FDA Updates Venetoclax CLL Label With MRD Data

John F. Seymour, MBBS, PhD

The FDA has added minimal residual disease (MRD) data from the phase III MURANO trial to the label for venetoclax (Venclexta) for its approved use in combination with rituximab (Rituxan) for previously-treated patients with chronic lymphocytic leukemia (CLL).

AbbVie, which is co-developing venetoclax with Roche, noted in a press release that, “MRD-negativity occurs when less than 1 CLL cell per 10,000 lymphocytes can be detected in the blood or bone marrow.” In MURANO, the MRD-negativity rate was 53% (103/194) following 9 months of treatment with venetoclax plus rituximab compared with 12% (23/195) in the bendamustine plus rituximab (BR) arm.¹ 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.

"CLL is a chronic, life-altering cancer marked by periods of remission and relapse, making it an emotional rollercoaster for patients. Many patients who enter remission worry that the disease will relapse," said John Seymour, MBBS, PhD, lead investigator of the MURANO study and director of Clinical Haematology at the Peter MacCallum Cancer Centre & Royal Melbourne Hospital in Australia, said in a statement.

"The rates of MRD-negativity seen with Venclexta plus rituximab are very encouraging. A goal in treating patients with CLL is to help them achieve the longest remission possible. MRD-negativity provides us with yet another potential tool for evaluating the effectiveness of new therapies," added Seymour.

The FDA action was based on the overall data from MURANO, 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 BR (HR, 0.19; 95% CI, 0.13-0.28; P <.0001).² The overall response rate was 92% versus 72%, respectively.

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).

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%).

References

1. Minimal Residual Disease Negativity Data, a Measure of Undetectable Disease, Added to VENCLEXTA® (venetoclax tablets) Label. AbbVie. Published September 11, 2018. Accessed September 11, 2018. https://bit.ly/2N4E3RY.
2. 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.

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In April 2016, the FDA granted an accelerated approval to venetoclax for patients with CLL or small lymphocytic lymphoma (SLL) harboring a 17p deletion (del[17p]), following at least 1 prior therapy. The FDA converted this to a standard approval in June 2018 for the treatment of patients with CLL/SLL, with or without del(17p), following at least 1 prior therapy. The FDA simultaneously approved the BCL-2 inhibitor for use in combination with rituximab in the same patient population.