The US Food and Drug Administration (FDA) has approved venetoclax tablets (Venclexta ®) in combination with rituximab to treat patients with chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL) who have received 1 prior therapy.
The combination is approved for patients with or without deletion of 17p (del 17p).
The FDA based its approval on the phase 3 MURANO trial, in which venetoclax in combination with rituximab (VEN+R) significantly improved progression-free survival (PFS) in relapsed or refractory CLL patients compared to the chemoimmunotherapy regimen of bendamustine plus rituximab(B+R).
This approval, according to the drug’s developers, makes venetoclax plus rituximab the first oral-based, chemotherapy-free combination with a fixed treatment duration for CLL.
The FDA has also converted venetoclax's accelerated approval to a full approval. The drug was previously granted accelerated approval as a single agent for the treatment of people with CLL with 17p deletion.
Venetoclax is being developed by AbbVie and Roche and jointly commercialized by AbbVie and Genentech in the US and by AbbVie outside the US.
Phase 3 MURANO trial (NCT02005471)
The multicenter, open-label trial randomized 389 patients to VEN+R (194 patients) or B+R (195 patients). Median age of the patients was 65 years (range, 22 – 85).
Patients in the VEN+R arm completed a 5-week ramp-up of venetoclax followed by venetoclax 400 mg once daily for 24 months measured from the rituximab start date.
Tumor lysis syndrome (TLS), caused by a rapid reduction in tumor volume, is an identified risk with venetoclax treatment. The dose ramp-up was intended to mitigate this risk.
Rituximab was initiated after venetoclax ramp-up and given for 6 cycles (375 mg/m2 intravenously on cycle 1 day 1 and 500 mg/m2 intravenously on day 1 of cycles 2-6, with a 28-day cycle length).
Patients in the B+R arm received 6 cycles of B+R (bendamustine 70 mg/m2 on days 1 and 2 of each 28-day cycle and rituximab at the above described dose and schedule).
Efficacy was based on PFS as assessed by an independent review committee.
After a median follow-up of 23 months, the median PFS was not reached in the VEN+R arm and was 18.1 months in the B+R arm (P<0.0001).
The overall response rate was 92% for patients treated with VEN+R compared to 72% for those treated with B+R.
The most common adverse events (AEs) in the VEN+R arms that occurred in 20% or more patients were neutropenia (65%), diarrhea (40%), upper respiratory tract infection (39%), fatigue (22%), cough (22%), and nausea (21%).
Grade 3 or 4 neutropenia developed in 64% of patients, and grade 4 neutropenia in 31%.
Serious adverse events (SAEs) developed in 46% of patients and serious infections in 21%, consisting most frequently of pneumonia (9%).
The incidence of TLS was 3%, occurring in 6 of 194 patients.
In the VEN+R arm, discontinuations due to any AEs occurred in 16% of patients, dose reductions in 15%, and dose interruptions in 71%.
Neutropenia led to dose interruptions in 46% of patients and discontinuations in 3%. Thrombocytopenia led to discontinuations in 3% of patients.
Fatal AEs that occurred in the absence of disease progression and within 30 days of the last VEN+R treatment and/or 90 days of the last rituximab infusion were reported in 2% (4/194) of patients.
In the B+R arm, AEs led to treatment discontinuations in 10% of patients, dose reductions in 15%, and dose interruptions in 40 %.
John Seymour, MBBS, PhD, lead investigator of the MURANO study, said in the corporate release, the approval "validates the results seen in the phase 3 trial, including the significant improvement in progression-free survival over a standard of care comparator arm."
"Progression-free survival is considered a gold standard for demonstrating clinical benefit in oncology," he added.
Full prescribing information for venetoclax is available here.