New Data Reinforce the Long-Term Benefit of Venetoclax-Based Combination for People With Relapsed/Refractory CLL

New data from a pair of pivotal phase 3 studies support the efficacy of fixed-duration, chemotherapy-free, venetoclax (Venclexta; Genentech and AbbVie)-based combinations in certain people with chronic lymphocytic leukemia (CLL). These studies also provide more evidence on the potential value of minimal residual disease (MRD), according to Genentech.

Venetoclax is a targeted, prescription medicine designed to selectively bind and inhibit the B-cell lymphoma-2 (BCL-2) protein. Data from the pair of phase 3 trials were presented during the virtual 62nd American Society of Hematology Annual Meeting and Exposition.

CLL is the most common type of adult leukemia, with an estimated number of more than 20,000 new cases in the United States diagnosed in 2020. The disease is considered incurable and many people require additional treatment because cancerous cells return.

Five-year data from the MURANO (NCT02005471) trial continue to show sustained investigator-assessed progression-free survival (PFS) with venetoclax plus rituximab (Rituxan). The open-label, international, multicenter, randomized study included 389 patients with CLL, with or without 17p deletion, who had been previously treated with at least 1 line of therapy.

According to Genetech’s oral presentation, results of the trial showed as follows:

• Venetoclax plus rituximab reduced the risk of disease progression or death by 81% (HR=0.19; 95% CI: 0.15, 0.26; p<0.0001) compared with bendamustine plus Rituxan (BR) in people with relapsed or refractory CLL.
• At the time of analysis, median overall survival (OS) had not been reached in either arm (HR=0.40; 95% CI: 0.26, 0.62), however, 5-year OS was 82.1% in the Venclexta plus rituximab arm, compared with 62.2% in the BR arm.
• In the venetoclax arm, among the 130 patients who completed 2 years of treatment without progressive disease, 63.8% (n=83/130) had undetectable MRD (uMRD) levels at the end of treatment. In an analysis of this patient subgroup, uMRD was associated with improved PFS.
• No new safety events were reported in the study.

According to Genentech, data from the CLL14 (NCT02242942) study contributes to growing evidence regarding the potential of MRD measurements to predict future outcomes for certain people with previously untreated CLL who were treated with fixed-duration venetoclax plus obinutuzumab (Gazyva). In this study, 432 patients with previously untreated CLL were randomly assigned to receive either a 12-month duration of venetoclax with 6-month duration of obinutuzumab, or 6-month duration of obinutuzumab with 12-month duration of chlorambucil:

• Patients with uMRD and a partial response had longer PFS than patients with detectable MRD and a complete response.
• In collaboration with Adaptive Biotechnologies, clonal growth rate, a measure for how quickly cancer cells grow, was analyzed using a sequencing assay and insights were used to better understand the potential role of MRD in predicting outcomes. In this analysis, after treatment with fixed-duration venetoclax plus obinutuzumab , the estimated clonal growth rate was slower and lower, suggesting more effective MRD eradication in these patients compared to those treated with obinutuzumab plus chlorambucil. Early data suggest a correlation between MRD responses and PFS, which will be further evaluated by the study authors.

According to Genentech, venetoclax can cause serious adverse effects (AEs) such as tumor lysis syndrome (TLS). In turn, TLS may cause kidney failure. Neutropenia and infections are other potential serious AEs.

The most common AEs of using venetoclax in combination with obinutuzumab or rituximab, or alone in people with CLL or SLL include low white blood cell count, low platelet count, low red blood cell count, diarrhea, nausea, upper respiratory tract infection, cough, muscle and joint pain, tiredness, and swelling of arms, legs, hands, and feet.

The most common AEs of using venetoclax in combination with azacitidine or decitabine or low-dose cytarabine in people with AML include nausea, diarrhea, low platelet count, constipation, low white blood cell count, fever with low white blood cell count, tiredness, vomiting; swelling of arms, legs, hands, or feet; fever, lung infection, shortness of breath, bleeding, low red blood cell count, rash, abdominal pain, infection in the blood, muscle and joint pain, dizziness, cough, sore throat, and low blood pressure.

Genentech is continuing to investigate venetoclax in a robust clinical development program. This includes the phase 3 CRISTALLO (NCT04285567) trial in previously untreated CLL, which uses MRD as a primary endpoint.

REFERENCE

Genentech Announces New Data Reinforcing the Long-Term Benefit of Venclexta-Based Combination for People With Relapsed or Refractory Chronic Lymphocytic Leukemia [news release]. South San Francisco, CA; December 5, 2020: Genentech. Accessed December 9, 2020. https://www.gene.com/media/press-releases/14889/2020-12-05/genentech-announces-new-data-reinforcing.