Rituximab

“Bruin CLL-322 was an ambitious trial, building on an effective regimen, and these results outperformed our expectations,” Jacob Van Naarden, president of Lilly Oncology, said in an April 13 release. Eli Lilly has chalked up another victory in the chronic lymphocytic leukemia (CLL) space, as its BTK inhibitor Jaypirca delivered its fourth positive phase 3 readout in the blood cancer. Monday, Lilly said its phase 3 Bruin CLL-322 trial in patients with previously treated CLL or small lymphocytic lymphoma (SLL) has met its primary endpoint. In an industry first, the study showed that adding Jaypirca to a fixed-duration regimen of venetoclax and rituximab significantly extended progression-free survival (PFS) compared with the standard combo alone. As Lilly pointed out, Bruin CLL-322 is the first phase 3 in CLL to utilize and outperform a venetoclax-based regimen. Roche and AbbVie sell venetoclax, an oral BCL-2 inhibitor, under the brand name Venclexta. “Bruin CLL-322 was an ambitious trial, building on an effective regimen, and these results outperformed our expectations,” Jacob Van Naarden, president of Lilly Oncology, said in an April 13 release. Besides hitting its PFS goal, the trial also showed an overall survival trend in favor of the Jayirca combo regimen, although this secondary endpoint was not yet mature, according to Lilly. In addition, rates of adverse events and treatment discontinuations were similar between the two arms, the company added.Based on the data, Lilly said it plans to ask regulators for an approval this year. BTK inhibitors have been approved for previously treated CLL for some time. BeOne Medicines’ market-leading BTK drug Brukinsa scored an FDA label expansion in the indication in late 2023 after beating AbbVie and Johnson & Johnson’s first-to-market Imbruvica on PFS in second-line CLL.  As covalent BTK drugs like Brukinsa, Imbruvica and AstraZeneca’s Calquence are increasingly given upfront to treatment-naïve patients, a venetoclax-based regimen is usually reserved as a standard second-line option because patients cannot be retreated with a covalent BTK inhibitor for a second time. Even among patients who receive Venclexta in the first line, some doctors may choose to rechallenge their cancer with a venetoclax-based regimen—either by switching the combo partner or by adding another treatment.Jaypirca, a non-covalent BTK, recently emerged as a new second-line option, but its prior FDA approval in the space was based on a phase 3 study against investigator’s choice of rituximab and either Gilead Sciences’ Zydelig or bendamustine. The phase 3 Bruin CLL-321 trial showed that Jaypirca alone significantly improved PFS versus those combos.  In that study, Jaypirca was used indefinitely until disease progression or unacceptable toxicity, which can be a disadvantage compared to a time-limited venetoclax-based regimen, especially when there’s no head-to-head comparison showing which is more efficacious. But that dynamic has changed with the latest readout.“For doctors and patients who prefer a time-limited approach, these Bruin CLL-322 data demonstrate that the addition of Jaypirca could further extend the duration of benefit in second-line CLL,” Van Naarden said.Jaypirca’s latest PFS results were consistent across key subgroups and regardless of whether patients had previously received a covalent BTK inhibitor, Lilly said. Alongside Bruin CLL-321 and -322, Lilly also counts -313 and -314, which include treatment-naïve CLL patients, among positive phase 3 studies that Jaypirca has produced. Jaypirca is not the first BTK drug to succeed in a fixed-duration regimen. In February, AZ’s Calquence-Venclexta cocktail became the first all-oral, fixed-duration regimen approved in the U.S. for first-line CLL. Meanwhile, a phase 3 trial of BeOne’s fixed-duration pairing of Brukinsa and the company’s next-generation BCL-2 drug sonrotoclax in previously untreated CLL recently completed enrollment.

Eli Lilly is moving to expand the label for Jaypirca (pirtobrutinib) after reporting a fourth Phase III leukaemia study, with new data showing the non-covalent BTK inhibitor significantly prolonged progression-free survival (PFS) when added to a time-limited venetoclax-based regimen.The results "outperformed our expectations," stated Jacob Van Naarden, Lilly Oncology president, in a release Monday.The BRUIN CLL-322 study enrolled 639 patients, most of whom had prior exposure to covalent BTK inhibitors. Participants were randomly assigned to receive Jaypirca added to venetoclax plus rituximab, or venetoclax plus rituximab alone. Treatment in both study arms was given for up to two years, after which patients do not take any CLL therapy until their disease progresses.OS trending in favourThe Jaypirca regimen outperformed venetoclax and rituximab alone in patients with relapsed or refractory chronic lymphocytic leukemia or small lymphocytic lymphoma (CLL/SLL), meeting the study's main goal. The key secondary endpoint of overall survival is "trending in favour" of the Jayprica combo arm, though the data are still immature, according to Lilly.The regimen's overall safety profile was consistent with the known profiles of each drug. More results will be presented at a medical congress and submitted for peer review.Lilly will submit the results to regulators later this year to broaden Jaypirca's use beyond its current approvals in previously treated CLL/SLL following a covalent BTK inhibitor and in later-line mantle cell lymphoma."Modern CLL treatment regimens provide such durable disease control that the vast majority of patients see their entire disease course managed by only one or two lines of therapy," Van Naarden said. The BRUIN CLL-322 results "reinforce the potential role that [Jaypirca] may have, whether as a time-limited combination as a second line treatment or as a continuously dosed monotherapy in either line of therapy."Monday's readout is the latest to emerge from the BRUIN programme. The company previously reported results from the Phase III BRUIN CLL-321 trial in post-covalent BTK inhibitor patients testing Jaypirca against investigator's choice of Gilead Sciences' Zydelig (idelalisib) plus rituximab or bendamustine plus rituximab.Last year, it also unveiled data from BRUIN CLL-313 in which patients with treatment-naïve disease received either Jaypirca or bendamustine plus rituximab; and BRUIN CLL-314, which compared Jaypirca head-to-head with AbbVie and Johnson & Johnson's Imbruvica (ibrutinib) in patients who were treatment-naïve or BTK inhibitor-naïve.