Pirtobrutinib Yields Noninferior ORR Vs Ibrutinib in CLL/SLL

In the open-label phase 3 BRUIN CLL-314 trial, 650 patients were randomly assigned to receive pirtobrutinib at 200 mg orally once daily or ibrutinib at 420 mg orally once daily.

Pirtobrutinib (Jaypirca) demonstrated a noninferior objective response rate (ORR) vs ibrutinib (Imbruvica) among patients with previously managed or treatment-naïve chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL), according to a press release on findings from the phase 3 BRUIN CLL-314 trial (NCT05254743).¹

Based on independent review committee assessment, pirtobrutinib met the primary end point of noninferiority for ORR across the pretreated and intent-to-treat populations of the trial. Additionally, ORR nominally favored pirtobrutinib vs ibrutinib (P <.05).

Data for progression-free survival (PFS), a key secondary end point, were immature at the time of analysis, although current outcomes trended towards favoring pirtobrutinib. Investigators plan to formally test PFS in a future analysis. Additionally, treatment with pirtobrutinib demonstrated no overall survival (OS) detriment.

The safety profile of pirtobrutinib in the BRUIN CLL-314 trial was comparable with prior reports of the agent. Investigators will share detailed findings from the trial at a future medical meeting 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 Bruton tyrosine kinase [BTK] inhibitor-pretreated patients,” Jacob Van Naarden, executive vice president and president of Lilly Oncology, the developer of pirtobrutinib, stated in the press release.¹ “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 [patients] 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.”

In the open-label phase 3 BRUIN CLL-314 trial, 650 patients were randomly assigned to receive pirtobrutinib at 200 mg orally once daily or ibrutinib at 420 mg orally once daily. The head-to-head trial included 225 patients with treatment-naïve CLL or SLL.

The trial’s primary end point was ORR per blinded independent review committee evaluation. Secondary end points included PFS per investigator and independent review committee assessment, duration of response, event-free survival, time to next treatment, OS, safety and tolerability, and patient-reported outcomes.

Patients 18 years and older with a confirmed diagnosis of CLL or SLL requiring therapy per the international Workshop on CLL 2018 criteria were eligible for enrollment on the trial.² Other eligibility criteria included having known 17p deletion status for part 1 of the trial, 17p deletion confirmed via fluorescence in situ hybridization testing for part 2 of the trial, an ECOG performance status of 0 to 2, and adequate organ function.

Those with known or suspected Richter’s transformation to diffuse large B-cell lymphoma, prolymphocytic leukemia, or Hodgkin lymphoma at any point before enrollment; known or suspected central nervous system involvement; or a significant history of renal, neurologic, psychiatric, endocrine, metabolic, or immunologic disease were ineligible for study entry. Having an active cytomegalovirus infection was also grounds for exclusion from the trial.

According to the press release, pirtobrutinib is currently indicated for the treatment of adults with relapsed/refractory mantle cell lymphoma following 2 lines of systemic therapy, which includes a BTK inhibitor. It is also available for the treatment of adults with CLL or SLL who have received 2 or more prior lines of treatment, including a BTK inhibitor and a BCL-2 inhibitor.

Safety information for pirtobrutinib includes warnings for infections, hemorrhage, and cytopenia. Other potential adverse effects include cardiac arrhythmias, second primary malignancies, hepatotoxicity, and embryo-fetal toxicity.

References

1. Lilly's Jaypirca (pirtobrutinib), the first and only approved non-covalent (reversible) BTK inhibitor, met its primary endpoint in a head-to-head Phase 3 trial versus Imbruvica (ibrutinib) in CLL/SLL. News release. Eli Lilly and Company. July 29, 2025. Accessed July 29, 2025. https://tinyurl.com/5n782xn4
2. A study of pirtobrutinib (LOXO-305) versus ibrutinib in participants with chronic lymphocytic leukemia (CLL)/​small lymphocytic lymphoma (SLL) (BRUIN-CLL-314). ClinicalTrials.gov. Updated July 16, 2025. Accessed July 29, 2025. https://tinyurl.com/3ekdupa2