With a phase 3 trial win claimed by AstraZeneca, the heated BTK inhibitor race might see its first triplet regimen in chronic lymphocytic leukemia (CLL).
Monday, AZ said its BTK drug Calquence, used in combination with venetoclax—both with or without Roche’s Gazyva—outperformed traditional chemoimmunotherapy at staving off tumor progression or death in patients with previously untreated CLL.
The trial's positive top-line results come from an interim analysis of the phase 3 AMPLIFY trial. Previously, AZ anticipated a readout from the trial to come in the second half of 2025. An AZ spokesperson confirmed to Fierce Pharma that the doublet and the triplet regimens met their progression-free survival goals separately under the trial design.
AZ said it will discuss the results with regulatory bodies. The two Calquence combos also showed a trend toward extending patients’ lives, although the overall survival data remained immature at the time of the analysis.
It’s been nearly five years since the FDA’s approval for Calquence, either alone or in combination with Gazyva, in CLL, the largest indication for the BTK inhibitor class. Past first-line CLL approvals for BTK inhibitors, including for Calquence, were based on positive PFS data—rather than survival findings—as patients with the disease can live for a very long time.
With the AMPLIFY trial win, the Calquence-venetoclax-Gazyva cocktail may become the first BTK-containing triplet treatment in CLL.
In Monday’s announcement, AZ placed a focus on the regimen’s design feature that allows patients to stop treatment after a certain amount of time. AbbVie and Johnson & Johnson’s first-to-market BTK med, Imbruvica, also offers a fixed-duration combo with venetoclax in Europe and Canada thanks to results from the phase 3 GLOW study.
“This is an important advance in this setting as fixed-duration regimens allow those living with this chronic disease to take breaks from their treatment, thereby decreasing the possibility of long-term adverse events and drug resistance and improving quality of life,” Jennifer Brown, M.D., Ph.D., from the Dana-Farber Cancer Institute and an investigator of AMPLIFY, said in a statement.
“If approved, Calquence would become the only second-generation BTK inhibitor available as both a treat-to-progression and fixed-duration treatment, providing more options for patients and their healthcare providers," AstraZeneca's executive vice president of oncology R&D, Susan Galbraith, Ph.D., said in a statement.
Still, whether these Calquence combos can become new treatment standards remains to be seen.
Importantly, AMPLIFY’s comparator arm used chemoimmunotherapies such as the combination of bendamustine and rituximab, which are less common in the U.S. under current National Comprehensive Cancer Network (NCCN) guidelines for treatment.
Calquence with or without Gazyva, BeiGene’s rival BTK drug Brukinsa and the venetoclax-Gazyva combo serve as the preferred first-line regimens in CLL without del(17p) or TP53 mutations, the same population enrolled in AMPLIFY, according to NCCN guidelines. Various therapies using Imbruvica constitute other recommended regimens.
AZ does also have the phase 3 MAJIC trial, which is pitting finite treatment with Calquence-venetoclax against venetoclax-Gazyva in front-line CLL.
Better safety profiles have made Calquence and Brukinsa the favored BTK drugs compared with Imbruvica. In Monday’s release, AZ pointed to low rates of cardiac toxicity observed with Calquence in the AMPLIFY trial.
In the second quarter, Calquence’s sales grew 10% sequentially, reaching $790 million, as AZ touted the drug’s leadership in first-line CLL.
Meanwhile, Calquence’s combination with bendamustine and rituximab recently showed a positive overall survival trend against the chemoimmunotherapy in previously untreated mantle cell lymphoma.
In the key battleground of first-line CLL, BeiGene is pairing Brukinsa with the company’s own BCL2 inhibitor sonrotoclax in a phase 3 trial against the venetoclax-Gazyva combo. Sonrotoclax appears to be an improved version of venetoclax with better potency and safety.
Without a combo nod, Brukinsa generated $489 million in the first quarter. But after an FDA nod in follicular lymphoma in March, the BeiGene drug boasts the broadest label within the BTK class in terms of disease types.