On December 3, 2025, the U.S. Food and Drug Administration granted traditional approval to pirtobrutinib (Jaypirca, Eli Lilly and Company) for adult patients with relapsed or refractory chronic lymphocytic leukemia or small lymphocytic lymphoma (CLL/SLL) who have previously been treated with a covalent BTK inhibitor.
In 2023, pirtobrutinib received accelerated approval for adults with CLL/SLL who had received at least two prior lines of therapy, including both a BTK inhibitor and a BCL-2 inhibitor.
The new decision converts this to traditional approval based on confirmatory evidence from a randomized trial.
BRUIN-CLL-321 trial (NCT04666038)
Efficacy was evaluated in BRUIN-CLL-321, a randomized, open-label, active-controlled trial.
- Study population
- 238 patients with previously treated CLL/SLL
- All had prior exposure to a covalent BTK inhibitor
- Patients previously treated with a non-covalent BTK inhibitor were not eligible
- Treatment arms (1:1 randomization)
- Pirtobrutinib monotherapy
- Investigator’s choice of:
- Idelalisib plus a rituximab product (IR), or
- Bendamustine plus a rituximab product (BR)
- Crossover
- Patients in the investigator’s choice arm were allowed to cross over to Jaypirca monotherapy upon confirmed disease progression.
- Primary endpoint
- Progression-free survival (PFS), assessed by an independent review committee according to 2018 iwCLL criteria
- Key secondary endpoint
- Overall survival (OS), among others
Efficacy: PFS benefit vs investigator’s choice
Pirtobrutinib demonstrated a statistically significant improvement in PFS compared with investigator’s choice of IR/BR.
- Median PFS
- Pirtobrutinib: 11.2 months (95% CI: 9.5, 11.4)
- IR/BR: 8.7 months (95% CI: 7.2, 10.2)
- Hazard ratio: 0.58 (95% CI: 0.38, 0.89); p = 0.0105
- Overall survival (updated analysis, median follow-up 19.8 months)
- HR for OS: 1.09 (95% CI: 0.68, 1.75)
Thus, while PFS was clearly improved, OS differences have not yet emerged, likely reflecting crossover and subsequent therapies.
Safety profile and key warnings
The prescribing information for Jaypirca includes warnings and precautions for:
- Infections
- Hemorrhage
- Cytopenias
- Cardiac arrhythmias
- Secondary primary malignancies
- Hepatotoxicity
- Embryo-fetal toxicity
Given that patients with relapsed/refractory CLL/SLL are often older and heavily pretreated, careful monitoring of infection risk, bleeding, blood counts, cardiac status, and liver function is essential in routine practice.
Recommended dosage
The recommended dose of pirtobrutinib is:
- 200 mg orally once daily
- Continued until disease progression or unacceptable toxicity
Regulatory notes: traditional approval and orphan designation
- This review utilized the Assessment Aid, a voluntary submission from the sponsor designed to facilitate the FDA’s assessment.
- Pirtobrutinib has received orphan drug designation for CLL/SLL.
The approval fits within the broader FDA framework of expedited programs for serious conditions, described in the guidance “Expedited Programs for Serious Conditions – Drugs and Biologics.”
Editorial perspective (Morningglorysciences)
Pirtobrutinib is a highly selective, non-covalent BTK inhibitor developed to address resistance and intolerance to first-generation covalent BTK inhibitors.
In modern CLL management, where covalent BTK inhibitors and BCL-2 inhibitors are widely used, therapeutic sequencing in the relapsed/refractory setting has become increasingly complex.
BRUIN-CLL-321 provides randomized evidence that, in patients previously treated with a covalent BTK inhibitor, pirtobrutinib can:
- Prolong PFS versus physician’s choice of IR/BR
- Offer an oral, once-daily option that avoids some of the logistical burdens of chemoimmunotherapy
However, several questions remain:
- How best to position pirtobrutinib relative to BCL-2 inhibitor–based regimens in earlier or later lines
- Long-term safety signals, including secondary malignancies and infection risk with extended BTK inhibition
- Impact on OS in the presence of crossover and evolving subsequent therapies
In summary, conversion from accelerated to traditional approval solidifies Jaypirca as a key component of the post–covalent BTK treatment landscape in CLL/SLL, while ongoing data will further refine its place in personalized sequencing strategies.
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