In patients with BTK-pretreated chronic lymphocytic leukemia (CLL), AbbVie and Roche’s Venclexta (venetoclax) is the drug to beat. But no companies had taken a daunting head-to-head challenge—until Eli Lilly made the leap of faith with its Jaypirca.
Now, Lilly can say that the bet has paid off.
The phase 3 Bruin CLL-322 trial tested whether adding Jaypirca, a non-covalent BTK inhibitor, could improve on venetoclax and rituximab in patients with relapsed or refractory CLL or small lymphocytic lymphoma (SLL).
Before this trial, new drugs venturing into previously treated CLL have never been pitted against a BCL2-based regimen. Instead, they were mostly compared with a combination of chemotherapy and rituximab. These include Lilly’s own Bruin CLL-321 trial that won Jaypirca its second-line approval in December 2025.
Because the control arm is very active, experts knew the trial had a good chance of failing, Jake Van Naarden, president of Lilly Oncology, recalled to Fierce.
“I was extremely nervous about this readout,” Van Naarden said in an interview. “In light of that, to see data that are this compelling, I was blown away when we unblinded this.”
The data Van Naarden saw, presented Sunday at the 2026 European Hematology Association, showed that the addition of Jaypirca to a fixed-duration regimen with venetoclax and rituximab reduced the risk of disease progression or death by 45.3%.
The median progression-free survival (PFS) time was not reached for the Jaypirca triplet and was 39.7 months for venetoclax plus rituximab. At two years, 86.9% of patients in the Jaypirca arm were alive without their disease worsening, while 71.8% of those in the control arm could say that.
Among a subgroup of second-line patients who had progressed on a covalent BTK inhibitor as their first-line treatment—a setting that Van Naarden called the “central idea of the Jaypirca story”—adding Jaypirca led to a massive 67.7% PFS improvement. For all patients who had previously progressed following a BTK drug at any time, Jaypirca’s PFS benefit stood at 55.6%.
The latest phase 3 readout won’t get Jaypirca into a new treatment setting. But if endorsed by the FDA, it could enable the drug to be used in a time-limited fashion on top of a venetoclax-based regimen, rather than being taken alone indefinitely until disease progression or unacceptable toxicity. With the majority of patients having previously tried a covalent BTK inhibitor, the trial reflects the modern CLL treatment practice.
“It’s really in the second-line, post-covalent world where I think there’s the most energy for the medicine,” Van Naarden said. “And for that idea, this randomized trial probably comes the closest to encapsulating that.”
Among all 639 patients enrolled in Bruin CLL-322, 43.5% only received one prior line of therapy and nearly 80% had received a BTK inhibitor before.
Previously, the Bruin CLL-321 enrolled a sicker group of patients, or, in Van Naarden’s words, it was “almost like a fourth-line study.”
In that study, Jaypirca showed a median PFS of 14 months, versus 8.7 months for patients who received a combo that included rituximab either with bendamustine or Gilead’s PI3K inhibitor Zydelig.
Among venetoclax-naïve patients, the median time to next-line treatment (TTNT) in the Jaypirca arm of that study was 29.5 months.
The current Bruin CLL-322 trial does not allow prior BCL2 exposure. By 24 months, 87.7% of Jaypirca recipients have not yet reached their next line of treatment, compared with 77.2% for the control arm. The median TTNT looks to be trending beyond 52 months for both arms.
Van Naarden also touted Jaypirca’s toxicity profile as part of “a really compelling package.” Despite the addition of a third medicine, patients didn’t experience much additional side effects.
Grade 3 or above treatment-emergent adverse events were recorded in 78.8% of patients in the Jaypirca arm, versus 73% for control. The rates of cardiovascular toxicity, an issue of concern for the BTK class, were low in both arms. Any grade or grade 3 or above atrial fibrillation or flutter were seen in 3.5% and 1.9% of patients in the Jaypirca arm, respectively, versus 2.6% and 1% for control. For hypertension, the numbers were 12% and 5.1%, versus 7.4% and 2.9%, respectively.
Tumor lysis syndrome, a potentially serious problem with venetoclax, somehow got better in the Jaypirca group, with a rate of 1.3% (0.9% of grade 3 or above), compared with 4.2% (3.9% grade 3 or above) in the control arm.
Overall survival data remained immature with a median follow-up of 30.6 months but favoring Jaypirca with a preliminary 10.9% improvement.
Despite the unexpectedly strong results, Bruin CLL-322 did not answer the question of whether Jaypirca should be used in a fixed duration or indefinitely.
“I don’t think we need to prove that question,” Van Naarden said. “The reason I say that is because, when I speak to physicians out there, they just want to have choice.”
The message from both Bruin CLL-321 and Bruin CLL-322 is that CLL patients should get Jaypirca as a second-line treatment, he said.
As to whether some doctors would want to save Jaypirca following Venclexta, Van Naarden noted that most CLL patients only get up to two lines of therapy, so doctors are coming around to the idea of using the best treatments upfront.
Besides, the Lilly exec figured that patients who relapsed following about two years of treatment on the Bruin CLL-322 regimen could be rechallenged with those drugs, although he acknowledged that he doesn’t have the data to back it up. At least for Venclexta, doctors have been retreating some patients with the BCL2 drug with decent efficacy.
AstraZeneca’s covalent BTK inhibitor Calquence, used on top of Venclexta, recently became the first all-oral, fixed-duration regimen approved for first-line CLL/SLL. Lilly is working with the German CLL Study Group on a three-arm phase 3 study testing Jaypirca as part of a fixed-duration first-line regimen as well. The study has a component aiming to leverage minimal residual disease findings to guide treatment duration decisions.