The European Medicines Agency’s Committee for Medicinal Products for Human Use (CHMP) is supporting the approval of venetoclax (Venclexta) in combination with rituximab (Rituxan) for patients with chronic lymphocytic leukemia (CLL) who have received at least 1 previous therapy. AbbVie, who is a co-developer of venetoclax with Roche, announced the CHMP’s decision in a news release.
The CHMP’s positive opinion, as well as the FDA approval, are based on data from the phase III MURANO trial. Findings showed that, at a median follow-up of 23 months, the median progression-free survival (PFS) was not reached with venetoclax/rituximab compared with 18.1 months (95% CI, 15.8-22.3) in the bendamustine-plus-rituximab arm (BR; HR, 0.19; 95% CI, 0.13-0.28; P
The overall response rate favored the venetoclax arm, 92% versus 72%.
The open-label, international, multicenter phase III 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).
Investigators administered venetoclax at 400 mg orally once daily from cycle 1, day 1 until progression, unacceptable toxicity, or a maximum of 2 years. Treatment was initiated with a 5-week ramp-up schedule with a dose beginning at 20 mg/day for 1 week and then gradually increased to the 400-mg dose. Rituximab was administered at 375 mg/m2
on day 1, cycle 1, followed by 500 mg/m2
on day 1 of cycles 2 through 6. The bendamustine regimen was 70 mg/m2 on days 1 and 2 of cycles 1 through 6.
The median age in the venetoclax arm was 64.5 (range 28-83), 27% (46/173) of patients had del(17p), 68% (123/180) of patients had unmutated IGHV, and 25% of patients harbored a TP53 mutation. A total 111 patients received 1 prior therapy, 57 patients had 2, 2 patients had 3, and 4 patients had more than 3. Prior treatments including alkylating agent (93%), purine analog (81%), anti-CD20 antibody (78%), and BCR inhibitor (5 patients).
In the BR arm, the median age was 66.0 years (range, 22-85), 27% had del(17p), 68% (123/180) of patients had unmutated IGHV, and 28% of patients harbored a mutation. The number of prior therapies included 1 (n = 117), 2 (n = 43), 3 (n = 34), and more than 3 (n = 1). Prior therapies included alkylating agent (95%), purine analog (81%), anti-CD20 antibody (76%), and BCR inhibitor (3 patients).
Additional data showed that 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
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%). This difference was not statistically significant and neither arm reached median OS (HR, 0.48; 95% CI, 0.25-0.90).
Regarding safety, grade 3/4 adverse events were more common with venetoclax at 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.
Ten patients (5.2%) died in the venetoclax arm compared with 11 patients (5.9%) in the BR arm.
Earlier this month, the FDA added minimal residual disease (MRD) data from the MURANO trial to the label for venetoclax. The MRD-negativity rate was 53% (103/194) following 9 months of treatment with venetoclax plus rituximab compared with 12% (23/195) in the BR arm. Among patients in the 2 arms who achieved a complete response (CR) or CR with incomplete marrow recovery, the MRD-negativity rates were 3% (6/194) versus 2% (3/195), respectively.2
"This positive CHMP opinion is one important step forward as AbbVie continues to further the research and development of novel medicines with the potential to transform the standard of care in blood cancers," said Michael Severino, MD, executive vice president, research and development and chief scientific officer, AbbVie. "The combination of [venetoclax] with rituximab has the potential to give patients with relapsed/refractory chronic lymphocytic leukemia a chance to live longer without their disease progressing, and to stop treatment after their two-year course."
- 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.
- Minimal residual disease negativity data, a measure of undetectable disease, added to VENCLEXTA® (venetoclax tablets) label. AbbVie. Published September 11, 2018. https://bit.ly/2N4E3RY. Accessed September 21, 2018.