Trying to break from the decade-old practice of using BTK inhibitors indefinitely to treat blood cancer, AstraZeneca has positive data suggesting two fixed-duration combinations containing its Calquence can work in newly diagnosed chronic lymphocytic leukemia (CLL).
Calquence, given alongside venetoclax both with and without Roche’s Gazyva for a finite period, was able to significantly extend the time before tumor progression or death compared with traditional chemoimmunotherapy in healthy patients with treatment-naïve CLL. The results, from the phase 3 AMPLIFY trial, will be presented at the American Society of Hematology (ASH) 2024 annual meeting.
Specifically, the Calquence-venetoclax doublet reduced the risk of progression or death by 35% versus chemoimmunotherapy, whereas the Gazyva-containing triplet delivered a 58% reduction, according to an interim analysis of the AMPLIFY trial performed at a median follow-up of 41 months. Investigators chose between fludarabine-cyclophosphamide-rituximab and bendamustine-rituximab for the control arm.
With AMPLIFY, the driving idea centers on providing treatment options for different patient populations and making sure multiple drugs can be combined to offer better efficacy, Susan Galbraith, Ph.D., AstraZeneca’s oncology R&D chief, said in an interview with Fierce Pharma.
Many CLL patients are older—with comorbidities—who can be better served with a monotherapy, she said. “But there are patients who are fitter, who are younger, who don’t want to be on a therapy permanently for the rest of their lives," she explained.
While the triplet showed a better progression-free survival benefit, the doublet offers an oral-only regimen, which is attractive for some patients and community physicians, Galbraith noted.
However, the two regimens’ profiles can look confusing when it comes to patient survival data.
At the interim analysis, the doublet cut the risk of death by 67% versus control, whereas the improvement from the triplet was surprisingly much smaller at just 24%, even though neither number was mature. The doublet’s showing, which Galbraith described as “quite remarkable,” was considered nominally statistically significant thanks to the trial’s statistical plan. Because the doublet didn’t top chemoimmunotherapy on the key secondary endpoint of undetectable minimal residual disease, overall survival was not formally tested.
The trial ran through the peak of the pandemic, so COVID-related deaths affected its findings, especially in the triplet arm, Galbraith noted.
However, even after adjusting for COVID deaths, the doublet’s death risk reduction over control, at 73%, was still notably better than the triplet’s 53%. Still, Galbraith argued that the data were immature at this point. Even in the control arm, an estimated 86% of patients were still alive after three years.
AZ is now having discussions with the FDA, aiming to bring the AMPLIFY regimens to patients as soon as possible, Galbraith said. But whether the agency would want to see more mature survival data, especially from the triplet, remains a big question mark.
Besides AMPLIFY, AZ also has the phase 3 MAJIC trial, which is comparing Calquence-venetoclax with venetoclax-Gazyva in first-line CLL.
AZ is trying to innovate Calquence regimens as competition intensifies in the BTK class, what with BeiGene’s Brukinsa quickly gaining share in the all-important first-line CLL setting. For Brukinsa, BeiGene is trying to replace venetoclax with its own, supposedly more tolerable BCL-2 inhibitor sonrotoclax. A phase 3 trial of the Brukinsa-sonrotoclax combo in CLL was launched in November 2023.
Beyond Calquence, Galbraith pointed to a CD19xCD3 T-cell engager that AZ got from its $100 million acquisition of Teneobio spinoff TeneoTwo. At this year’s ASH meeting, AZ is reporting some encouraging early-stage follicular lymphoma and diffuse large B-cell lymphoma data for the asset, coded AZD0486. The drug represents an opportunity across B-cell malignancies, including CLL, Galbraith said.