FDA Grants Venetoclax Combination Full Approval for CLL

Based on results from the phase III MURANO trial, the FDA has granted a regular approval to venetoclax (Venclexta) in combination with rituximab for the treatment of patients with chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL), with or without 17p deletion, following at least 1 prior therapy.

In the trial, median progression-free survival (PFS) at a median follow-up of 23 months was not reached with venetoclax plus rituximab compared with 18.1 95% CI, 15.8-22.3) months with bendamustine plus rituximab (HR, 0.19; 95% CI, 0.13-0.28; P<.0001). The overall response rate was 92% versus 72%, respectively.

"Venclexta now gives indicated patients a new opportunity to significantly reduce the risk of their disease progressing, compared to a current standard of care. This combination provides previously treated CLL or SLL patients with a chemotherapy-free, fixed duration treatment allowing patients the ability to stop treatment after approximately two years,” Michael Severino, MD, executive vice president, research and development, and chief scientific officer, AbbVie, which codevelops ibrutinib with Janssen, said in a statement.

In April 2016, the FDA granted an accelerated approval to the BCL-2 inhibitor venetoclax (Venclexta) for patients with CLL/SLL harboring a 17p deletion (del[17p]), following at least 1 prior therapy.

The MURANO Trial

The open-label, international, multicenter phase III MURANO trial included 389 patients with relapsed/refractory CLL who had previously received between 1 and 3 lines of therapy, including at least 1 chemotherapy regimen. Patients were randomly assigned to rituximab plus either venetoclax (n = 194) or bendamustine (n = 195).

Results from the MURANO trial were published in March 2018 in the New England Journal of Medicine. The findings showed that after a median follow-up period of 23.8 months, the PFS rate per investigator assessment was 84.9% for venetoclax/rituximab and 36.3% for BR (HR, 0.17; 95% CI, 0.11-0.25; P <.001). An independent review committee found a PFS benefit for the venetoclax regimen that was consistent with the investigator findings (HR, 0.19; 95% CI, 0.13-0.28; P <.0001).

The PFS benefit extended across patient subgroups, including high- and low-risk groups. The 2-year PFS rate among patients with chromosome 17p deletion was 81.5% in the venetoclax arm versus 27.8% with BR (HR, 0.13; 95% CI, 0.05-0.29). For patients without chromosome 17p deletion, the 2-year PFS rate was 85.9% versus 41.0% in favor of the venetoclax arm (HR, 0.19; 95% CI, 0.12-0.32).

Two-year event-free survival also favored the venetoclax group (84.9% vs 34.8%; HR, 0.17; 95% CI, 0.11-0.25). The rate of overall survival (OS) favored the venetoclax arm at 24 months (91.9% vs 86.6%). However, the difference was not statistically significant and neither arm reached median OS (HR, 0.48; 95% CI, 0.25-0.90).

Adverse Events

Grade 3/4 AEs were more common with venetoclax, 82.0% versus 70.2%. Neutropenia was the most common grade 3/4 AE with a higher incidence in the venetoclax arm (57.7% vs. 38.8%). However, incidences of grade 3/4 febrile neutropenia (3.6% vs 9.6%) and grade 3/4 infections or infestations (17.5% vs 21.8%) were lower in the experimental arm.

There were 10 (5.2%) patient deaths in the venetoclax arm, similar to the BR arm (n = 11; 5.9%).

Reference

Seymour JF, Kippes TJ, Eichhorst B, et al. Venetoclax—rituximab in relapsed or refractory chronic lymphocytic leukemia [published online March 22, 2018]. N Engl J Med. 2018; 378:1107-1120. doi: 10.1056/NEJMoa1713976.