With a positive phase 3 trial in chronic lymphocytic leukemia (CLL), Eli Lilly hopes to convert Jaypirca’s unique accelerated approval—which allows the BTK inhibitor to be used following another drug in the class—into a full nod.
Jaypirca reduced the risk of progression or death by 46% compared with rituximab’s combination with either Gilead Sciences' PI3K inhibitor Zydelig or the chemotherapy bendamustine in CLL or small lymphocytic lymphoma (SLL) patients previously treated with a BTK inhibitor, Lilly announced during the American Society of Hematology (ASH) 2024 annual meeting.
Patients in the Jaypirca arm went a median 14 months without their disease worsening, whereas those in the control arm went a median 8.7 months on the same endpoint.
The results were based on reads by an independent review committee performed in tandem with the final overall survival analysis of the BRUIN CLL-321 trial, the first randomized study conducted exclusively in a BTK-pretreated CLL/SLL population. Assessments by investigators were similar, showing a progression-free survival (PFS) improvement of 52% for the Jaypirca group.
The randomized trial had actually met its primary endpoint of PFS last year before the FDA used tumor shrinkage data from a phase 1/2 study to grant Jaypirca its accelerated approval as a post-BTK and post-BCL2 treatment. At that time, the agency and Lilly figured the phase 3 data were too immature to support a traditional nod given the trial’s short follow-up time of 7.5 months at the median, Jake Van Naarden, president of Lilly Oncology, explained in an interview with Fierce Pharma.
Now, after a median follow-up of 17.2 months, the 238-patient trial has reached its prespecified final overall survival analysis after 70 deaths.
But the analysis has created a bit of a problem for Lilly. The 1-to-1 randomized trial recorded more death cases in the Jaypirca arm than in the control group. This led to a risk of death in favor of the control arm with a hazard ratio reaching above 1, at 1.09.
To explain this, Van Naarden pointed to the trial’s high crossover rate. Among patients in the control group who were eligible, 76% received Jaypirca upon disease progression. After adjusting for crossovers, Jaypirca was linked to a 13% lower risk of death compared with control.
Practicing doctors that Lilly has spoken with were not concerned about a slightly negative overall survival trend given the crossover, Van Naarden said.
Besides, although this marks the prespecified final analysis, Lilly will continue to follow the trial and update the FDA, Lilly’s chief medical officer, David Hyman, M.D., said in the interview.
“I think this is not the only evidence that we generate on the utility of the medicine and CLL,” Hyman said. “There’s sort of a totality-of-evidence concept in this disease as well that I think plays an important role.”
To help provide further evidence of Jaypirca’s benefit-risk profile, three of four other phase 3 trials of the drug could report top-line data in 2025, Van Naarden noted. The three studies include BRUIN CLL-322, which adds Jaypirca to the BCL2 inhibitor venetoclax and rituximab in previously treated CLL/SLL, without requirement for prior exposure to a BTK inhibitor.
“If FDA wants to see them, they know the schedule of projected readouts,” Van Naarden said. “So, if they want to see those data in the process of reviewing this, that’s okay. We can do that.”
In BRUIN CLL-321, Jaypirca’s PFS benefit was seen regardless of whether patients had previously tried venetoclax. The Lilly drug reduced the risk of progression or death by 46% by independent review among those who had received the drug, or by 37% among those who had not.
Jaypirca also reduced the risk of progression, initiation of subsequence therapy, unacceptable toxicity leading to treatment discontinuation or death by 61%. It more than doubled the time to next treatment or death, from a median 10.9 months in control to a median 24 months.
Grade 3 or above treatment-emergent adverse event happened at a lower 57.7% rate in the Jaypirca arm, versus 73.4% in the control group.
In the past, the FDA has approved blood cancer drugs despite slightly unfavorable overall survival data. The FDA recently expanded the label of Bristol Myers Squibb’s CAR-T therapy Abecma to cover third-line multiple myeloma, even though the KarMMa-3 trial’s overall survival data suggested a negative trend against Abecma with a hazard ratio of 1.01. As was the case with BRUIN CLL-321, investigators and BMS pointed to a high 56% crossover rate to explain the survival finding.
Roche’s approval for Polivy in first-line diffuse large B-cell lymphoma (DLBCL) went through a similar ordeal. Although the entire phase 3 POLARIX trial was favorable for the Polivy-R-CHP combo against the traditional R-CHOP regimen during the final prespecified overall survival analysis, the FDA found in a descriptive analysis that the hazard ratio was 1.02 in favor of control in the largest subgroup of patients with DLBCL.
Roche provided an updated five-year analysis of POLARIX at this year’s ASH meeting. The death risk reduction improved to 15% from the previous 6% in the overall trial population. Data in the DLBCL subgroup also turned in favor of the Polivy-R-CHP regimen, with the death-risk reduction in the group reaching 11%.