RN-486

SAN DIEGO — Some of the biggest names in BTK inhibitors presented updated datasets at the American Society of Hematology annual meeting this weekend, most notably AstraZeneca and Eli Lilly. AstraZeneca and Eli Lilly outlined how their drugs Calquence and Jaypirca can help patients with chronic lymphocytic leukemia (CLL). Individuals live with CLL chronically, unlike more aggressive cancers like acute lymphoblastic leukemia or multiple myeloma, and if they relapse often have other effective drugs to turn to. In addition, BeiGene reported five-year follow-up data for its drug Brukinsa in first-line CLL. Mehrdad Mobasher, BeiGene’s chief medical officer in hematology, said the follow-up is “one of the most important” updates for Brukinsa at the medical meeting, as it shows sustained efficacy following the drug’s approval in CLL last January. AstraZeneca this weekend expanded on its Phase 3 win from July for fixed-dose Calquence regimens in first-line CLL, combining the drug with AbbVie and Roche’s Venclexta, with or without Roche’s Gazyva. Researchers tested the regimens in 867 patients, randomizing them 1-to-1-to-1 against Rituxan plus chemo. Both regimens met the primary endpoint of progression-free survival, with the triple regimen of Calquence, Venclexta and Gazyva lowering patients’ risk of disease progression or death by 58% and achieving a progression-free survival (PFS) rate of 83.1% after 36 months of treatment. The Calquence and Venclexta combo reported a PFS of 76.5%, reducing disease progression or death by 35%, and the control group achieved a 65.5% PFS rate. Both results were statistically significant. AstraZeneca also conducted analyses that excluded deaths in the trial that were a result of Covid-19, since the company was enrolling patients during the height of the pandemic. When those deaths were excluded, the triple regimen reduced patients’ risk of disease progression or death by 74%, and the double regimen by 29%. Susan Galbraith, AstraZeneca’s EVP of oncology R&D, declined to comment on the company’s regulatory plans. But she told Endpoints News that she doesn’t believe it will be difficult to market the drug since patients and physicians are already familiar with all three therapies. “We have it established with both community oncologists, as well as physicians who are in academic centers,” Galbraith said. “I don’t think it will be difficult to drive uptake of this.” Galbraith added she thinks it will be mostly new CLL patients who end up taking the regimens, rather than those who have been taking Calquence already without Venclexta. Calquence is currently approved in CLL as a monotherapy and in combination with Gazyva. Eli Lilly’s third-generation BTK inhibitor Jaypirca bested investigators’ choice treatments in previously treated CLL and small lymphocytic leukemia (SLL), meeting the primary endpoint in a confirmatory trial. In the Phase 3 BRUIN CLL-321 study, Jaypirca reduced patients’ risk of relapse, disease or death by 46% compared to two regimens consisting of either idelalisib plus rituximab or bendamustine plus rituximab. The drug won accelerated approval last December in patients who’ve been treated with at least two prior therapies, including one other BTK inhibitor and a BCL-2 inhibitor. Lilly Oncology president Jacob Van Naarden said the company will file with the FDA for full approval “soon.” “We almost doubled the progression-free survival in the clinical trial,” chief medical officer David Hyman told Endpoints . At a median follow-up of 19 months, median progression-free survival in the Jaypirca arm was 14 months compared with 8.7 months in the control arm, as assessed by an independent review committee. Van Naarden said this was the first randomized Phase 3 CLL trial in patients who previously received a BTK inhibitor. The results, he said, could potentially make the case for Jaypirca’s use in earlier settings. “In real clinical practice, most patients start with a covalent BTK inhibitor, they eventually relapse. They get a venetoclax-based regimen, they eventually relapse, and then they’re getting pirtobrutinib,” Van Naarden said ahead of Lilly’s data release. “The data we’re presenting tomorrow raise the question of whether or not pirto should be used before venetoclax in certain patients or not.” While there wasn’t a statistically significant difference between the Jaypirca and control arms in overall survival, Van Naarden and Hyman said the data were confounded by high degrees of crossover. Patients in the control arm were allowed to switch to Jaypirca after seeing disease progression, and a majority of them (76%) did. Lilly reported that multiple analyses adjusting for the crossover effect showed trends in favor of Jaypirca. “We never, ever powered or contemplated this study to be designed to demonstrate a survival benefit,” Hyman said. “In CLL, basically all of the things that we do are based on progression-free survival.” BeiGene touted a “deepening of responses” in five-year follow-up data for its BTK inhibitor Brukinsa in CLL or SLL. At a median follow-up of 61.2 months, Brukinsa reduced first-line patients’ risk of disease progression or death by 71% compared to a combination of the cancer drugs bendamustine and Rituxan, BeiGene said at ASH. The results are from the Phase 3 SEQUOIA study, which helped support Brukinsa’s approval in CLL last year. “Efficacy is sustained. Responses are getting deeper,” BeiGene’s Mobasher told Endpoints. “Brukinsa has now proven to be the best-in-class BTK inhibitor.” BeiGene is also studying Brukinsa in combination with its experimental BCL2 inhibitor sonrotoclax. The company reported updated Phase 1/1b results at this year’s ASH suggesting the combination was well-tolerated and achieved a 99% overall response rate in patients with mature B-cell malignancies at a median follow-up of 19.4 months. The Brukinsa sonrotoclax combination is currently in an ongoing fixed-duration Phase 3 study, which started last year and is “enrolling extremely well,” Mobasher said.