Pirtobrutinib met the primary endpoint of response rate non-inferiority, favoring pirtobrutinib with a nominal P-value for superiority < 0.05

Progression-free survival data was immature, but trending in favor of pirtobrutinib

BRUIN CLL-314 is the first-ever head-to-head Phase 3 study versus a covalent BTK inhibitor to include treatment-naïve patients

INDIANAPOLIS, July 29, 2025 /PRNewswire/ -- Eli Lilly and Company (NYSE: LLY) today announced positive topline results from the Phase 3 BRUIN CLL-314 clinical trial of Jaypirca (pirtobrutinib), a non-covalent (reversible) Bruton's tyrosine kinase (BTK) inhibitor, versus Imbruvica (ibrutinib), a covalent BTK inhibitor, in patients with chronic lymphocytic leukemia or small lymphocytic lymphoma (CLL/SLL). This study enrolled patients with treatment-naïve CLL/SLL and those who had been previously treated but were BTK inhibitor-naïve. The study met its primary endpoint of non-inferiority on overall response rate (ORR) as assessed by an independent review committee (IRC) in both the pre-treated and intent-to-treat populations. ORR favored pirtobrutinib with a nominal P-value for superiority¹ (p <0.05). Progression free survival (PFS), a key secondary endpoint, was not yet mature at this analysis, but was trending in favor of pirtobrutinib. A formal PFS analysis testing for superiority is planned at a future analysis. No detriment was observed for overall survival (OS).

BRUIN CLL-314 is the first ever head-to-head trial versus ibrutinib in CLL to include treatment-naïve patients. This important subpopulation (n=225) had the longest follow-up and a particularly pronounced PFS effect size in favor of pirtobrutinib.

The overall safety profile of pirtobrutinib in BRUIN CLL-314 was similar to previously reported trials. Detailed results will be presented at a medical congress later in 2025.

"We launched the pirtobrutinib randomized development program with an ambitious suite of clinical trials, including head-to-head studies against modern standards of care and examinations of patient populations that reflect real world use, such as BTK inhibitor-pretreated patients," said Jacob Van Naarden, executive vice president and president of Lilly Oncology. "These data mark the second positive Phase 3 study in the program, as we continue to build evidence supporting the potential role of pirtobrutinib in treating people with CLL/SLL and hopefully enabling future regulatory approvals that allow physicians to use the medicine in various disease settings, whether treatment-naïve or BTK inhibitor-pretreated."

These data build on the previously reported positive results from the BRUIN Phase 1/2 trial and the Phase 3 BRUIN CLL-321 trial, the first randomized, controlled study ever conducted in an exclusively post-covalent BTK inhibitor population. The BRUIN CLL-313 Phase 3 study of pirtobrutinib versus chemoimmunotherapy in treatment naïve CLL/SLL is expected to read out later in 2025 and combined with the results of BRUIN CLL-314, will form the basis of regulatory submissions globally. For more information on the BRUIN Phase 3 clinical trial program, please visit clinicaltrials.gov.

About BRUIN CLL-314 
BRUIN CLL-314 is a Phase 3, randomized, open-label study of pirtobrutinib versus ibrutinib in patients with chronic lymphocytic leukemia or small lymphocytic lymphoma (CLL/SLL) who were either treatment-naïve, or who were previously treated and were BTK inhibitor-naïve. The trial planned to enroll 650 patients who were randomized 1:1 to receive pirtobrutinib (200 mg orally, once daily) or ibrutinib (420 mg orally, once daily). The primary endpoint is overall response rate (ORR) as assessed by blinded independent review committee (IRC). Secondary endpoints include investigator and IRC assessed progression-free survival (PFS), duration of response (DoR) and event-free survival (EFS), and time to next treatment (TTNT), overall survival (OS), safety and tolerability, and patient-reported outcomes (PRO).  

About Jaypirca (pirtobrutinib) 
Jaypirca (pirtobrutinib, formerly known as LOXO-305) (pronounced jay-pihr-kaa) is a highly selective (300 times more selective for BTK versus 98% of other kinases tested in preclinical studies), non-covalent (reversible) inhibitor of the enzyme BTK.² BTK is a validated molecular target found across numerous B-cell leukemias and lymphomas including mantle cell lymphoma (MCL) and chronic lymphocytic leukemia (CLL).^3,4 Jaypirca is a U.S. FDA-approved oral prescription medicine, 100 mg or 50 mg tablets taken as a once-daily 200 mg dose with or without food until disease progression or unacceptable toxicity.

