FDA Grants Venetoclax Full Approval for CLL, Regardless of 17p Deletion

The FDA has granted a standard approval to venetoclax (Venclexta) 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. The BCL-2 inhibitor is now also approved for use in combination with rituximab (Rituxan) in the same patient population.

The approval is based on the phase III MURANO trial, in which the median progression-free survival (PFS) at 23 months' median follow-up was not reached with venetoclax plus rituximab compared with 18.1 months (95% CI, 15.8-22.3) with bendamustine plus rituximab (HR, 0.19; 95% CI, 0.13-0.28; P <.0001). The overall response rate was 92% versus 72%, respectively.

"The approval of the combination of Venclexta plus rituximab for patients with relapsed/refractory CLL or SLL validates the results seen in the phase III trial, including the significant improvement in progression-free survival over a standard of care comparator arm," lead MURANO investigator John Seymour, MBBS, PhD, director of Cancer Medicine at the Peter MacCallum Cancer Centre & Royal Melbourne Hospital in Australia, said in a statement. "Progression-free survival is considered a gold standard for demonstrating clinical benefit in oncology," added Seymour.

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

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 bendamustine plus rituximab (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).

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).

“Venclexta plus Rituxan provides a new chemotherapy-free option shown to help people live longer without their disease progressing compared to a standard-of-care therapy,” Sandra Horning, MD, chief medical officer and head of Global Product Development, Genentech, which codevelops venetoclax with AbbVie, said in a statement.

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).

Venetoclax was administered 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.

In the venetoclax arm, the median age 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. One hundred eleven 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).

The median age in the BR arm 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).

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%).

"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, said in a statement.

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.

The PFS benefit extended across patients 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).