Pirtobrutinib Earns Positive CHMP Opinion Across All CLL Treatment Lines

The Committee for Medicinal Products for Human Use (CHMP) of the European Medicines Agency has issued a positive opinion for pirtobrutinib (Jaypirca), a non-covalent Bruton tyrosine kinase (BTK) inhibitor, for the treatment of adults with chronic lymphocytic leukemia (CLL) across all lines of therapy and regardless of prior BTK inhibitor treatment, according to a news release from Eli Lilly and Company.¹

The recommendation is supported by results from the phase 3 BRUIN CLL-313 (NCT05023980) and BRUIN CLL-314 trials (NCT05254743). The application has been referred to the European Commission, with a final decision expected in the next 1 to 2 months.

What did BRUIN CLL-313 show in treatment-naive CLL?

BRUIN CLL-313 evaluated pirtobrutinib against bendamustine (Treanda) plus rituximab (Rituxan; BR) in patients with treatment-naive CLL or small lymphocytic lymphoma (SLL) without 17p deletions.² At a median follow-up of 28.1 months, pirtobrutinib met the primary end point of independent review committee (IRC)–assessed progression-free survival (PFS), reducing the risk of disease progression or death by 80% (HR, 0.20; 95% CI, 0.11-0.37; P <.0001). The PFS benefit was consistent across all prespecified subgroups, including patients with high-risk features such as TP53 mutations, complex karyotype, and unmutated IGHV. Overall survival (OS) data remained immature at the time of analysis but trended in favor of pirtobrutinib (HR, 0.257; 95% CI, 0.070-0.934; P = .0261) despite 52.9% of patients in the BR arm crossing over to pirtobrutinib after confirmed progression. Grade 3 or higher treatment-emergent adverse events (TEAEs) occurred in 40.0% of patients given pirtobrutinib vs 67.4% of those who received BR.

What did BRUIN CLL-314 show vs ibrutinib?

BRUIN CLL-314 compared pirtobrutinib with the covalent BTK inhibitor ibrutinib (Imbruvica) in patients with treatment-naive or BTK inhibitor–naive CLL/SLL.³ Pirtobrutinib met its primary end point of noninferiority for IRC-assessed overall response rate (ORR), with a numerically higher rate of 87.0% (95% CI, 82.90%-90.44%) vs 78.5% (95% CI, 73.73%-82.85%) for ibrutinib (P <.0001). PFS data were immature but trended in favor of pirtobrutinib across populations, including a 76% reduction in the risk of progression or death in the treatment-naive subgroup (HR, 0.239; 95% CI, 0.098-0.586), which had the longest follow-up. No OS detriment was observed in the intent-to-treat population (HR, 0.961; 95% CI, 0.55-1.69). Rates of atrial fibrillation or flutter (2.4% vs 13.5%) and hypertension (10.6% vs 15.1%) were lower with pirtobrutinib than ibrutinib.

“Results from BRUIN CLL-313 and BRUIN CLL-314 provide compelling evidence that pirtobrutinib can make a meaningful difference for people living with CLL across multiple lines of therapy,” said Paolo Ghia, MD, professor of medical oncology at Università Vita-Salute San Raffaele and IRCCS Ospedale San Raffaele in Milan, Italy, in the press release.¹ “The strong efficacy and tolerability demonstrated in these trials underscores the clinical value pirtobrutinib may offer patients. This positive opinion from the CHMP is an exciting and significant milestone, bringing us closer to a future where pirtobrutinib is an option for more people with CLL across the [EU].”

How were the BRUIN CLL-313 and CLL-314 trials designed?

BRUIN CLL-313 was a global, randomized, open-label, phase 3 study that enrolled 282 patients who were randomly assigned 1:1 to pirtobrutinib at 200 mg orally once daily or BR. The primary end point was blinded IRC-assessed PFS, with secondary end points including ORR, duration of response (DOR), OS, time to next treatment, and safety.

BRUIN CLL-314 was a randomized, open-label, phase 3 study that enrolled 662 patients who were randomly assigned 1:1 to pirtobrutinib at 200 mg orally once daily or ibrutinib at 420 mg orally once daily. Its primary end point was blinded IRC-assessed ORR, with secondary end points including PFS, DOR, event-free survival, time to next treatment, OS, and safety.

How does pirtobrutinib work?

Pirtobrutinib is a highly selective, non-covalent inhibitor of BTK, a validated target across B-cell leukemias and lymphomas including CLL and mantle cell lymphoma. If granted marketing authorization by the European Commission, the positive CHMP opinion would expand pirtobrutinib’s indication to patients with CLL in the EU across all lines of therapy.

References

1. Lilly’s Jaypirca (pirtobrutinib) recommended by CHMP for approval in the European Union for adults with chronic lymphocytic leukemia (CLL) across all lines of therapy. News release. Eli Lilly and Company. June 26, 2026. Accessed June 26, 2026. https://tinyurl.com/ek23sse6
2. Lilly’s Jaypirca (pirtobrutinib) significantly improved progression-free survival, reducing the risk of progression or death by 80%, versus chemoimmunotherapy in patients with treatment-naïve CLL/SLL. News release. Eli Lilly and Company. December 9, 2025. Accessed June 26, 2026. https://tinyurl.com/yhtvdxmb
3. Lilly’s Jaypirca (pirtobrutinib) met its primary endpoint in first-of-its-kind, head-to-head phase 3 study versus Imbruvica (ibrutinib). News release. Eli Lilly and Company. December 7, 2025. Accessed June 26, 2026. https://tinyurl.com/mpw87sc9