Pirtobrutinib Improves Survival in Treatment-Naive CLL/SLL

Topline data from the phase 3 BRUIN CLL-313 trial (NCT05023980) showed that the noncovalent BTK inhibitor pirtobrutinib (Jaypirca) led to a statistically significant and clinically meaningful improvement in progression-free survival (PFS) compared with chemoimmunotherapy consisting of bendamustine and rituximab (Rituxan; BR) in patients with treatment-naïve chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL) without 17p deletions.¹

Overall survival (OS) data was not mature at the time of this analysis but demonstrated a positive trend in favor of pirtobrutinib. Full data will be presented at an upcoming medical conference and published in a peer-reviewed journal.

"The results from BRUIN CLL-313 are striking and provocative across both PFS and OS endpoints, further demonstrating the potential of pirtobrutinib to be a meaningful treatment option for people with untreated CLL/SLL," said Jacob Van Naarden, executive vice president and president of Lilly Oncology, in a press release. "With this third positive phase 3 study, we continue to build the clinical evidence supporting the possible role of pirtobrutinib in a variety of CLL/SLL treatment settings, including treatment-naive, BTK inhibitor-naive, and BTK inhibitor-exposed. We look forward to presenting these data, as well as data from the recently announced positive BRUIN CLL-314 study [NCT05254743], at upcoming medical meetings and preparing global regulatory submissions, with the goal of making pirtobrutinib an option for a wider group of patients who might benefit."

Positive topline data from BRUIN CLL-314 were announced in July 2025 and demonstrated that pirtobrutinib was noninferior to ibrutinib (Imbruvica) in overall response rate (ORR) in patients with treatment-naive and BTK inhibitor-naïve patients.² BRUIN CLL-314 is the first head-to-head study comparing a noncovalent BTK inhibitor with ibrutinib in a treatment-naïve population.

About BRUIN CLL-313

The phase 3, global, randomized, open-label BRUIN CLL-313 study enrolled 282 patients with CLL/SLL without 17p deletions who have not previously received treatment. Patients were randomized 1:1 to receive 200 mg pirtobrutinib once daily or BR. The study’s primary end point is PFS, and secondary end points include OS, time to next treatment, ORR, duration of response, and patient-reported outcomes.³

In order for study participation, patients were required to have a confirmed diagnosis of CLL/SLL per iwCLL 2018 criteria, an ECOG performance status of 0 to 2, adequate organ function, adequate creatinine clearance, and adequate platelet levels. Those with known or suspected Richter’s transformation, central nervous system involvement, active uncontrolled autoimmune cytopenia, significant cardiovascular disease, or active uncontrolled infection were not eligible for study participation.

The study has a planned completion date of August 2026.

FAQs

What is the mechanism of action of pirtobrutinib?

Pirtobrutinib is a highly selective, noncovalent (reversible) Bruton tyrosine kinase (BTK) inhibitor. Unlike first- and second-generation covalent BTK inhibitors (like ibrutinib), pirtobrutinib binds to the BTK enzyme in a reversible manner. This unique binding mechanism allows it to maintain efficacy even in the presence of the C481S mutation, a common resistance mechanism for covalent BTK inhibitors.

How does pirtobrutinib differ from covalent BTK inhibitors like ibrutinib?

The primary difference lies in their mechanism of binding. Covalent BTK inhibitors form a permanent bond with the BTK protein, while pirtobrutinib binds reversibly. This allows it to overcome acquired resistance mutations and may offer a more favorable safety profile due to reduced off-target binding. The BRUIN CLL-314 trial (NCT05254743) is the first head-to-head study to compare these 2 classes of inhibitors directly.

What is the approved indication for pirtobrutinib?

Pirtobrutinib has received accelerated approval from the FDA for the treatment of adult patients with chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL) who have received at least 2 prior lines of therapy, including a BTK inhibitor and a BCL-2 inhibitor. Its approval for earlier lines of therapy is pending the results of ongoing confirmatory trials.

REFERENCES:

1. Lilly's Jaypirca (pirtobrutinib), the first and only approved non-covalent (reversible) BTK inhibitor, significantly improved progression-free survival in patients with treatment-naïve CLL/SLL. News release. Eli Lilly and Company. September 8, 2025. Accessed September 8, 2025. https://tinyurl.com/y5n48buc

2. 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 September 8, 2025. https://tinyurl.com/5atx7fyc

3. A 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). ClinicalTrials.gov. Updated July 23, 2025. Accessed September 8, 2025. https://clinicaltrials.gov/study/NCT05023980