In the world of oncology drug development, the standard playbook is simple: Race to earlier lines of treatment, where patient populations are larger. But Eli Lilly is flipping that script with its blood cancer offering, Jaypirca.
Despite holding positive phase 3 data that position its BTK inhibitor Jaypirca for a first-line approval in chronic lymphocytic leukemia (CLL), Jacob Van Naarden, president of Lilly Oncology, maintained that the drug’s primary value proposition remains in serving patients who require second-line treatment.
“The main use case of the medicine, I think, remains in second-line,” Van Naarden said in an interview with Fierce Pharma.
Lilly is defying the typical earlier-is-better strategy of cancer drug commercialization, but not because Jaypirca’s first-line data are weak. In fact, results from two phase 3 studies unveiled at the American Society of Hematology (ASH) 2025 annual meeting suggest Jaypirca could be a competitive first-line drug in CLL, posing a threat to existing BTK inhibitors from BeOne Medicines, AstraZeneca, and a partnership between AbbVie and Johnson & Johnson.
Jaypirca significantly reduced the risk of progression or death by 80% compared with the traditional regimen of bendamustine and rituximab (BR) in patients with previously untreated CLL or small lymphocytic lymphoma (SLL), according to data from the Bruin CLL-313 trial presented at ASH on Dec. 9.
At two years, an estimated 93% of patients who received Jaypirca were still alive without progression, versus 71% for those on BR. The median follow-up time of the data was about 28 months.
Progression-free survival (PFS) benefits of Jaypirca were consistent across patient subpopulations, with an effect size around or above 70% for every prespecified subgroup analyzed.
That data set immediately drew a comparison to results from the phase 3 Sequoia trial of BeOne’s Brukinsa, which recently became the best-selling BTK by quarterly sales. In that first-line CLL/SLL study, Brukinsa improved PFS by 58% compared with, BR with a median follow-up of about 26 months. After a long-term, median five-year follow-up, Brukinsa’s PFS benefit increased to 71%.
“These data suggest [Jaypirca] could be an option for 1L CLL patients and may command a larger market presence than was previously anticipated,” Leerink Partners analysts said in a Nov. 24 note when ASH released the top-line Bruin CLL-313 data in a late-breaking abstract.
In another phase 3 study, coded Bruin CLL-314, Jaypirca showed a numerically higher overall response rate of 87% compared with 78.5% for AbbVie and J&J’s aging Imbruvica in CLL/SLL patients who were treatment-naïve or were new to a BTK inhibitor. PFS results were not mature in the head-to-head study yet, but so far strongly favored Jaypirca by a risk reduction of 43% in the overall population or 76% in the first-line subgroup, according to investigators’ assessments.
The rate of cardiovascular side effects—specifically atrial fibrillation and flutter—which are known problems with Imbruvica, was notably lower in the Jaypirca group, at 2.4% at any grade, versus 13.5% for Imbruvica. Similarly, in the Bruin CLL-313 trial, this rate was 1.4% for the Jaypirca arm and 1.5% for BR. For context, BeOne’s Brukinsa showed a 3.3% rate in Sequoia after a similar follow-up period.
Despite the impressive first-line data, Lilly’s Van Naarden argued that Jaypirca’s value lies not in displacing entrenched first-line options, but in serving as a unique option in the second-line setting. “What Jaypirca can do in second-line, none of the other BTKs can do,” he said.
Van Naarden has held that view ever since Jaypirca delivered its pivotal data in relapsed or refractory CLL three years ago.
CLL patients are typically diagnosed at a relatively old age. And, because of how well BTK drugs can control the disease, the vast majority of CLL patients may get just two lines of therapy before they die of other causes. As a result, doctors want to have a reliable second-line option, Van Naarden explained.
Jaypirca, as the first nonvalent, reversible BTK inhibitor, is currently the only BTK med approved for use after other covalent BTK inhibitors.
For now, there’s no conclusive evidence on whether a covalent BTK inhibitor can be used after a noncovalent counterpart, an important data gap that Van Naarden acknowledged needs to be addressed. Additional Bruin CLL-313 results might provide some answers to that question, but, with only 13 (9.2%) patients having progressed following Jaypirca by the data cutoff, more follow-up is needed to offer any meaningful information, the Lilly exec noted. Without that, most doctors, while trying to preserve treatment options for relapsed patients, are expected to save Jaypirca for the second line.
That is not to say that Jaypirca won’t get any first-line use if approved. Doctors may estimate that some patients might only ever get one line of therapy, while some doctors are comfortable using AbbVie and Roche’s Venclexta in the second-line setting, Van Naarden said. In addition, some docs may want to be mindful of the cardiovascular toxicity profiles of the various options.
“When you add it all together, do I think Jaypirca will be the dominant player in first-line? No, I don’t. That’s never been our thesis, and I’m sticking with it,” Van Naarden said. “But I think that these data are good enough that it will make people think about it in certain situations.”
Lilly is now bringing the data to the FDA for potential filing discussions. But a couple of uncertainties remain for the company’s regulatory path.
First, the two phase 3 trials only included a small number of U.S. patients. In Bruin CLL-313, only seven (2.5%) patients were from North America. In Bruin-CLL-314, the proportion was 7.1%.
In rejecting a combo of Roche’s Columvi for the second-line treatment of another blood cancer, diffuse large B-cell lymphoma, the FDA highlighted a lack of representation of the U.S. population, along with inconsistent data in U.S. patients compared with those in Asia.
Jaypirca’s situation is different, Van Naarden argued. Columvi’s case was anchored on a large Asian population and data discordance across geographies. Jaypirca’s trials enrolled many patients from Europe, and their data are consistent across regions.
There’s also a possibility that the FDA may want to see longer-term data. Overall survival data from Bruin CLL-313 were immature but favored Jaypirca, with a preliminary 74% reduction in the risk of death versus BR despite a 53% crossover rate. However, BR is a weak comparator in the first-line setting, which might explain the low U.S. enrollment. And PFS data from the Imbruvica head-to-head trial, Bruin CLL-314, remained immature.
Lilly will submit the data and get the FDA’s reaction, Van Naarden said. “I think the data are objectively strong and, in many ways, better than my expectations going into them.”