Dr Lamanna on the FDA Approval of Acalabrutinib Plus Venetoclax for CLL

“We now have our first oral-oral [frontline] combination [approved by the FDA for CLL]”

Nicole Lamanna, MD, an associate clinical professor of medicine in the Hematologic Malignancies Section of the Hematology/Oncology Division at Columbia University Irving Medical Center, discussed implications of the FDA approval of first-line acalabrutinib (Calquence) plus venetoclax (Venclexta) for chronic lymphocytic leukemia (CLL) and the data that supported the decision.

Lamanna began by highlighting the phase 3 AMPLIFY trial (NCT03836261) that backed the approval. The trial evaluated time-limited approaches for acalabrutinib and venetoclax with or without obinutuzumab (Gazyva) vs investigator’s choice of chemoimmunotherapy with fludarabine plus cyclophosphamide and rituximab (Rituxan) or bendamustine plus rituximab. The study included patients with CLL who did not have 17p deletions or TP53 mutations, she noted.

Data from the trial published in the New England Journal of Medicine showed that patients who received acalabrutinib plus venetoclax without obinutuzumab (n = 291) achieved a 3-year progression-free survival (PFS) rate of 76.5% (95% CI, 71.0%-81.1%) compared with 66.5% (95% CI, 59.8%-72.3%) for patients who received standard-of-care (SOC) chemoimmunotherapy (n = 290). Additionally, at a median follow-up of 42.6 months, patients in the experimental arm achieved a median PFS that was not evaluable (NE; 95% CI, 51.1-NE) compared with 47.6 months (95% CI, 43.3-NE) for those in the control arm. Undetectable minimal residual disease at 10^-4 sensitivity at the end of treatment and 3 months after treatment occurred at the respective rates of 45% and 38% for the SOC arm compared with 72.9% and 77.9%, respectively, for the combination arm.

Lamanna pointed out how these data ultimately helped bring the first all-oral combination to the frontline CLL setting in the United States. Improved PFS and other data for the combination vs SOC chemoimmunotherapy was expected, she added, although both the trial and approval leave some unanswered questions for the CLL space.

She explained that patients with higher-risk disease in the form of unmutated IGHV experienced improved outcomes with the addition of obinutuzumab to acalabrutinib and compared with acalabrutinib plus venetoclax alone, adding that outcomes were similar for patients with mutated IGHV between the doublet and triplet arms. Determininb how to provide more tailored treatments for patients with higher-risk disease should be prioritized in moving forward in future clinical trials, according to Lamanna.