FDA Approves Pirtobrutinib for Relapsed or Refractory Chronic Lymphocytic Leukemia

The FDA has granted traditional approval to pirtobrutinib (Jaypirca; Eli Lilly and Company) 100-mg and 50-mg tablets for adults with relapsed or refractory (RR) chronic lymphocytic leukemia or small lymphocytic lymphoma (CLL/SLL) who were previously treated with a covalent Bruton tyrosine kinase (BTK) inhibitor, according to news releases from Eli Lilly and the FDA.^1,2

Pirtobrutinib was previously granted accelerated approval by the FDA for the same indication for patients who have received at least 2 prior lines of therapy, including a BTK inhibitor and a BCL-2 inhibitor. This new action expands the label to include patients earlier in their course of treatment and allows for pirtobrutinib to be used immediately following a covalent BTK inhibitor. According to Eli Lilly, pirtobrutinib remains the only available non-covalent (reversible) BTK inhibitor on the market.³

"Pirtobrutinib is the only medicine in CLL or SLL that has been prospectively studied in a randomized trial of patients previously treated with a covalent BTK inhibitor, and I am excited to see this expanded FDA approval recognize the benefit it can deliver to this broader group of patients," Jeff Sharman, MD, one of the principal investigators of the pivotal BRUIN CLL-321 (NCT04666038), said in a news release from Eli Lilly.^1,4

How Effective Was Pirtobrutinib in Increasing Progression-Free Survival?

In BRUIN CLL-321, a phase 3, randomized, open-label, active-controlled trial, 238 patients were randomized 1:1 to receive 200 mg orally of pirtobrutinib once daily or an investigator's choice of idelalisib (Zydelig; Gilead Sciences) plus rituximab (Rituxan; Genentech) (IdelaR) or bendamustine (Bendeka; Teva Pharmaceuticals) plus rituximab (BR). The primary end point of BRUIN CLL-321 was progression-free survival (PFS) as determined by the 2018 International Workshop on Chronic Lymphocytic Leukemia (iwCLL) guidelines. Secondary end points included overall response rate (ORR) and duration of response (DoR), in addition to safety, tolerability, and patient-reported outcomes.^1,2

An independent review committee assessed PFS. The median PFS was 11.2 months (95% CI, 9.5–11.4) in the pirotbrutinib arm and 8.7 months (95% CI, 7.2–10.2) in the investigator’s choice arm. A crossover from the IdelaR/BR arm to pirtobrutinib monotherapy was permitted following confirmed disease progression; of the 119 patients in the investigator’s choice arm, 50 crossed over to receive pirtobrutinib therapy, according to study investigators.^2,5

Updated analyses, undertaken after a median follow-up time of 19.8 months, indicated the hazard ratio for overall survival (OS) in treated patients was 1.09 (95% CI, 0.68–1.75). The 18-month OS rate was 73.4% (95% CI, 63.9–80.7) in the pirtobrutinib group and 70.8% (95% CI, 60.9–78.7).^2,5

Safety at a median follow-up of 17.2 months was reported. Grade 3 or higher treatment-emergent adverse events (AEs) were found to be lower in patients treated with pirtobrutinib (57.7%) compared with the investigator’s choice (73.4%). Furthermore, treatment was discontinued due to an AE in 20 patients (17.2%) receiving pirtobrutinib and 38 (34.9%) patients receiving an investigator’s choice of treatment, demonstrating favorable tolerability.⁵

"For CLL or SLL patients who progress following treatment with an irreversible or covalently binding BTK inhibitor, having additional therapeutic options is critical," Brian Koffman, MD, co-founder and chief medical officer emeritus at the CLL Society, said in the news release from Eli Lilly. “With this approval, physicians and patients can stay in the same broad class of medicines with a treatment that offers meaningful impact on patient outcomes, saving the potential to use medicines with different targets for later therapy."¹

Oncologists and pharmacists that work as part of oncology teams will now have greater ability to treat patients with RR CLL/SLL earlier in their treatment course, potentially improving outcomes for thousands. Pharmacists will play a critical role in managing patients using pirtobrutinib, staying aware for AEs, and dosing and treatment administration.

REFERENCES

1. U.S. FDA approves expanded indication for Lilly's Jaypirca (pirtobrutinib), the first and only non-covalent (reversible) BTK inhibitor, for adults with relapsed or refractory CLL/SLL previously treated with a covalent BTK inhibitor. News Release. Eli Lilly and Company. Released December 3, 2025. Accessed December 3, 2025. https://investor.lilly.com/news-releases/news-release-details/us-fda-approves-expanded-indication-lillys-jaypirca

2. FDA grants traditional approval to pirtobrutinib for chronic lymphocytic leukemia and small lymphocytic lymphoma. News Release. FDA. Released December 3, 2025. Accessed December 3, 2025. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-grants-traditional-approval-pirtobrutinib-chronic-lymphocytic-leukemia-and-small-lymphocytic?utm_medium=email&utm_source=govdelivery

3. McGovern G. FDA approves pirtobrutinib for treatment of adult patients with CLL, SLL. Pharmacy Times. Published December 4, 2023. Accessed December 3, 2025. https://www.pharmacytimes.com/view/fda-approves-pirtobrutinib-for-treatment-of-adult-patients-with-cll-sll

4. Study of LOXO-305 (pirtobrutinib) versus investigator’s choice (idelalsib plus rituximab or bendamustine plus rituximab) in patients with previously treated chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma (SLL) (BRUIN CLL-321). ClinicalTrials.gov Identifier: NCT04666038. Updated April 4, 2025. Accessed December 3, 2025. https://www.clinicaltrials.gov/study/NCT04666038

5. Sharman JP, Munir T, Grosicki S, et al. Phase III trial of pirtobrutinib versus idelalisib/rituximab in covalent Bruton tyrosine kinase inhibitor—pretreated chronic lymphocytic leukemia/small lymphocytic lymphoma (BRUIN CLL-321). J Clin Oncol. 2025:43(22). doi:10.1200/JCO-25-00166