New Pirtobrutinib Data Compare Favorably With Ibrutinib in CLL/SLL

The non-covalent Bruton tyrosine kinase (BTK) inhibitor pirtobrutinib (Jaypirca; Eli Lilly) appears to perform as well as ibrutinib (Imbruvica) in patients with chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL), according to a new study. The results of the phase 3 BRUIN CLL-314 trial were announced in a press release last week.¹

The open-label trial was designed to enroll 650 patients with CLL or SLL who were treatment naive or who were previously treated but BTK-inhibitor naive. The patients were randomized to receive either 200 mg of oral pirtobrutinib or 420 mg of oral ibrutinib once daily. The trial was a non-inferiority trial with its primary endpoint based on overall response rate (ORR) as reviewed by an independent review committee. The investigators found that pirtobrutinib had a nominally superior ORR (P < .05). Similarly, while the progression-free survival (PFS) data was immature at the time of their analysis, the investigators said it was trending in favor of pirtobrutinib.

The company said BRUIN CLL-314 was the first-ever head-to-head trial of pirtobrutinib versus ibrutinib that included treatment-naive patients. | Image credit: fotogurmespb - stock.adobe.com

Jacob Van Naarden, the company’s executive vice president and president of Lilly Oncology, said in a press release that the trial is part of a broader effort at demonstrating pirtobrutinib’s competitiveness with existing therapies.

“We launched the pirtobrutinib randomized development program with an ambitious suite of clinical trials, including head-to-head studies against modern standards of care and examinations of patient populations that reflect real-world use, such as BTK inhibitor-pretreated patients,” he said.

The company said BRUIN CLL-314 was the first-ever head-to-head trial of pirtobrutinib versus ibrutinib that included treatment-naive patients. A total of 225 treatment-naive patients were included. The company said these patients had the longest follow-up and a “particularly pronounced” PFS effect size favoring pirtobrutinib.

Pirtobrutinib is already approved in the United States for the treatment of adults with relapsed or refractory mantle cell lymphoma after at least 2 lines of systemic therapy, including a BTK inhibitor, and for adults with CLL or SLL who have had at least 2 prior lines of therapy, including a BTK inhibitor and a BCL-2 inhibitor.

Van Naarden said the new BRUIN CLL-314 data mark the second positive phase 3 results in their pirtobrutinib development program. In the phase 3 BRUIN-321 trial, the results of which were published in June, investigators found that pirtobrutinib led to improved PFS and time to next treatment or death in a head-to-head comparison with an investigator’s choice of either idelalisib (Zydelig) and rituximab (Rituxan) or bendamustine and rituximab.² The patient population in that trial was patients with relapsed or refractory CLL/SLL who had previously been treated with a covalent BTK inhibitor. The investigators found that patients treated with pirtobrutinib had a median PFS of 14 months (95% CI, 11.2-16.6), while those in the investigator’s choice cohort had a median PFS of 8.7 months (95% CI, 8.1-10.4). The patients in the pirtobrutinib group also had a lower rate of grade 3 or above treatment-emergent adverse events and a lower rate of patients discontinuing due to adverse events.

As for the new trial, Eli Lilly said the safety profile of pirtobrutinib in BRUIN CLL-314 was similar to that reported in previous trials, though they said full data would be presented at a medical conference later this year.¹

“These data mark the second positive phase 3 study in the program, as we continue to build evidence supporting the potential role of pirtobrutinib in treating people with CLL/SLL and hopefully enabling future regulatory approvals that allow physicians to use the medicine in various disease settings, whether treatment-naive or BTK inhibitor-pretreated,” Van Naarden said.

References

1. Lilly's Jaypirca (pirtobrutinib), the first and only approved non-covalent (reversible) BTK inhibitor, met its primary endpoint in a head-to-head Phase 3 trial versus Imbruvica (ibrutinib) in CLL/SLL. News release. Eli Lilly. July 29, 2025. Accessed August 4, 2025. https://investor.lilly.com/news-releases/news-release-details/lillys-jaypirca-pirtobrutinib-first-and-only-approved-non

2. Sharman JP, Munir T, Grosicki S, et al. Phase III Trial of pirtobrutinib versus idelalisib/rituximab or bendamustine/rituximab in covalent Bruton tyrosine kinase inhibitor-pretreated chronic lymphocytic leukemia/small lymphocytic lymphoma (BRUIN CLL-321). J Clin Oncol. 2025;43(22):2538-2549. doi:10.1200/JCO-25-00166