The objective was to evaluate the efficacy/safety of pirtobrutinib in the treatment of B-cell malignancies and distinguish it from other available Bruton’s tyrosine kinase (BTK) inhibitors.
Data sources:
A literature search of PubMed (January 2021 through November 2023) and Clinicaltrials.gov was conducted using terms pirtobrutinib, Jaypirca, and LOXO 305. Licensing trials of available BTK inhibitors were also reviewed.
Study selection and data extraction:
Relevant English-language clinical trials were evaluated.
Data synthesis:
Pirtobrutinib was approved by the US Food and Drug Administration for the treatment of relapsed/refractory mantle cell lymphoma (MCL) and chronic lymphocytic leukemia (CLL) based largely on a phase 1/2 study in B-cell malignancies. Pirtobrutinib demonstrated a 73% overall response rate (ORR) in the CLL population and 58% in MCL. Pirtobrutinib has activity in patients resistant to earlier-generation, covalent BTK inhibitors. In fact, the ORRs were similar in BTK-pretreated and naïve patients. Adverse effects include fatigue, diarrhea, bleeding, and infection. Atrial fibrillation, a class effect of BTK inhibitors, may be less common with pirtobrutinib.
Relevance to patient care and clinical practice in comparison with existing drugs:
Compared with earlier-generation BTK inhibitors, pirtobrutinib is more selective for BTK and binds noncovalently to the receptor. Ongoing studies are evaluating pirtobrutinib’s use in multiple B-cell malignancies and comparing it with other BTK inhibitors.
Conclusion:
The characteristics of pirtobrutinib render it useful in the treatment of B-cell malignancies no longer responding to a previous BTK inhibitor, and results from ongoing clinical trials may support future expanded use.
ShirleyM.Bruton tyrosine kinase inhibitors in B-Cell malignancies: their use and differential features. Target Oncol. 2022;17(1):69-84. doi:10.1007/s11523-021-00857-8
2.
AslanBKismaliGIlesLR, et al. Pirtobrutinib inhibits wild-type and mutant Bruton’s tyrosine kinase-mediated signaling in chronic lymphocytic leukemia. Blood Cancer J. 2022;12(5):80. doi:10.1038/s41408-022-00675-9
3.
Jaypirca (Pirtobrutinib) [package insert]. Eli Lilly and Company; 2023.
4.
MatoARShahNNJurczakW, et al. Pirtobrutinib in relapsed or refractory B-cell malignancies (BRUIN): a phase 1/2 study. Lancet. 2021;397(10277):892-901. doi:10.1016/S0140-6736(21)00224-5
5.
MatoARWoyachJABrownJR, et al. Pirtobrutinib after a covalent BTK inhibitor in chronic lymphocytic leukemia. N Engl J Med. 2023;389(1):33-44. doi:10.1056/NEJMoa2300696
6.
WangMLJurczakWZinzaniPL, et al. Pirtobrutinib in covalent Bruton tyrosine kinase inhibitor pretreated mantle-cell lymphoma. J Clin Oncol. 2023;41:3988-3997. doi:10.1200/JCO.23.00562
7.
WoyachJARuppertASGuinnD, et al. BTKC481S-mediated resistance to ibrutinib in chronic lymphocytic leukemia. J Clin Oncol. 2017;35(13):1437-1443. doi:10.1200/JCO.2016.70.2282
Brukinsa (Zanubrutinib) [package insert]. BeiGene USA, Inc; 2023.
11.
Eli Lilly and Company (Loxo Oncology, Inc.). Study of LOXO-305 Versus Investigator’s Choice (IdelaR or BR) in Patients With Previously Treated Chronic Lymphocytic (CLL)/Small Lymphocytic Lymphoma (SLL) (BRUIN CLL-321) (NCT466038). ClinicalTrials.gov; 2023. Accessed October 1, 2023. https://clinicaltrials.gov/study/NCT04666038
12.
Eli Lilly and Company (Loxo Oncology, Inc.). Study of Pirtobrutinib (LOXO-305) Versus Ibrutinib in Patients With Chronic Lymphocytic Leukemia (CLL)/Small Lymphocytic Lymphoma (SLL) (BRUIN CLL-314) (NCT05254743). Clinicaltrials.gov; 2023. Accessed October 1, 2023. https://clinicaltrials.gov/study/NCT05254743
13.
Eli Lilly and Company (Loxo Oncology, Inc.). Study of Pirtobrutinib (LOXO-305) Versus Bendamustine Plus Rituximab (BR) in Untreated Patients With Chronic Lymphocytic Leukemia (CLL)/Small Lymphocytic Lymphoma (SLL) (BRUIN CLL-313) (NCT05023980). Clinicaltrials.gov;2023. Accessed October 1, 2023. https://clinicaltrials.gov/study/NCT05023980
14.
