AstraZeneca's fixed-duration Calquence combo wins FDA nod as BeOne CLL rivalry heats up

 AstraZeneca has secured a key regulatory win in its effort to reclaim the lead in the BTK inhibitor market, with the FDA approving its combination of Calquence plus Venclexta as the first all-oral, fixed-duration regimen for first-line chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL).

While patients with newly diagnosed CLL typically take a BTK drug like Calquence indefinitely until disease progression, the new approval offers a better quality-of-life alternative by limiting treatment to 14 months. 

“The continuous regimens frequently used to treat chronic lymphocytic leukemia often come with side effects that may become burdensome to patients over time,” Jennifer Brown, M.D., Ph.D., from the Dana-Farber Cancer Institute, said in a Feb. 20 statement, adding that the Calquence combo gives doctors greater flexibility to tailor treatment plans.

The approval arrives as BeOne Medicines continues to widen its lead in the BTK inhibitor space with Brukinsa (zanubrutinib). While AZ hopes its time-limited option will sway clinicians, BeOne leadership has historically dismissed any threat from the Calquence regimen, betting instead on its own BTK/BCL-2 candidate.

Brown is the principal investigator of the phase 3 Amplify trial that supported the FDA decision on Calquence. 

In the study, patients who received Calquence (acalabrutinib) and AbbVie and Roche’s Venclexta (venetoclax) had a 35% lower chance of disease progression or death compared with those who received the investigator’s choice of a rituximab-based chemotherapy. At the time of the analysis, patients’ median progression-free survival time was not estimable in the fixed-duration combo arm and landed at 47.6 months in the control group.

With a median follow-up of 41 months, 6% of patients in the Calquence-Venclexta group have died, compared with 14% in the comparator arm.

But while Brown described the combo as “highly effective and well-tolerated,” and AZ’s oncology hematology business chief Dave Fredrickson said it “has the potential to meaningfully change” first-line CLL treatment decisions, BeOne CEO John Oyler has labeled the Amplify data “underwhelming.”

When it comes to undetectable minimal residual disease (MRD), a deep response that’s an early indication of treatment success, the Calquence doublet underperformed historical data from fixed-duration Venclexta-Gazyva by cross-trial comparison, Oyler has noted at several investor events. 

In a statement to Fierce Pharma, an AZ spokesperson argued that Calquence “cannot be directly compared to other therapies in CLL without a head-to-head trial.”

Besides, the BeOne chief also highlighted a sudden acceleration of disease progression events in the Calquence arm later in the Amplify study, suggesting that its efficacy could deteriorate with longer follow-up.

There’s also a third arm in the Amplify trial that adds Gazyva on top of Calquence and Venclexta. However, the FDA submission only covered the now-approved doublet, according to AbbVie’s announcement in July. The U.S. filing came more than a month after the European Commission approved fixed-duration Calquence and Venclexta, with or without Gazyva, in first-line CLL.

The triplet regimen delivered a larger 58% improvement on progression-free survival in Amplify, but its overall survival readout was notably worse than the doublet at the time of the analysis. 

“Regulatory discussions in the US are ongoing,” the AZ spokesperson said, noting that a finite BTK inhibitor approach is more established in Europe, whereas Calquence-Venclexta marks the first finite BTK regimen approved in the U.S.

Oyler is laying the groundwork for BeOne’s upcoming phase 3 readout from the Celestial-TN-CLL trial for Brukinsa and sonrotoclax in its own fixed-duration regimen for first-line CLL. The Swiss company is billing sonrotoclax as a better BCL-2 drug than Venclexta. 

Brukinsa recently overtook Calquence as the top-selling BTK inhibitor. 

BeOne is scheduled to report full-year 2025 results on Feb. 26. In the third quarter, global Brukinsa revenues increased 51% year over year to $1 billion. During the same period, Calquence’s sales jumped 13% to $916 million. 

https://www.fiercepharma.com/pharma/astrazeneca-fixed-duration-calquence-combo-wins-fda-nod-amid-mounting-cll-rivalry-beone