INDICATIONS FOR JAYPIRCA (pirtobrutinib)
Jaypirca is a kinase inhibitor indicated for the treatment of 

• Adult patients with relapsed or refractory mantle cell lymphoma (MCL) after at least two lines of systemic therapy, including a BTK inhibitor.
• Adult patients with chronic lymphocytic leukemia or small lymphocytic lymphoma (CLL/SLL) who have received at least two prior lines of therapy, including a BTK inhibitor and a BCL-2 inhibitor.

These indications are approved under accelerated approval based on response rate. Continued approval for these indications may be contingent upon verification and description of clinical benefit in a confirmatory trial. 

IMPORTANT SAFETY INFORMATION FOR JAYPIRCA (pirtobrutinib) 

Infections: Fatal and serious infections (including bacterial, viral, fungal) and opportunistic infections occurred in Jaypirca-treated patients. In a clinical trial, Grade ≥3 infections occurred in 24% of patients with hematologic malignancies, most commonly pneumonia (14%); fatal infections occurred (4.4%). Sepsis (6%) and febrile neutropenia (4%) occurred. In patients with CLL/SLL, Grade ≥3 infections occurred (32%), with fatal infections occurring in 8%. Opportunistic infections included Pneumocystis jirovecii pneumonia and fungal infection. Consider prophylaxis, including vaccinations and antimicrobial prophylaxis, in patients at increased risk for infection, including opportunistic infections. Monitor patients for signs and symptoms, evaluate promptly, and treat appropriately. Based on severity, reduce dose, temporarily withhold, or permanently discontinue Jaypirca. 

Hemorrhage: Fatal and serious hemorrhage has occurred with Jaypirca. Major hemorrhage (Grade ≥3 bleeding or any central nervous system bleeding) occurred in 3% of patients, including gastrointestinal hemorrhage; fatal hemorrhage occurred (0.3%). Bleeding of any grade, excluding bruising and petechiae, occurred (17%). Major hemorrhage occurred in patients taking Jaypirca with (0.7%) and without (2.3%) antithrombotic agents. Consider risks/benefits of co-administering antithrombotic agents with Jaypirca. Monitor patients for signs of bleeding. Based on severity, reduce dose, temporarily withhold, or permanently discontinue Jaypirca. Consider benefit/risk of withholding Jaypirca 3-7 days pre- and post-surgery depending on type of surgery and bleeding risk. 

Cytopenias: Jaypirca can cause cytopenias, including neutropenia, thrombocytopenia, and anemia. In a clinical trial, Grade 3 or 4 cytopenias, including decreased neutrophils (26%), decreased platelets (12%), and decreased hemoglobin (12%), developed in Jaypirca-treated patients. Grade 4 decreased neutrophils (14%) and Grade 4 decreased platelets (6%) developed. Monitor complete blood counts regularly during treatment. Based on severity, reduce dose, temporarily withhold, or permanently discontinue Jaypirca. 

Cardiac Arrhythmias: Cardiac arrhythmias occurred in patients who received Jaypirca. In a clinical trial of patients with hematologic malignancies, atrial fibrillation or flutter were reported in 3.2% of Jaypirca-treated patients, with Grade 3 or 4 atrial fibrillation or flutter in 1.5%. Other serious cardiac arrhythmias such as supraventricular tachycardia and cardiac arrest occurred (0.5%). Patients with cardiac risk factors such as hypertension or previous arrhythmias may be at increased risk. Monitor for signs and symptoms of arrhythmias (e.g., palpitations, dizziness, syncope, dyspnea) and manage appropriately. Based on severity, reduce dose, temporarily withhold, or permanently discontinue Jaypirca. 

Second Primary Malignancies: Second primary malignancies, including non-skin carcinomas, developed in 9% of Jaypirca-treated patients. The most frequent malignancy was non-melanoma skin cancer (4.6%). Other second primary malignancies included solid tumors (including genitourinary and breast cancers) and melanoma. Advise patients to use sun protection and monitor for development of second primary malignancies. 

Hepatotoxicity, Including Drug-Induced Liver Injury (DILI): Hepatotoxicity, including severe, life-threatening, and potentially fatal cases of DILI, has occurred in patients treated with BTK inhibitors, including Jaypirca. Evaluate bilirubin and transaminases at baseline and throughout Jaypirca treatment. For patients who develop abnormal liver tests after Jaypirca, monitor more frequently for liver test abnormalities and clinical signs and symptoms of hepatic toxicity. If DILI is suspected, withhold Jaypirca. Upon confirmation of DILI, discontinue Jaypirca. 

Embryo-Fetal Toxicity: Jaypirca can cause fetal harm in pregnant women. Administration of pirtobrutinib to pregnant rats caused embryo-fetal toxicity, including embryo-fetal mortality and malformations at maternal exposures (AUC) approximately 3-times the recommended 200 mg/day dose. Advise pregnant women of potential fetal risk and females of reproductive potential to use effective contraception during treatment and for one week after last dose. 

