobrutinib monotherapy in patients with relapsed/refractory (R/R) B-cell malignancies who had previously been intolerant to a CBT. The multicenter phase 1/2 BRUIN study (NCT03740529) was used in this analysis and included 566 patients (CLL/SLL, n=276; MCL, n=150; other NHL, n=140) who had previously been exposed to a cBTKi-containing regimen (1 regimen, n=454; 2 regimens, n=93; ≥3 regimens, n=19). Intolerance to prior cBTKi was defined as persistent/recurrent adverse events that led to the patient discontinuing such treatment without progressive disease. Pirtobrutinib monotherapy was administered orally once daily in 28-day cycles until disease progression or until toxicity caused treatment discontinuation.
The median age for patients with prior cBTKi intolerance was 70 years (IQR: 64-75), and the Eastern Cooperative Oncology Group Performance Status (ECOG PS) was 0 for 58%, 1 for 35%, and 2 for 7% of patients. The most common adverse events (AEs) leading to prior cBTKi discontinuation were cardiac disorders [n=40, 33%; primarily atrial fibrillation (n=31, 25%)], infections (n=13, 11%), neutropenia (n=12, 10%), rash (n=12, 10%), bleeding/hemorrhage (n=11, 9%), arthralgias/myalgias (n=10, 8%), gastrointestinal disorders [n=9, 7%; diarrhea (n=6, 5%)], and fatigue (n=8, 7%). At a median time on treatment of 11 months (IQR, 4-18), 63% (n=78) of the 123 cBTKi-intolerant patients remained on pirtobrutinib at the time of data cut-off. Of the 45 patients who had discontinued pirtobrutinib, the majority did so due to progressive disease (62%, n=28).
Treatment-emergent adverse events (TEAEs) on pirtobrutinib were manageable, with dose reductions in 10 patients (8%) primarily due to neutropenia (n=6). The median pirtobrutinib relative dose intensity was 98% (IQR, 92-100). Grade ≥3 recurrences of TEAEs leading to prior cBTKi discontinuation was observed in 13% (n=16/123) of patients. In conclusion, pirtobrutinib monotherapy was safe and well-tolerated in most patients with B-cell malignancies with documented intolerance to prior cBTKi therapy. Most patients did not experience high-grade recurrence of the AE that led to discontinuation of the prior cBTKi, and among those who did, none discontinued pirtobrutinib for this AE. Pirtobrutinib may be a practical consideration to extend the benefit of BTK inhibition among patients with intolerance to a prior cBTKi.
Source:https://ash.confex.com/ash/2022/webprogram/Paper159035.html
Clinical Trial:https://clinicaltrials.gov/ct2/show/NCT03740529
Shah, N., Wang M, Brown J, Patel K, Woyach J, Wierda W, Ujjani C, Eyre T, Zinzani P, Alencar A, Gastinne T, Ghia P, Lamanna N, Hoffmann M, Patel M, Flinn I, Gerson J, Ma S, Coombs C, Cheah C, Maranda E, Fakhri B, Kim W, Barve M, Cohen J, Jurczak W, Munir T, Thompson M, Roeker L, Bao K, Cangemi N, Kherani J, Walgren R, Han H, Ruppert A, Mato A (2022). Safety and Tolerability of Pirtobrutinib Monotherapy in Patients with B-Cell Malignancies Who Were Previously Intolerant to a Covalent BTK Inhibitor: Results from the Phase 1/2 BRUIN Study. [online] ash.confex.com. Available at: https://ash.confex.com/ash/2022/webprogram/Paper159035.html [Accessed 20 Feb. 2023].