Eli Lilly and Company (Loxo Oncology, Inc.). A Trial of Pirtobrutinib (LOXO-305) Plus Venetoclax and Rituximab (PVR) Versus Venetoclax and Rituximab (VR) in Previously Treated Chronic Lymphocytic Leukemia/ Small Lymphocytic Lymphoma (CLL/ SLL) (BRUIN CLL-322) (NCT04965493). Clinicaltrials.gov; 2023. Accessed October 1, 2023. https://clinicaltrials.gov/study/NCT04965493.
15.
Eli Lilly and Company (Loxo Oncology, Inc.). Study of BTK Inhibitor LOXO-305 Versus Approved BTK Inhibitor Drugs in Patients With Mantle Cell Lymphoma (MCL) (BRUIN-MCL-321) (NCT04662255). Clinicaltrials.gov; 2023. Accessed October 1, 2023. https://clinicaltrials.gov/study/NCT04662255
16.
BurgerJATedeschiABarrT, et al. Ibrutinib as initial therapy for patients with chronic lymphocytic leukemia. N Engl J Med. 2015;373:2425-2437. doi:10.1056/NEJMoa1509388
17.
BarrPMOwenCRobakT, et al. Up to 8-year follow-up from RESONATE-2: first-line ibrutinib treatment for patients with chronic lymphocytic leukemia. Blood Adv. 2022;6:3440-3450. doi:10.1182/bloodadvances.2021006434
18.
TamCSOpatSD’SaS, et al. A randomized phase 3 trial of zanubrutinib vs ibrutinib in symptomatic Waldenstrom macroglobulinemia: the ASPEN study. Blood. 2020;136:2038-2050. doi:10.1182/blood.2020006844
19.
BrownJREichhorstBHillmanP, et al. Zanubrutinib or ibrutinib in relapsed or refractory chronic lymphocytic leukemia. N Engl J Med. 2023;388:319-332. doi:10.1056/NEJMoa2211582
20.
SeymourJFByrdJCGhiaP, et al. Detailed safety profile of acalabrutinib vs ibrutinib in previously treated chronic lymphocytic leukemia in the ELEVATE-RR trial. Blood. 2023;142:687-699. doi:10.1182/blood.2022018818
21.
TamCSBrownJRKahlBS, et al. Zanubrutinib versus bendamustine and rituximab in untreated chronic lymphocytic leukemia and small lymphocytic lymphoma (SEQUOIA): a randomized, controlled, phase 3 trial. Lancet Oncol. 2022;23:1031-1043. doi:10.1016/S1470-2045(22)00293-5
22.
GhiaPPlutaAWachM, et al. Acalabrutinib versus investigator’s choice in relapsed/refractory chronic lymphocytic leukemia: final ASCEND trial results. Hemasphere. 2022;6(12):e801. doi:10.1097/HS9.0000000000000801
23.
SharmanJPEgyedMJurczakW, et al. Efficacy and safety in a 4-year follow-up of the ELEVATE-TN study comparing acalabrutinib with or without obinutuzumab versus obinutuzumab plus chlorambucil in treatment-naïve chronic lymphocytic leukemia. Leukemia. 2022;36(4):1171-1175. doi:10.1038/s41375-021-01485-x
24.
WangMRuleSZinzaniPL, et al. Acalabrutinib in relapsed or refractory mantle cell lymphoma (ACE-LY-004): a single-arm, multicentre, phase 2 trial. Lancet. 2018;391:659-667. doi:10.1016/S0140-6736(17)33108-2
25.
LipskyALamannaN.Managing toxicities of Bruton tyrosine kinase inhibitors. Hematology Am Soc Hematol Educ Program. 2020;2020(1):336-345. doi:10.1182/hematology.2020000118
26.
RyanCEChengMPIssaNCBrownJRDavidsMS.Pneumocystis jirovecii pneumonia and institutional prophylaxis practices in CLL patients treated with BTK inhibitors. Blood Adv. 2020;4(7):1458-1463. doi:10.1182/bloodadvances.2020001678
27.
National Comprehensive Cancer Network. NCCN clinical practice guidelines in oncology: prevention and treatment of cancer-related infections (Version 2.2023). Accessed December 6, 2023. www.nccn.org/professionals/physician_gls/pdf/infections.pdf
National Comprehensive Cancer Network. NCCN clinical practice guidelines in oncology: chronic lymphocytic leukemia/small lymphocytic lymphoma (Version 1.2024). Accessed November 30, 2023. www.nccn.org/professionals/physician_gls/pdf/b-cell.pdf
30.
ByeAPKriekNSageT, et al. Pirtobrutinib results in reversible platelet dysfunction compared to ibrutinib and acalabrutinib. Hematologica. 2023;108:1429-1435. doi:10.3324/hematol.2022.281402
31.
BorianiGCorradiniPCuneoA, et al. Practical management of ibrutinib in the real life: focus on atrial fibrillation and bleeding. Hematol Oncol. 2018;36(4):624-632. doi:10.1002/hon.2503
