FDA Approves Pirtobrutinib for Previously Untreated CLL/SLL

The FDA has approved pirtobrutinib (Jaypirca; Eli Lilly and Company) for adults with previously untreated chronic lymphocytic leukemia or small lymphocytic lymphoma (CLL/SLL) with no known 17p deletion, moving the first noncovalent Bruton tyrosine kinase (BTK) inhibitor into the first-line setting. Because the once-daily oral agent is taken until disease progression or unacceptable toxicity, pharmacists may now manage its drug interactions, bleeding risk, and laboratory monitoring across years of continuous therapy.¹

The expansion follows a December 2025 approval for adults with relapsed or refractory CLL/SLL previously treated with a covalent BTK inhibitor. Pirtobrutinib also holds accelerated approval for relapsed or refractory mantle cell lymphoma after at least 2 lines of systemic therapy, including a BTK inhibitor.¹

BRUIN CLL-313 Results

The approval rests on the open-label phase 3 BRUIN CLL-313 trial (NCT05023980), which randomly assigned 282 patients with untreated CLL/SLL without del(17p) 1:1 to pirtobrutinib 200 mg once daily or bendamustine plus rituximab (BR). The primary end point was progression-free survival (PFS) assessed by an independent review committee.^1,2

At a median follow-up of 28 months, PFS was significantly longer with pirtobrutinib (HR, 0.20; 95% CI, 0.11-0.37; P < .0001). Median PFS was not reached with pirtobrutinib versus 33.5 months with BR, and 24-month PFS rates were 93.4% and 70.7%, respectively. Overall response rates were 94% vs 81%, although complete responses were more frequent with BR (21% vs 13%). An interim overall survival analysis favored pirtobrutinib (HR, 0.257; 95% CI, 0.070-0.934) despite an effective crossover rate of 52.9%.^1,2

Safety and Tolerability

Compared with BR, pirtobrutinib led to fewer adverse event–related dose reductions (3.6% vs 31.1%), fewer grade 3 or higher treatment-emergent adverse events (40.0% vs 67.4%), and fewer discontinuations due to adverse events (4.3% vs 15.2%).²

Serious adverse reactions occurred in 28% of patients receiving pirtobrutinib, most commonly pneumonia (5%). All-grade atrial fibrillation or flutter occurred in 1.4%, though patients with significant cardiovascular disease were excluded. The most common adverse reactions were upper respiratory tract infection (27%), rash (22%), and COVID-19 (21%).¹

Monitoring and Counseling Considerations

Labeling includes warnings for infections, hemorrhage, cytopenias, cardiac arrhythmias, second primary malignancies, hepatotoxicity including drug-induced liver injury, and embryo-fetal toxicity. Bilirubin and transaminases should be evaluated at baseline and throughout treatment, complete blood counts monitored regularly, and prophylaxis, including vaccinations and antimicrobials, considered for patients at increased infection risk.¹

Strong CYP3A inhibitors and strong or moderate CYP3A inducers should be avoided, with dose adjustments per labeling if coadministration is unavoidable. Pirtobrutinib also raises concentrations of sensitive CYP2C8, CYP2C19, CYP3A, P-gp, and BCRP substrates. Because major hemorrhage occurred with and without antithrombotic agents, the label advises weighing coadministration and considering holding pirtobrutinib 3 to 7 days before and after surgery. Patients with severe renal impairment need a dose reduction.¹

Counseling points include sun protection given the risk of nonmelanoma skin cancer, effective contraception, and no breastfeeding during treatment and for 1 week after the last dose.¹

Open Questions

Lilly reports that National Comprehensive Cancer Network guidelines list pirtobrutinib as a category 2A option for treatment-naive adults with CLL/SLL without del(17p). No data are available on optimal sequencing after progression on pirtobrutinib. A recent systematic review called for longer follow-up and head-to-head comparisons with covalent inhibitors to establish its frontline role.^1,3

REFERENCES

1. Lilly's Jaypirca (pirtobrutinib), the first-and-only approved non-covalent BTK inhibitor, receives expanded indication from U.S. FDA for certain patients with previously untreated CLL/SLL. News release. Eli Lilly and Company. October 2, 2026. Accessed October 2, 2026. https://www.prnewswire.com/news-releases/lillys-jaypirca-pirtobrutinib-the-first-and-only-approved-non-covalent-btk-inhibitor-receives-expanded-indication-from-us-fda-for-certain-patients-with-previously-untreated-cllsll-302897416.html

2. Jurczak W, Kwiatek M, Czyz J, et al. BRUIN CLL-313: randomized phase III trial of pirtobrutinib versus bendamustine plus rituximab in untreated patients with chronic lymphocytic leukemia/small lymphocytic lymphoma. J Clin Oncol. 2026;44(6):466-475. doi:10.1200/JCO-25-02380

3. Fatima F, Mirza A, Bhatti MI, Hussain F, Shahzad Z. Pirtobrutinib in chronic lymphocytic leukemia/small lymphocytic lymphoma: a systematic review. Am J Clin Oncol. Published online August 13, 2026. doi:10.1097/COC.0000000000001363