Pirtobrutinib Improves PFS in Treatment-Naïve CLL/SLL Without 17p Deletions

Results from the phase 3 BRUIN CLL-313 trial show that OS trended favorably for pirtobrutinib vs chemoimmunotherapy in this CLL and SLL population.

Pirtobrutinib (Jaypirca) demonstrated a highly statistically significant and clinically meaningful improvement in progression-free survival (PFS) compared with chemoimmunotherapy in treatment-naïve patients with chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL) without 17p deletions, according to a press release from the developer, Eli Lilly and Company.1

Results came from the open-label, randomized phase 3 BRUIN CLL-313 trial (NCT05023980) that evaluated pirtobrutinib monotherapy vs bendamustine (Treanda) plus rituximab (Rituxan) in patients with CLL and SLL. Based on independent review committee assessment, pirtobrutinib reached the trial’s primary end point. Updated results will be shared at an upcoming medical conference and submitted to a peer-reviewed journal.

Although overall survival (OS) was not fully mature at this analysis, it was trending in favor of pirtobrutinib; it will be tested for statistical significance at the time of the primary OS analysis, which is planned for 2026.

Regarding safety, the overall safety profile of pirtobrutinib was consistent with previously reported trials across various treatment settings.

"The results from BRUIN CLL-313 are striking and provocative, across both PFS and OS end points, further demonstrating the potential of pirtobrutinib to be a meaningful treatment option for people with untreated CLL/SLL," stated Jacob Van Naarden, executive vice president and president of Lilly Oncology.1 "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-naïve, Bruton’s tyrosine kinase [BTK] inhibitor-naïve 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."

A total of 282 patients with CLL or SLL without 17p deletions who were not previously treated were randomly assigned, in a 1:1 ratio, to receive either 200 mg of pirtobrutinib once daily or bendamustine plus rituximab per labeled doses. Eligible patients had an ECOG performance from 0 to 2; adequate organ function; and suitable platelets, hemoglobin, absolute neutrophil counts, and kidney function.2

Exclusion criteria included receipt of prior systemic therapy for CLL or SLL, central nervous system involvement, known or suspected Richter’s transformation preceding enrollment, active uncontrolled autoimmune cytopenia, significant cardiovascular disease, concurrent use of investigational agents or anticancer therapy except hormonal therapy, and requirement of therapeutic anticoagulation with warfarin or another Vitamin K antagonist.

The trial’s primary end point was PFS per blinded independent review committee evaluation; secondary end points were OS, overall response rate (ORR), duration of response, time to next treatment, safety and tolerability, and patient-reported outcomes.

Previously, pirtobrutinib reduced the risk of progression or death by 46% vs chemoimmunotherapy in patients with CLL or SLL previously treated with a covalent BTK inhibitor in the phase 3 BRUIN CLL-321 trial (NCT04666038).3 The agent also met the primary end point of non-inferiority for ORR vs ibrutinib (Imbruvica) in treatment-naïve patients with CLL or SLL and those who were previously treated but were BTK inhibitor-naïve in the phase 3 BRUIN CLL-314 trial (P < .05).4

The developer noted that data from BRUIN CLL-313 and BRUIN CLL-314 will be packaged to form the basis for label expansions in earlier lines of therapy, and global regulatory submissions will begin in late 2025.

The important safety information label for pirtobrutinib lists infections, hemorrhage, cytopenia, cardiac arrhythmias, second primary malignancies, hepatotoxicity, and embryo-fetal toxicity as notable toxicities.

Furthermore, in the pooled BRUIN safety population of patients with hematological malignancies, the most common adverse reactions were decreased neutrophil counts (46%), decreased hemoglobin (39%), fatigue (32%), and decreased lymphocyte counts (31%).

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/38ch9su4
2. 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://tinyurl.com/yn2cemvy
3. Phase 3 results for Lilly's Jaypirca® (pirtobrutinib) in covalent BTK inhibitor pre-treated chronic lymphocytic leukemia or small lymphocytic lymphoma to be presented at the 2024 ASH Annual Meeting. News release. Eli Lilly and Company. December 9, 2024. Accessed September 8, 2025. https://tinyurl.com/2zbch5za
4. 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/bdhwjkyk