Adverse Reactions (ARs) in Patients Who Received Jaypirca 

The most common (≥20%) ARs in the BRUIN pooled safety population of patients with hematologic malignancies (n=593) were decreased neutrophil count (46%), decreased hemoglobin (39%), fatigue (32%), decreased lymphocyte count (31%), musculoskeletal pain (30%), decreased platelet count (29%), diarrhea (24%), COVID-19 (22%), bruising (21%), cough (20%). 

Mantle Cell Lymphoma 

Serious ARs occurred in 38% of patients. Serious ARs occurring in ≥2% of patients were pneumonia (14%), COVID-19 (4.7%), musculoskeletal pain (3.9%), hemorrhage (2.3%), pleural effusion (2.3%), and sepsis (2.3%). Fatal ARs within 28 days of last Jaypirca dose occurred in 7% of patients, most commonly due to infections (4.7%), including COVID-19 (3.1% of all patients). 

Dose Modifications and Discontinuations: ARs led to dose reductions in 4.7%, treatment interruption in 32%, and permanent discontinuation of Jaypirca in 9% of patients. ARs resulting in dosage modification in >5% of patients included pneumonia and neutropenia. ARs resulting in permanent discontinuation in >1% of patients included pneumonia. 

Most common ARs (≥15%), excluding laboratory terms (all Grades %; Grade 3-4 %): fatigue (29; 1.6), musculoskeletal pain (27; 3.9), diarrhea (19; -), edema (18; 0.8), dyspnea (17; 2.3), pneumonia (16; 14), bruising (16; -). 

Select Laboratory Abnormalities (all Grades %; Grade 3 or 4 %) that Worsened from Baseline in ≥10% of Patients: hemoglobin decreased (42; 9), platelet count decreased (39; 14), neutrophil count decreased (36; 16), lymphocyte count decreased (32; 15), creatinine increased (30; 1.6), calcium decreased (19; 1.6), AST increased (17; 1.6), potassium decreased (13; 1.6), sodium decreased (13; -), lipase increased (12; 4.4), alkaline phosphatase increased (11; -), ALT increased (11; 1.6), potassium increased (11; 0.8). Grade 4 laboratory abnormalities in >5% of patients included neutrophils decreased (10), platelets decreased (7), lymphocytes decreased (6). 

Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma 

Serious ARs occurred in 56% of patients. Serious ARs occurring in ≥5% of patients were pneumonia (18%), COVID-19 (9%), sepsis (7%), and febrile neutropenia (7%). Fatal ARs within 28 days of last Jaypirca dose occurred in 11% of patients, most commonly due to infections (10%), including sepsis (5%) and COVID-19 (2.7%). 

Dose Modifications and Discontinuations: ARs led to dose reductions in 3.6%, treatment interruption in 42%, and permanent discontinuation of Jaypirca in 9% of patients. ARs resulting in dose reductions in >1% included neutropenia; treatment interruptions in >5% of patients included pneumonia, neutropenia, febrile neutropenia, and COVID-19; permanent discontinuation in >1% of patients included second primary malignancy, COVID-19, and sepsis. 

Most common ARs (≥20%), excluding laboratory terms (all Grades %; Grade 3-4 %): fatigue (36; 2.7), bruising (36; -), cough (33; -), musculoskeletal pain (32; 0.9), COVID-19 (28; 7), pneumonia (27; 16), diarrhea (26; -), abdominal pain (25; 2.7), dyspnea (22; 2.7), hemorrhage (22; 2.7), edema (21; -), nausea (21; -), pyrexia (20; 2.7), headache (20; 0.9). 

Select Laboratory Abnormalities (all Grades %; Grade 3 or 4 %) that Worsened from Baseline in ≥20% of Patients: neutrophil count decreased (63; 45), hemoglobin decreased (48; 19), calcium decreased (40; 2.8), platelet count decreased (30; 15), sodium decreased (30; -), lymphocyte count decreased (23; 8), ALT increased (23; 2.8), AST increased (23; 1.9), creatinine increased (23; -), lipase increased (21; 7), alkaline phosphatase increased (21; -). Grade 4 laboratory abnormalities in >5% of patients included neutrophils decreased (23). 

Drug Interactions 

Strong CYP3A Inhibitors: Concomitant use with Jaypirca increased pirtobrutinib systemic exposure, which may increase risk of Jaypirca ARs. Avoid use of strong CYP3A inhibitors with Jaypirca. If concomitant use is unavoidable, reduce Jaypirca dosage according to approved labeling. 

