Pivotal phase III CLL14 results for Venclexta/Venclyxto in combination with Gazyva/Gazyvaro for chronic lymphocytic leukaemia presented at ASCO 2019 and published in the New England Journal o
- Venclexta/Venclyxto plus Gazyva/Gazyvaro showed improvements across multiple efficacy measures compared to Gazyva/Gazyvaro plus chlorambucil, including progression-free survival and deep remissions as determined by minimal residual disease measurement
- This 12-month, fixed-duration, chemotherapy-free combination was recently approved for previously untreated chronic lymphocytic leukaemia under the FDA's Real-Time Oncology Review pilot programme
- Overall response (84.7% vs. 71.3%; p<0.001).
- Complete response with at least partial blood count recovery (49.5% vs. 23.1%; p<0.001).
- Minimal residual disease (MRD)-negativity in the bone marrow (56.9% vs. 17.1%; p<0.001) and peripheral blood (75.5% vs. 35.2%; p<0.001) three months after treatment. MRD-negativity means no cancer can be detected using a specific, highly sensitive test, and was defined as less than one CLL cell in 10,000 white blood cells.
About the CLL14 study2
CLL14 (NCT02242942) is a randomised phase III study evaluating the combination of fixed-duration Venclexta/Venclyxto plus Gazyva/Gazyvaro compared to Gazyva/Gazyvaro plus chlorambucil in patients with previously untreated chronic lymphocytic leukaemia (CLL) and co-existing medical conditions. Co-existing medical conditions included reduced kidney function or co-morbidities assessed by a standard scale (Cumulative Illness Rating Scale). 432 patients with previously untreated CLL were randomly assigned to receive either a 12-month duration of Venclexta/Venclyxto alongside six-month duration of Gazyva/Gazyvaro (Arm A) or six-month duration of Gazyva/Gazyvaro alongside 12-month duration of chlorambucil (Arm B). Arm A started with an initial dosing of Gazyva/Gazyvaro followed by a five-week Venclexta/Venclyxto dose ramp-up to help reduce the risk of tumour lysis syndrome. The primary endpoint of the study is investigator-assessed progression-free survival (PFS). Secondary endpoints include PFS assessed by independent review committee (IRC), minimal residual disease (MRD) status, overall response rate (ORR), complete response (with or without complete blood count recovery), overall survival, duration of response, event-free survival, time to next CLL treatment, and safety. The CLL14 study is being conducted in cooperation with the German CLL Study Group, headed by Michael Hallek, MD, University of Cologne. After a median follow-up of 28 months, results showed:- Patients who received Venclexta/Venclyxto plus Gazyva/Gazyvaro lived significantly longer without their disease worsening (PFS, as assessed by investigator) compared to those who received Gazyva/Gazyvaro plus chlorambucil (HR 0.35; 95% CI 0.23-0.53; p<0.001).
- At two years, 88.2% of patients in the Venclexta/Venclyxto plus Gazyva/Gazyvaro arm had not experienced disease progression, compared to 64.1% with Gazyva/Gazyvaro plus chlorambucil.
- Median PFS reported by investigators was not yet reached in either arm. IRC assessment of PFS was consistent (HR 0.33; 95% CI, 0.22- 0.51; p<0.001).
- Clinical benefit observed for Venclexta/Venclyxto plus Gazyva/Gazyvaro compared to Gazyva/Gazyvaro plus chlorambucil was consistent across secondary endpoints, including ORR (84.7% vs. 71.3%; p<0.001) and CR including incomplete marrow recovery (49.5% vs. 23.1%; p<0.001).
- In addition, higher rates of MRD-negativity in the bone marrow (56.9% vs. 17.1%; p<0.001) and peripheral blood (75.5% vs. 35.2%; p<0.001) were observed three months after treatment with Venclexta/Venclyxto plus Gazyva/Gazyvaro compared to Gazyva/Gazyvaro plus chlorambucil. MRD-negativity was defined as less than one CLL cell in 10,000 leukocytes.
- Safety for Venclexta/Venclyxto plus Gazyva/Gazyvaro appeared consistent with the known safety profile of the individual medicines, and no new safety signals were identified with the combination. Common Grade 3-4 adverse events with Venclexta/Venclyxto plus Gazyva/Gazyvaro compared to Gazyva/Gazyvaro plus chlorambucil, respectively, were low white blood cell count (52.8% vs. 48.1%) and infections (17.5% vs. 15.0%).