FDA Approves Pirtobrutinib for Untreated CLL/SLL

The U.S. Food and Drug Administration (FDA) has expanded the approved indication for pirtobrutinib (Jaypirca) to include the treatment of adult patients with previously untreated chronic lymphocytic leukemia or small lymphocytic lymphoma (CLL/SLL) with no known 17p deletion [del(17p)].

Approved on October 2, 2026, this decision authorizes pirtobrutinib as a first-line monotherapy option for eligible treatment-naïve patients. Pirtobrutinib is a highly selective, non-covalent (reversible) Bruton tyrosine kinase (BTK) inhibitor engineered to target both wild-type and C481-mutated BTK proteins without requiring covalent binding to the C481 residue.

Chronic lymphocytic leukemia and small lymphocytic lymphoma represent slow-growing B-cell lymphoproliferative malignancies that account for approximately 25% of new leukemia diagnoses in the United States, with an estimated 22,760 new cases annually. Approximately 92% to 95% of newly diagnosed CLL/SLL cases lack the 17p deletion. The expanded indication establishes pirtobrutinib as an initial targeted option prior to disease progression or exposure to standard covalent BTK inhibitors.

Trial Design and Efficacy Data From BRUIN CLL-313

Regulatory approval was supported by primary results from the pivotal phase 3 BRUIN CLL-313 trial (NCT05023980). The global, open-label, randomized study evaluated 282 adult patients with previously untreated CLL/SLL lacking del(17p). Participants were randomized 1:1 to receive oral pirtobrutinib 200 mg once daily (n = 141) or standard chemoimmunotherapy comprising bendamustine plus rituximab (BR; n = 141).

The primary endpoint of Independent Review Committee (IRC)-assessed progression-free survival (PFS) demonstrated a statistically significant improvement with pirtobrutinib compared to BR. At a median follow-up of 28 months, pirtobrutinib reduced the risk of disease progression or death by 80% (hazard ratio [HR], 0.20; 95% CI, 0.11–0.37; p < 0.0001). Median PFS was not reached in the pirtobrutinib group versus 33.5 months in the BR group. The IRC-assessed overall response rate (ORR) was 94% (95% CI, 89–98) for pirtobrutinib (13% complete response [CR], 81% partial response [PR]) compared to 81% (95% CI, 73–87) for BR (21% CR, 60% PR).

Key Clinical Takeaways for Oncology Nurses: Efficacy and Indications

• Target Population Verification: Confirm that adult patients diagnosed with untreated CLL/SLL undergo cytogenetic testing to verify the absence of a known 17p deletion prior to starting first-line pirtobrutinib therapy.
• Superior PFS Performance: BRUIN CLL-313 (NCT05023980) trial data demonstrate an 80% reduction in the risk of progression or death (HR, 0.20; p < 0.0001) with pirtobrutinib monotherapy compared to bendamustine plus rituximab.
• High Overall Response Rate: Pirtobrutinib produced a 94% IRC-assessed ORR in the front-line setting, establishing durable disease control with a median PFS that was not reached at 28 months.
• First-in-Class Reversible Binding: As the first non-covalent BTK inhibitor approved in the first-line setting, pirtobrutinib provides targeted BTK inhibition without requiring covalent modification of C481.

Safety Profile, Warnings, and Adverse Event Management

The prescribing information for pirtobrutinib includes warnings and precautions regarding serious infections, hemorrhage, cytopenias, cardiac arrhythmias, second primary malignancies, hepatotoxicity (including drug-induced liver injury [DILI]), and embryo-fetal toxicity.

In the BRUIN CLL-313 trial, adverse reactions led to pirtobrutinib dose reductions in 3.6% of patients and permanent treatment discontinuation in 4.3%.

Serious adverse reactions occurred in 28% of patients receiving pirtobrutinib, with pneumonia being the most frequent serious event (5%). All-grade atrial fibrillation or flutter occurred in 1.4% of pirtobrutinib-treated patients.

Common all-grade adverse reactions (≥20%) reported with pirtobrutinib included upper respiratory tract infection (27%), rash (22%), and COVID-19 (21%). Common worsening laboratory abnormalities (≥20%) included decreased neutrophil count (48%), increased total bilirubin (30%), increased ALT (27%), decreased hemoglobin (24%), and elevated sodium (20%).

Across pooled safety data in B-cell malignancies, severe (Grade ≥3) infections occurred in 23% to 24% of patients, and major hemorrhage occurred in 3.1%. Baseline and ongoing evaluations of liver function tests (bilirubin and transaminases) and complete blood counts are required.

Key Clinical Takeaways for Oncology Nurses: Safety and Patient Management

• Infection and Cytopenia Surveillance: Obtain baseline complete blood counts and monitor regularly for neutropenia (48%) and anemia (24%); educate patients on reporting fever or signs of pneumonia immediately.
• Cardiac Risk Assessment: Screen patients for history of cardiac arrhythmias or hypertension; monitor for palpitations, dizziness, and dyspnea, noting a 1.4% rate of atrial fibrillation/flutter in front-line trial data.
• Hemorrhage Precaution Protocols: Assess for bleeding signs and evaluate antithrombotic therapy use; consider withholding pirtobrutinib for 3 to 7 days before and after elective surgical procedures based on bleeding risk.
• Hepatotoxicity and DILI Monitoring: Perform baseline transaminase and bilirubin tests; increase lab frequency if liver enzyme elevations occur and discontinue treatment if DILI is confirmed.
• Pregnancy and Lactation Guidance: Verify negative pregnancy status before initiating therapy; counsel female patients of reproductive potential to use effective contraception during treatment and for one week after the final dose, and instruct lactating women not to breastfeed.

Administration, Drug Interactions, and Guidelines

Pirtobrutinib is supplied as 100 mg and 50 mg tablets. The recommended dosage is 200 mg taken orally once daily with or without food until disease progression or unacceptable toxicity.

Concomitant use with strong CYP3A inhibitors increases pirtobrutinib exposure and should be avoided; if unavoidable, pirtobrutinib dosage should be reduced per labeling guidelines. Strong and moderate CYP3A inducers decrease exposure and should be avoided. A starting dose reduction is required in patients with severe renal impairment. National Comprehensive Cancer Network (NCCN) Guidelines list pirtobrutinib as a Category 2A recommendation for treatment-naïve patients with CLL/SLL without del(17p).

Reference

1. Eli Lilly and Company. 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. Press release. Published October 2, 2026. Accessed October 2, 2026. https://investor.lilly.com/news-releases/news-release-details/lillys-jaypirca-pirtobrutinib-first-and-only-approved-non-1