FDA approves Lilly's Jaypirca as first-line CLL therapy

On October 5, 2026, the FDA approved Eli Lilly's pirtobrutinib (Jaypirca) as a first-line therapy for adults with untreated chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL) without 17p deletions. Unlike covalent BTK inhibitors, pirtobrutinib is noncovalent, allowing it to overcome resistance mutations. The approval is based on the BRUIN CLL-313 trial, where pirtobrutinib demonstrated superior progression-free survival compared to standard chemoimmunotherapy.

Indications for pirtobrutinib

• ▪Pirtobrutinib was previously approved for chronic lymphocytic leukemia or small lymphocytic lymphoma only after at least two prior lines of therapy, including a Bruton tyrosine kinase inhibitor and a BCL-2 inhibitor
• ▪The CLL/SLL indications for covalent Bruton tyrosine kinase inhibitors acalabrutinib, zanubrutinib, and ibrutinib do not exclude patients with chromosome 17p deletions, whereas the first-line CLL/SLL indication for pirtobrutinib does
• ▪On October 5, 2026, the FDA approved Eli Lilly's pirtobrutinib, marketed as Jaypirca, for adults with previously untreated chronic lymphocytic leukemia or small lymphocytic lymphoma with no known 17p deletion

BRUIN CLL-313 trial design

• ▪Patients with chromosome 17p deletions were excluded from the BRUIN CLL-313 trial because bendamustine plus a rituximab product was not considered appropriate treatment for them
• ▪The FDA approval of pirtobrutinib was based on the BRUIN CLL-313 trial, which randomized 282 previously untreated patients to receive either pirtobrutinib or bendamustine plus a rituximab product

Safety results of the BRUIN CLL-313 trial

• ▪In the BRUIN CLL-313 trial, the most common adverse events in the pirtobrutinib arm were upper respiratory tract infections (27%), rash (22%), and COVID-19 (21%)
• ▪In the BRUIN CLL-313 trial, 28% of patients receiving pirtobrutinib experienced serious adverse events, including pneumonia in 5% of patients, with neutropenia being the most common grade 3 or 4 laboratory abnormality

Debatable claims

• ▪Reserving Jaypirca for later-line therapy is clinically superior to using it as a first-line treatment
• ▪Excluding high-risk patients from first-line leukemia trials is unjustified
• ▪Progression-free survival is an insufficient metric for approving first-line leukemia treatments
• ▪The FDA should reject clinical trials that use outdated control arms for drug approvals