Strong or Moderate CYP3A Inducers: Concomitant use with Jaypirca decreased pirtobrutinib systemic exposure, which may reduce Jaypirca efficacy. Avoid concomitant use of Jaypirca with strong or moderate CYP3A inducers. If concomitant use with moderate CYP3A inducers is unavoidable, increase Jaypirca dosage according to approved labeling. 

Sensitive CYP2C8, CYP2C19, CYP3A, P-gp, or BCRP Substrates: Concomitant use with Jaypirca increased their plasma concentrations, which may increase risk of adverse reactions related to these substrates for drugs that are sensitive to minimal concentration changes. Follow recommendations for these sensitive substrates in their approved labeling. 

Use in Special Populations 

Pregnancy and Lactation: Due to potential for Jaypirca to cause fetal harm, verify pregnancy status in females of reproductive potential prior to starting Jaypirca and advise use of effective contraception during treatment and for one week after last dose. Presence of pirtobrutinib in human milk is unknown. Advise women not to breastfeed while taking Jaypirca and for one week after last dose. 

Geriatric Use: In the pooled safety population of patients with hematologic malignancies, patients aged ≥65 years experienced higher rates of Grade ≥3 ARs and serious ARs compared to patients <65 years of age. 

Renal Impairment: Severe renal impairment increases pirtobrutinib exposure. Reduce Jaypirca dosage in patients with severe renal impairment according to approved labeling. 

PT HCP ISI MCL_CLL AA JUN2024 

Please see Prescribing Information and Patient Information for Jaypirca. 

About Lilly
Lilly is a medicine company turning science into healing to make life better for people around the world. We've been pioneering life-changing discoveries for nearly 150 years, and today our medicines help tens of millions of people across the globe. Harnessing the power of biotechnology, chemistry and genetic medicine, our scientists are urgently advancing new discoveries to solve some of the world's most significant health challenges: redefining diabetes care; treating obesity and curtailing its most devastating long-term effects; advancing the fight against Alzheimer's disease; providing solutions to some of the most debilitating immune system disorders; and transforming the most difficult-to-treat cancers into manageable diseases. With each step toward a healthier world, we're motivated by one thing: making life better for millions more people. That includes delivering innovative clinical trials that reflect the diversity of our world and working to ensure our medicines are accessible and affordable. To learn more, visit Lilly.com and Lilly.com/news, or follow us on Facebook, Instagram, and LinkedIn. P-LLY

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© Lilly USA, LLC 2025. ALL RIGHTS RESERVED.

Cautionary Statement Regarding Forward-Looking Statements
This press release contains forward-looking statements (as that term is defined in the Private Securities Litigation Reform Act of 1995) about Jaypirca (pirtobrutinib), as a potential treatment for adults with chronic lymphocytic leukemia or small lymphocytic lymphoma (CLL/SLL) who are previously untreated or have received prior therapy but are Bruton's tyrosine kinase (BTK) inhibitor-naïve and as a treatment for adult patients with CLL/SLL who have received at least two prior lines of therapy, including a BTK inhibitor and a B-cell lymphoma 2 (BCL-2) inhibitor, or adult patients with relapsed or refractory mantle cell lymphoma (MCL) after at least two lines of systemic therapy, including a BTK inhibitor, and the timeline for future readouts, presentations, and other milestones relating to Jaypirca and its clinical trials, and reflects Lilly's current beliefs and expectations. However, as with any pharmaceutical product, there are substantial risks and uncertainties in the process of drug research, development, and commercialization. Among other things, there is no guarantee that planned or ongoing studies will be completed as planned, that future study results will be consistent with study results to date, that Jaypirca will receive additional regulatory approvals, or that Lilly will execute its strategy as expected. For further discussion of these and other risks and uncertainties that could cause actual results to differ from Lilly's expectations, see Lilly's Form 10-K and Form 10-Q filings with the United States Securities and Exchange Commission. Except as required by law, Lilly undertakes no duty to update forward-looking statements to reflect events after the date of this release.

Endnotes and References:

1. ORR superiority was not part of the graphical testing scheme.
2. Mato AR, Shah NN, Jurczak W, 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
3. Hanel W, Epperla N. Emerging therapies in mantle cell lymphoma. J Hematol Oncol. 2020;13(1):79. Published 2020 Jun 17. doi:10.1186/s13045-020-00914-1
4. Gu D, Tang H, Wu J, Li J, Miao Y. Targeting Bruton tyrosine kinase using non-covalent inhibitors in B cell malignancies. J Hematol Oncol. 2021;14(1):40. Published 2021 Mar 6. doi:10.1186/s13045-021-01049-7

 

 

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