Jaypirca (pirtobrutinib)

P2, N=622, Recruiting, Genmab | Trial completion date: Jun 2031 --> Nov 2032 | Trial primary completion date: Jun 2031 --> Nov 2032

The first-in-class covalent BTK inhibitor, Ibrutinib, binds to the C481 amino acid residue to block the BTK enzyme and prevent the downstream signaling...To bypass the C481S mutation, non-covalent BTKi, such as Pirtobrutinib, were developed and are active against both wild-type and the C481S mutation...In addition, we discuss the new emerging class of BTK degraders, which utilize the evolution of proteolysis-targeting chimeras (PROTACs) to degrade the BTK protein and constitute an important avenue of overcoming resistance. The moving landscape of resistance to BTKi and the development of new therapeutic strategies highlight the ongoing advances being made towards the pursuit of a cure for B-cell lymphoid malignancies.

Knock-out or inhibition of FoxO1 or Rictor led to a dramatic decrease in Akt phosphorylation and growth disadvantage for malignant B cells in the presence of ibrutinib (or PI3K inhibitor idelalisib) in vitro and in vivo. FoxO1/Rictor/pAktS473 axis represents an early non-genetic adaptation to BCR inhibitor therapy not requiring PI3Kδ or BTK kinase activity. We further demonstrate that FoxO1 can be targeted therapeutically, and its inhibition induces CLL cells' apoptosis alone or in combination with BTK inhibitors (ibrutinib, acalabrutinib, pirtobrutinib) and blocks their proliferation triggered by T-cell factors (CD40L, IL-4, and IL-21).

P2, N=23, Not yet recruiting, University of Utah | Trial completion date: Dec 2025 --> Dec 2032 | Initiation date: May 2024 --> Dec 2024 | Trial primary completion date: Dec 2025 --> Dec 2031

P2, N=44, Active, not recruiting, M.D. Anderson Cancer Center | Recruiting --> Active, not recruiting

We show that pirtobrutinib blocked p-ERK1/2, ERK1/2-driven inflammatory cytokines, and overcame paracrine-mediated resistance in MYD88Mut lymphoma cells expressing mutated BTKCys481. Our results provide important mechanistic insights for the activity of pirtobrutinib in MYD88Mut lymphomas carrying BTKCys481 mutations.

P2, N=249, Not yet recruiting, Loxo Oncology, Inc.

P2, N=622, Recruiting, Genmab | N=394 --> 622 | Trial completion date: Nov 2032 --> Jun 2031 | Trial primary completion date: Nov 2032 --> Jun 2031

P2, N=60, Recruiting, H. Lee Moffitt Cancer Center and Research Institute | Not yet recruiting --> Recruiting

New treatment modalities, such as pirtobrutinib, lisocabtagene maraleucel, and ongoing studies combining BTK inhibitors with venetoclax, raise new questions on the significance of prognostic factors of survival for patients with CLL. Testing for prognostic biomarkers will remain relevant to identify patients who may have increased benefit from novel therapeutic strategies, such as combination therapies and novel agents. Patients with high-risk disease should be encouraged to participate in clinical trials.

P2, N=60, Not yet recruiting, H. Lee Moffitt Cancer Center and Research Institute

P2; Trial completion date: Jul 2025 --> Aug 2027 | Trial primary completion date: Jul 2024 --> Aug 2026

BTK signaling is implicated in various B-cell lymphomas such as mantle cell lymphoma, Waldenström Macroglobulinemia, follicular lymphoma, and diffuse large B cell lymphoma, leading to the development of transformative treatments like ibrutinib, the first-in-class covalent BTK inhibitor, and pirtobrutinib, the first-in-class noncovalent BTK inhibitor. This non-enzymatic role promotes cell survival and proliferation independently of kinase activity. Understanding BTK's dual roles unveils opportunities for therapeutics targeting its scaffolding function, promising advancements in disrupting lymphomagenesis and refining B cell lymphoma treatments.

P3, N=650, Active, not recruiting, Loxo Oncology, Inc. | Recruiting --> Active, not recruiting

P2, N=40, Not yet recruiting, M.D. Anderson Cancer Center

P2, N=87, Active, not recruiting, Eli Lilly and Company | N=126 --> 87

No abstract available

P2, N=50, Recruiting, M.D. Anderson Cancer Center | Suspended --> Recruiting

P2; Not yet recruiting --> Recruiting | Trial completion date: Mar 2028 --> Jul 2028 | Trial primary completion date: Mar 2028 --> Jul 2028

P1/2; Adverse events led to dose reduction in 3 patients and discontinuation in 2. In conclusion, fixed-duration PV or PVR was well tolerated and had promising efficacy in patients with R/R CLL, including patients previously treated with a covalent BTKi.

