Acotinib/venetoclax sNDA under FDA review for previously untreated CLL

A supplemental New Drug Application (sNDA) has been submitted to the U.S. Food and Drug Administration seeking approval for the treatment of patients with previously untreated chronic lymphocytic leukemia (CLL) in the fixed phase A combination of limited, fully oral administration of venetoclax and acalabrutinib. The application is supported by data from the phase 3 AMPLIFY trial (NCT03836261), which showed a statistically significant improvement in progression-free survival (PFS) with combination chemotherapy compared with standard chemoimmunotherapy in this patient population.

Published study results showed that compared with chemoimmunotherapy47.6 months, acotinib combined with venetoclax or acotinib combined with venetoclat and obinutuzumab did not reach the median PFS. This means that the risk of disease progression or death was reduced by 35% for acotinitine plus venetoclax (HR, 0.65; 95% CI, 0.49-0.87; P=0.0004), and by 58% for acotinitine plus venetoclat and otuzumab (HR, 0.42; 95% CI: 0.30-0.59; P<0.0001).

This submission from the U.S. Food and Drug Administration marks a milestone in the treatment of CLL and could lead to the approval of the first oral combination of venetoclax and acotinib for patients with previously untreated chronic blood cancers. If approved, this new fixed treatment duration approach could give patients the opportunity to take time off from treatment and potentially practice in front-line CLL care. It is worth noting that AMPLIFY’s data also supports Europe’s approval in June 2025 of fixed-duration acotinib combined with venetoclax, with or without otuzumab, in patients with previously untreated CLL.

The AMPLIFY trial is a global, multicenter, open-label trial evaluating venetoclax plus acotinib alone or in combination with chemoimmunotherapy in patients with previously untreated CLL without 17p deletions or TP53 mutations. The primary endpoint of the study was PFS as assessed by an independent review committee in the acomitinib plus venetoclax arm. Secondary endpoints were PFS, overall survival (OS), and undetectable measurable residual disease in the acotinib plus venetoclax and otuzumab arms.

Additional efficacy data from AMPLIFY showed that at a median follow-up of 40.8 months, the estimated 36-month progression-free survival rate was 76.5% for acomitinib plus venetoclax, 83.1% for acotinib plus venetoclax and otuzumab, and 66.5% for chemoimmunotherapy (HR, 0.65; 95% CI, 0.49-0.87; P=0.004). 3 The 36-month overall survival rates for these respective regimens were 94.1%, 87.7%, and 85.9%, respectively.

The safety and tolerability of the combination regimen was also consistent with what is known about each drug alone, and no new safety signals were identified. The most common adverse reactions (AEs) of any grade with the acotinib plus venetoclax regimen were neutropenia, bleeding, and COVID-19.

Regarding adverse events of clinical concern, the most common grade 3 or higher adverse event was neutropenia; this was reported in 32.3%, 46.1%, and 43.2% of the acotinib plus veneclase, acotinib plus veneclase and otuzumab, and chemoimmunotherapy groups, respectively. 3 The incidence of tumor lysis syndrome of any grade was low, ranging from 0.3% in patients treated with acotinib plus venetoclax to 3.1% in patients treated with chemoimmunotherapy.

References:https://www.onclive.com/view/acalabrutinib-venetoclax-snda-under-fda-review-for-previously-untreated-cll