Pirtobrutinib Triplet Boosts PFS in Relapsed/Refractory CLL/SLL Trial

Adding pirtobrutinib (Jaypirca) to venetoclax (Venclexta) and rituximab (Rituxan) significantly prolonged progression-free survival (PFS) vs venetoclax/rituximab alone among patients with relapsed/refractory chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL), according to a press release on findings from the phase 3 BRUIN-322 trial (NCT04965493).¹

What were the key findings?

The BRUIN CLL-322 trial fulfilled its primary end point by demonstrating a clinically meaningful and statistically significant PFS improvement per independent review committee evaluation in the pirtobrutinib arm. These PFS outcomes were consistent across various patient subgroups and regardless of prior receipt of covalent BTK inhibitors.

Although data for the key secondary end point of overall survival (OS) were immature at the time of analysis, investigators noted a trend in favor of the pirtobrutinib-based regimen. Additionally, the safety profile of the pirtobrutinib combination was comparable with prior reports of each individual agent, as the rates of adverse effects (AEs) and treatment discontinuation were similar across study arms.

Investigators plan to share detailed findings from the BRUIN CLL-322 trial at a future medical meeting and submit them for publication in a peer-reviewed journal. Additionally, developers at Eli Lilly and Company intend to submit findings to regulatory authorities to support potential label expansions.

“BRUIN CLL-322 was an ambitious trial, building on an effective regimen, and these results outperformed our expectations. Modern CLL treatment regimens provide such durable disease control that the vast majority of patients see their entire disease course managed by only 1 or 2 lines of therapy. For doctors and patients who prefer a time-limited approach, these BRUIN CLL-322 data demonstrate that the addition of [pirtobrutinib] could further extend the duration of benefit in second-line CLL,” Jacob Van Naarden, executive vice president and president at Lilly Oncology, stated in the press release.¹ “Together with the other phase 3 data recently published from the BRUIN clinical program, these data reinforce the potential role that pirtobrutinib may have, whether as a time-limited combination as a second line treatment or as a continuously dosed monotherapy in either line of therapy. We look forward to sharing the detailed data later this year and pursuing regulatory approvals to enable broad access.”

According to the press release, the findings reported in BRUIN CLL-322 affirm prior data from the BRUIN clinical program, which include the following trials:

• The phase 3 BRUIN CLL-321 trial (NCT04666038) assessing pirtobrutinib vs investigator’s choice of idelalisib (Zydelig) plus rituximab or bendamustine (Treanda) plus rituximab;²
• The phase 3 BRUIN CLL-314 trial (NCT05254743) evaluating pirtobrutinib vs ibrutinib (Imbruvica);³
• The phase 3 BRUIN CLL-313 trial (NCT05023980) investigating pirtobrutinib vs bendamustine/rituximab.⁴

How was the BRUIN-322 trial designed?

Investigators of the international, open-label phase 3 BRUIN-322 study assessed time-limited pirtobrutinib plus venetoclax/rituximab vs venetoclax/rituximab alone among those with previously treated CLL or SLL. Overall, 639 patients were randomly assigned 1:1 to receive venetoclax/rituximab alone or in combination with pirtobrutinib at 200 mg once daily.

The trial’s primary end point was PFS per blinded independent review committee assessment. Secondary end points included OS, time to next treatment, event-free survival, overall response rate, time to worsening of physical function, and safety.

Patients 18 years and older with a confirmed diagnosis of CLL/SLL per International Workshop on CLL 2018 criteria were eligible for enrollment on the trial.⁵ Other eligibility requirements included having prior treatment with at least 1 line of treatment, which may have included a covalent BTK inhibitor; adequate organ function; and an ECOG performance status of 0 to 2.

References

1. Lilly's Jaypirca (pirtobrutinib) significantly extended progression-free survival when added to a venetoclax time-limited regimen in patients with previously treated CLL/SLL. News release. Eli Lilly and Company. April 13, 2026. Accessed April 14, 2026. https://tinyurl.com/bdzc4ja8
2. 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 April 14, 2026. https://tinyurl.com/35v9ry65
3. Lilly's Jaypirca (pirtobrutinib) met its primary endpoint in first-of-its-kind, head-to-head phase 3 study versus Imbruvica (ibrutinib). News release. Eli Lilly and Company. December 7, 2025. Accessed April 14, 2026. https://tinyurl.com/32kc8p3k
4. Lilly's Jaypirca (pirtobrutinib) significantly improved progression-free survival, reducing the risk of progression or death by 80%, versus chemoimmunotherapy in patients with treatment-naïve CLL/SLL. News release. Eli Lilly and Company. December 9, 2025. Accessed April 14, 2026. https://tinyurl.com/d2w66zb2
5. 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). ClinicalTrials.gov. Updated January 29, 2026. Accessed April 14, 2026. https://tinyurl.com/39nw9ac9