Randomized trials have demonstrated superiority of covalent bruton tyrosine kinase inhibitors (cBTKis) over CIT, and second-generation compounds such as acalabrutinib and zanubrutinib appear to have a more favorable efficacy/safety profile than ibrutinib. The noncovalent BTKi, pirtobrutinib, has shown impressive activity after failure of the cBTKis and is quite tolerable. The Bcl-2 inhibitor venetoclax plus a CD20, generally obinutuzumab, provides a high level of efficacy as initial treatment or after failure on a cBTKi, with many patients achieving a state of undetectable minimal residual disease. Promising novel approaches include BTK degraders, bispecific antibodies, and chimeric antigen receptor T-cell (CAR-T)-cell therapy. What is clear is that CIT is archaic, and current and future targeted approaches will continue to improve the outcome for patients with chronic lymphocytic leukemia.

P2, N=50, Suspended, M.D. Anderson Cancer Center | Initiation date: Aug 2024 --> May 2024 | Not yet recruiting --> Suspended

P1, N=316, Active, not recruiting, Eli Lilly and Company | Trial completion date: Dec 2023 --> Dec 2024

Ibrutinib is the first-in-class BTKi which has changed the treatment landscape of CLL. Over the last few years, novel, covalent (acalabrutinib, zanubrutinib), and non-covalent (pirtobrutinib) BTKi have been approved for the treatment of CLL...Moreover, novel mutations resulting in resistance to non-covalent BTKi have been recently suggested. This article summarizes the clinical efficacy and the latest data regarding resistance to all of the registered BTKi.

P1, N=12, Not yet recruiting, Medical College of Wisconsin | Trial completion date: Feb 2025 --> Jul 2027 | Initiation date: Apr 2024 --> Jul 2024 | Trial primary completion date: Nov 2024 --> Jul 2026

Background: Treatment with combined covalent BTK-inhibitor (cBTKi such as ibrutinib, acalabrutinib, zanubrutinib) withBCL2-inhibitor, venetoclax +/- CD20 monoclonal antibody obinutuzumab showed high rates of undetectableMRD (U-MRD) remission in patients (pts) with CLL (Jain, NEJM 2019; Munir NEJM 2023; Wierda, JCO 2021; Kater, NEJM Evidence 2022). We report the first results for first-line combined pirtobrutinib, venetoclax, and obinutuzumab in pts with CLL. Avery high rate of bone marrow U-MRD at 10-6 sensitivity was noted at 6-months of combined treatment. Adverse event profile was similar to what was noted in previous studies with these agents.

P3, N=600, Recruiting, Loxo Oncology, Inc. | Trial primary completion date: Oct 2025 --> Apr 2026

P3, N=500, Active, not recruiting, Loxo Oncology, Inc. | Recruiting --> Active, not recruiting | Trial completion date: Apr 2025 --> Jul 2026 | Trial primary completion date: Apr 2025 --> Dec 2025

P3, N=650, Recruiting, Loxo Oncology, Inc. | Trial completion date: Mar 2029 --> Aug 2028 | Trial primary completion date: Mar 2028 --> Feb 2025

P2, N=23, Not yet recruiting, Narendranath Epperla

P3, N=250, Active, not recruiting, Loxo Oncology, Inc. | Recruiting --> Active, not recruiting

P2, N=60, Recruiting, Inhye Ahn | Not yet recruiting --> Recruiting | Initiation date: Sep 2024 --> Apr 2024

P3, N=250, Active, not recruiting, Loxo Oncology, Inc. | Recruiting --> Active, not recruiting

P2, N=0, Withdrawn, Loxo Oncology, Inc. | N=200 --> 0 | Not yet recruiting --> Withdrawn

P2, N=60, Not yet recruiting, Inhye Ahn

P1/2, N=860, Active, not recruiting, Loxo Oncology, Inc. | Trial completion date: Apr 2024 --> Jan 2028 | Trial primary completion date: Apr 2024 --> Sep 2027

Findings suggest that brexu-cel may offer clinically and statistically significant benefits regarding objective response, complete response, and progression-free survival compared to pirtobrutinib among patients with R/R MCL after prior cBTKi therapy. Given the short follow-up and high degree of censoring in BRUIN, an analysis incorporating updated BRUIN data may provide more definitive overall survival results.

P2, N=50, Not yet recruiting, M.D. Anderson Cancer Center

P2; N=50; Not yet recruiting; Sponsor:C. Babis Andreadis

P1, N=28, Completed, Eli Lilly and Company

P1, N=16, Completed, Eli Lilly and Company

P1, N=31, Completed, Eli Lilly and Company