Jaypirca (pirtobrutinib)

Aberrant B cell receptor signaling occurs in several B cell neoplasms including follicular lymphoma (treated with zanubrutinib, a BTK inhibitor), mantle cell lymphoma (acalabrutinib, pirtobrutinib, zanubrutinib), marginal zone lymphoma (zanubrutinib), chronic lymphocytic leukemia and small lymphocytic lymphoma (ibrutinib, acalabrutinib, zanubrutinib, pirtobrutinib), and Waldenström macroglobulinemia (ibrutinib, zanubrutinib)...Pirtobrutinib fails to form a covalent bond and is a reversible BTK inhibitor. The FDA-approvals of rilzabrutinib and remibrutinib (2025) represent the first nononcologic authorizations for BTK antagonists.

Noncovalent BTK inhibitors, particularly pirtobrutinib, has shown impressive activity in patients who have progressed on covalent BTKi. The FDA approval of lisocabtagene maraleucel represents a significant milestone in the treatment of double refractory CLL, providing a potentially curative option for eligible patients. The development of effective treatments for double refractory CLL represents an urgent unmet clinical need and the promising results from emerging therapies offer hope for improved outcomes in this challenging patient population.

P2/3, N=57, Not yet recruiting, University Of Cologne

P2/3, N=41, Not yet recruiting, University Of Cologne

In patients with cBTKi-pretreated relapsed/refractory (R/R) CLL, the BRUIN-CLL-321 trial demonstrated improved progression-free survival (PFS) and time to next treatment (TTNT) compared with idelalisib/rituximab or bendamustine/rituximab, accompanied by a favorable tolerability profile. Data from randomized phase III BRUIN-CLL-313 and BRUIN-CLL-314 trials demonstrate the superiority of pirtobrutinib over chemoimmunotherapy in untreated patients and non-inferiority to ibrutinib in untreated patients or in patients with R/R disease who had no prior exposure to cBTKis. These data are not sufficient to justify a change in clinical practice; however, they lay the groundwork for a potential future repositioning of pirtobrutinib from the treatment of R/R CLL to earlier lines of therapy. In this review, we address a range of current and prospective aspects of pirtobrutinib-based therapies: (1) the strengths and limitations of the trial datasets; (2) the biological rationale for frontline noncovalent BTK inhibition; (3) sequencing trade-offs; and (4) prospective scenarios, including combination strategies and time-limited regimens.

In the matched cohort (n = 42), venetoclax and pirtobrutinib demonstrated comparable outcomes for MRR (p = 0.91) and PFS (p = 0.83). Despite the retrospective design and limited sample size, these findings indicate comparable efficacy between venetoclax and pirtobrutinib with distinct molecular vulnerabilities and support consideration of pirtobrutinib sequencing when transitioning from a cBTKi, as well as further exploration of combination strategies that may exploit complementary vulnerabilities.

P1, N=316, Active, not recruiting, Eli Lilly and Company | Trial completion date: Dec 2025 --> Jun 2026

P1/2, N=56, Not yet recruiting, Fondazione Italiana Linfomi Ets

P1, N=30, Recruiting, National Heart, Lung, and Blood Institute (NHLBI)

P2, N=24, Recruiting, Zhejiang Cancer Hospital

P1, N=22, Recruiting, F. Hoffmann-La Roche AG

P1/2, N=82, Not yet recruiting, French Innovative Leukemia Organization