According to Jake Van Naarden, president of Lilly Oncology, the excess deaths could be due to the high rate of crossover in BRUIN CLL-321.
Eli Lilly on Monday released results from the Phase III BRUIN CLL-321 study, touting promising survival outcomes in patients with chronic or small lymphocytic leukemia, though safety signals cast a shadow on these findings.
At the final prespecified analysis, Jaypirca reduced the risk of relapse, disease progression or death by 46% as compared with idealisib plus rituximab or bendamustine plus rituximab. The late-stage study focused on adults with chronic lymphocytic leukemia (CLL) or small lymphocytic leukemia (SLL) who had previously been exposed to a covalent BTK blocker.
Jaypirca likewise aced key secondary endpoints, including investigator-assessed progression-free survival, which showed a 52% advantage with the non-covalent BTK inhibitor versus controls. Event-free survival was also significantly better by 61%. Median time to next treatment was 23.9 months in those taking Jaypirca, compared to 10.9 months in comparators—a treatment difference that corresponded to a significant 63% benefit.
Ultimately, 73% of patients in the control arm crossed over to the Jaypirca group, a move that the protocol of BRUIN CLL-321 allowed in the case of confirmed disease progression.
Chief Medical Officer David Hyman said in a company statement that BRUIN CLL-321 is “the only randomized CL or SLL study ever conducted exclusively in the BTK-inhibitor pre-treated population” and its results underscore Jaypirca’s “ability to meaningfully delay disease progression and time to next treatment in this setting.” The pharma will continue to “build the body of evidence” to support the use of Jaypirca in B-cell malignancies, he added.
Designed to be taken orally, Jaypirca is an inhibitor of the Bruton’s tyrosine kinase protein, a key signaling molecule involved in the proliferation, survival and activity of B-cells. This mechanism of action allows Jaypirca to disrupt key cascades that cancer cells exploit to grow and divide.
Unlike other BTK blockers, Jaypirca binds to its target via non-covalent bonds, meaning its interaction is reversible. This binding profile enables the drug to maintain consistently high levels of target coverage regardless of BTK turnover rate, while also helping preserve therapeutic activity despite resistance mutations.
In January 2023, Jaypirca became the industry’s first-ever FDA-approved reversible BTK inhibitor, allowing its use in patients with relapsed or refractory mantle cell lymphoma. The regulator granted Jaypirca approval through its accelerated pathway, under which Lilly will need to validate the drug’s clinical efficacy through the Phase III BRUIN MCL-321 confirmatory trial.
GSK has several other studies under the late-stage BRUIN program—including BRUIN CLL-321—to establish Jaypirca’s safety and efficacy in hematologic malignancies. However, certain safety signals on Monday could pose a roadblock to the pharma’s aspirations.
As reported by Fierce Pharma, at a median follow-up of 17.2 months, BRUIN CLL-321 recorded 70 patient deaths. Fatalities were more common in the Jaypirca arm, resulting in a hazard ratio of 1.09 versus the control—a finding that could point to a greater risk of death associated with the reversible BTK blocker.
Jake Van Naarden, president of Lilly Oncology, explained this risk as a result of the high crossover rate, as reported by Fierce. After controlling for these switches in group assignments, according to Van Naarden, Jaypirca patients saw a 13% drop in the risk of death.
