Venetoclax Combination Improves PFS in Phase III CLL Trial

Sandra Horning, MD

The combination of venetoclax (Venclexta) and rituximab (Rituxan) significantly improved progression-free survival (PFS) compared with rituximab plus bendamustine (Treanda) in patients with relapsed or refractory chronic lymphocytic leukemia (CLL), according to findings from the phase III MURANO study.

No data have been released yet, with Genentech (Roche) and AbbVie, the developers of the BCL-2 inhibitor, planning to share the results at an upcoming medical meeting. The FDA previously granted the venetoclax/rituximab combination a breakthrough therapy designation in January 2016. Additionally, the MURANO results are intended to support the conversion of the accelerated approval of single-agent venetoclax into a full approval for the treatment of patients with CLL who harbor a 17p deletion (del[17p]) and have received at least 1 prior therapy.

“Chronic lymphocytic leukemia is considered incurable and becomes harder to treat with each relapse,” Sandra Horning, MD, chief medical officer and head of Global Product Development, Genentech, said in a statement. “This is the first study to show that Venclexta plus Rituxan can help people with this type of leukemia live significantly longer without their disease worsening compared to a standard-of-care regimen. We will work with health authorities to bring this potential chemotherapy-free treatment option to the people who need it as quickly as possible.”

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. Patients were randomized 1:1 to rituximab plus either venetoclax or bendamustine. Beyond the primary endpoint of PFS, secondary endpoints included best overall response, CR, duration of response, overall survival, event-free survival, time to next CLL treatment, and minimal residual disease (MRD) status.

The breakthrough designation for venetoclax plus rituximab was based on data from the phase Ib M13-365 study. In the trial, the combination had an overall response rate (ORR) of 86%, with deep and durable responses in patients with relapsed/refractory CLL.¹

Results from the phase Ib M13-365 study were presented at the 2015 ASH Annual Meeting. The trial included 48 patients with CLL and 1 patient with small lymphocytic lymphoma.

Forty-one patients were enrolled in 1 of 5 dose escalation cohorts. Patients received continuous venetoclax starting at 20 or 50 mg daily and then were escalated to their cohort dose of 200 to 600 mg daily, followed by rituximab, given every 4 weeks for a total of 6 doses.

There was also a safety expansion cohort comprising 8 patients for which the venetoclax dose was 400 mg daily. The recommended phase II dose for venetoclax established by the study was 400 mg daily.

For the overall study population, the median age was 68 years (range, 50-88) and patients had received a median of 2 prior regimens (range, 1-5). Among the 45 (92%) patients who received prior rituximab, 14 (29%) were rituximab-refractory. Among the 29 patients (59%) who received prior fludarabine, 18% (n = 9) were fludarabine-refractory. Nine of 46 (20%) evaluable patients had a del(17p) and 19 of 27 (70%) evaluable patients expressed unmutated IGHV.

The investigators assessed responses by iwCLL criteria at 7 months using CT scan and bone marrow biopsy. Assessment of MRD was conducted on bone marrow aspirates in local laboratories with ≥4 color flow cytometry (minimum sensitivity, 0.01%).

By investigator assessment, responses were observed in 42 of 49 (86%) of patients, including 20 (41%) CRs or CRs with incomplete marrow recovery (CRi). MRD-negative status was achieved in 26 (53%) patients overall, including 15 (75%) of the patients who reached CR/CRi.

There was 1 (2%) nodular partial remission and 21 (43%) partial responses (PR). Four patients had stable disease (SD), 2 patients had progressive disease, and 1 patient died of tumor lysis syndrome (TLS) prior to assessment. Nine patients with PR or SD on the combination at the 7-month analysis achieved CR after a median of 6 months (range, 2-9) of single-agent venetoclax.

Five (12%) of the 42 responders have progressed. The median PFS has not been reached. At a median follow-up of 17.5 months (range, 0.03-32), the 12- and 24-month PFS rates were 87% and 84%, respectively. Ninety-four percent of patients were alive at 12 months. The median overall survival has not been reached.

The response and survival rates remained consistent among high-risk subgroups, including patients aged ≥70 years and the del[17p], unmutated IGHV, and fludarabine-refractory cohorts.

At the time of the data analysis, 12 patients had discontinued the study: 6 had PD, 3 due to adverse events (AEs; neuropathy, TLS, and myelodysplasia), and 3 withdrew consent (1 following an MRD-negative CR).

The most common AEs in the study included neutropenia (55%), diarrhea (53%), nausea (49%), upper respiratory tract infection (45%), fatigue and pyrexia (37% each), cough (35%), and headache (33%). The most frequently occurring grade 3/4 AEs were neutropenia (53%), thrombocytopenia (16%), anemia (14%), febrile neutropenia (12%), and leukopenia (10%). There were 2 deaths that occurred following PD.

The accelerated approval of single-agent venetoclax in del(17p)-positive CLL was primarily based on data from the phase II M13-982 study, in which venetoclax elicited responses in nearly 80% of patients with relapsed/refractory del(17p) CLL.²

References

1. Ma S, Brander DM, Seymour JM, et al. Deep and durable responses following venetoclax (ABT-199/GDC-0199) combined with rituximab in patients with relapsed/refractory chronic lymphocytic leukemia: results from a phase 1b study. Presented at: 2015 ASH Annual Meeting; December 5-8, 2015; Orlando, Florida. Abstract 830.
2. Stilgenbauer S, Eichhorst BF, Schetelig JS, et al. Venetoclax (ABT-199/GDC-0199) monotherapy induces deep remissions, including complete remission and undetectable MRD, in ultra-high risk relapsed/refractory chronic lymphocytic leukemia with 17p deletion: results of the pivotal international phase II study. Presented at: 57th American Society of Hematology Annual Meeting; Orlando, Florida; December 5-8, 2015. Abstract LBA6.