CHMP Recommends Pirtobrutinib for EU Approval in CLL Across All Lines of Therapy

The European Medicines Agency's Committee for Medicinal Products for Human Use (CHMP) has adopted a positive opinion recommending pirtobrutinib (Jaypirca) for the treatment of adults with chronic lymphocytic leukemia (CLL) spanning all lines of therapy and irrespective of previous exposure to BTK inhibition, according to a news release from Eli Lilly and Company.¹ The application now advances to the European Commission, with a final decision expected within 1 to 2 months.

The recommendation is supported by findings from the phase 3 BRUIN CLL-313 (NCT05023980) and BRUIN CLL-314 (NCT05254743) trials, presented at the 2025 ASH Annual Meeting and published in the Journal of Clinical Oncology.^2,3

"The strong efficacy and tolerability demonstrated in these trials underscores the clinical value pirtobrutinib may offer patients," Paolo Ghia, MD, professor of medical oncology at Universita Vita-Salute San Raffaele and IRCCS Ospedale San Raffaele in Milan, Italy, stated in the news release.

What did BRUIN CLL-313 show with pirtobrutinib vs bendamustine plus rituximab in treatment-naive CLL/SLL?

BRUIN CLL-313 was a global, randomized, open-label study comparing continuous pirtobrutinib monotherapy at 200 mg orally once daily with 6 cycles of bendamustine plus rituximab (Rituxan; BR) in 282 patients with treatment-naive CLL/SLL without del(17p).² Patients were randomly assigned 1:1 and stratified by IGHV mutation status and Rai stage. Patients assigned to BR were able to crossover to pirtobrutinib upon independent review committee (IRC)–confirmed progression; the effective crossover rate was 52.9%.

Pirtobrutinib met the primary end point of IRC-assessed progression-free survival (PFS), reducing the risk of progression or death by 80.1% (HR, 0.199; 95% CI, 0.107-0.367; P < .0001). The median PFS was not reached with pirtobrutinib vs 33.5 months (95% CI, 32.7-not estimable) with BR, with 24-month PFS rates of 93.4% (95% CI, 87.6-96.5) and 70.7% (95% CI, 61.5-78.1). The investigator-assessed PFS was consistent (HR, 0.186; 95% CI, 0.093-0.371).

The benefit held across high-risk subgroups, including those with TP53 mutations (HR, 0.14; 95% CI, 0.02-1.19) and unmutated IGHV (HR, 0.17; 95% CI, 0.08-0.36). Moreover, IRC-assessed overall response rate (ORR) was 94.3% vs 80.9% (P = .0006). At the time of the interim analysis, which had a median follow-up of 32.2 months, the overall survival (OS) trended in favor of pirtobrutinib (HR, 0.257; 95% CI, 0.070-0.934; P = .0261) despite the crossover allowance.

How did pirtobrutinib compare with ibrutinib in BRUIN CLL-314 across treatment-naive and relapsed/refractory disease?

BRUIN CLL-314 randomly assigned 662 BTK inhibitor-naive patients 1:1 to pirtobrutinib at a once-daily dose of 200 mg or ibrutinib (Imbruvica) at a once daily dose of 420 mg.³ Patients were stratified by del(17p) status and previous lines of therapy; no crossover was allowed. The intention-to-treat (ITT) population comprised 225 treatment-naive (TN) patients and 437 patients with relapsed/refractory (R/R) disease. The dual primary end points were IRC-assessed ORR in the ITT and R/R populations.

Pirtobrutinib showcased statistically significant noninferiority for IRC-assessed ORR in both populations (P < .0001).³ In the ITT population, the ORR was 87.0% (95% CI, 82.9%-90.4%) with pirtobrutinib vs 78.5% (95% CI, 73.7%-82.9%) with ibrutinib (odds ratio, 1.11; 95% CI, 1.03-1.19). In the R/R population (n = 437), the respective ORRs were 84.0% (95% CI, 78.5%-88.6%) and 74.8% (95% CI, 68.5%-80.4%; odds ratio, 1.12; 95% CI, 1.02-1.24). Among TN patients (n = 225), the ORR was 92.9% (95% CI, 86.4%-96.9%) with pirtobrutinib vs 85.8% (95% CI, 78.0%-91.7%) with ibrutinib.

Investigator-assessed PFS favored pirtobrutinib in the ITT (HR, 0.57; 95% CI, 0.39-0.83), R/R (HR, 0.73; 95% CI, 0.47-1.13), and TN (HR, 0.24; 95% CI, 0.10-0.59) populations, with the largest treatment effect and longest follow-up in the TN subgroup. OS remained immature (ITT HR, 0.96; 95% CI, 0.55-1.69).

What was the safety profile of pirtobrutinib across the BRUIN CLL trials?

In BRUIN CLL-313, grade 3 or higher treatment-emergent adverse effects (TEAEs) were reported in 40.0% of pirtobrutinib-treated patients vs 67.4% of those receiving BR, with neutropenia the most common in both arms (7.1% vs 34.8%).² AE-related dose reductions occurred in 3.6% vs 31.1% of patients, and discontinuations due to TEAEs occurred in 4.3% vs 15.2% of patients. Any-grade bleeding was more frequent with pirtobrutinib (25.7% vs 1.5%), although grade 3 or higher hemorrhage was rare (0.7%); rates of atrial fibrillation/flutter were low in both arms (1.4% vs 1.5%).

In BRUIN CLL-314, any-grade TEAEs (97.0% vs 97.8%) and grade 3 or higher TEAEs (54.8% vs 53.5%) were comparable between the pirtobrutinib and ibrutinib arms.³ Cardiac AEs of interest favored pirtobrutinib: atrial fibrillation/flutter occurred in 2.4% (grade ≥ 3, 0.9%) vs 13.5% (grade ≥ 3, 4.0%) with ibrutinib, and hypertension occurred in 10.6% vs 15.1% of patients. Patient-reported symptomatic AEs, including myalgia, bruising, headache, diarrhea, and cough, were numerically lower with pirtobrutinib in an exploratory analysis.

What’s next for pirtobrutinib?

Lilly has also submitted the data to the FDA, with a decision anticipated in the second half of 2026.¹

References

1. Eli Lilly and Company. 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. June 26, 2026. Accessed June 26, 2026. https://investor.lilly.com/news-releases/news-release-details/lillys-jaypirca-pirtobrutinib-recommended-chmp-approval-0
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. 2025;44(6):466-475. doi:10.1200/JCO-25-02380
3. Woyach JA, Qiu L, Grosicki S, et al. Pirtobrutinib versus ibrutinib in treatment-naive and relapsed/refractory chronic lymphocytic leukemia/small lymphocytic lymphoma. J Clin Oncol. 2025;44(6):476-485. doi:10.1200/JCO-25-02477