The European Commission has approved a fixed-dose combination of venetoclax and obinutuzumab for the treatment of patients with previously untreated chronic lymphocytic leukemia.
Michael Hallek, MD
The European Commission has approved a fixed-dose combination of venetoclax (Venclexta) and obinutuzumab (Gazyva) for the treatment of patients with previously untreated chronic lymphocytic leukemia (CLL).1
The approval is based on findings from the phase III CLL14 trial, in which the combination led to a 65% reduction in the risk of disease progression or death compared with obinutuzumab plus chlorambucil in this patient population (HR, 0.35; 95% CI, 0.23-0.53; P <.001).2,3 Additionally, the adverse events (AEs) with the venetoclax regimen were consistent with the known safety profiles of each agent alone.
"CLL is the most common of the nearly 95,000 new cases of leukemia in Europe each year, and chemotherapy is often the first line of treatment," lead study investigator Michael Hallek, MD, director of the Department of Internal Medicine and Center of Integrated Oncology Cologne-Bonn, University Hospital Cologne, and head, German CLL Study Group, stated in a press release. "Having the option to utilize a first-line, chemotherapy-free treatment combination that can produce a deep response, thus allowing patients to stop treatment, will change the way we treat CLL and have a significant impact on patients."
In the international, open-label, phase III CLL14 trial, investigators evaluated a fixed-duration treatment using venetoclax, known by the trade name Venclyxto in Europe, plus obinutuzumab in 432 patients with previously untreated CLL and coexisting conditions. Such conditions included reduced kidney function or comorbidities assessed by the Cumulative Illness Rating Scale, which ranges from 0 to 56, with higher scores indicating more impaired function of organ systems.
Patients were randomized to receive either a 12-month duration of venetoclax plus a 6-month duration of obinutuzumab (n = 216) or a 6-month duration of obinutuzumab plus a 12-month duration of chlorambucil (n = 216). The venetoclax arm started with an initial dosing of obinutuzumab followed by a 5-week venetoclax dosage ramp-up to help reduce the risk of tumor lysis syndrome (TLS).
To be eligible for enrollment, patients must have had a Cumulative Illness Rating Scale score ≥6 and a calculated creatinine clearance of <70 ml per minute.
The primary endpoint was investigator-assessed PFS; secondary endpoints included PFS assessed by an independent review committee (IRC), minimal residual disease (MRD) status, overall response rate (ORR), complete response (CR) with at least partial blood count recovery, overall survival (OS), duration of response, event-free survival, time to next CLL treatment, and safety.
The median age was 72 years old (range, 41-89); the median Cumulative Illness Rating Scale score was 8 and the median creatinine clearance of 66.4 ml per minute.
After a median follow-up of 28.1 months, the 2-year PFS rate was 88.2% (95% CI, 83.7-92.6) with venetoclax/obinutuzumab compared with 64.1% (95% CI, 57.4-70.8) for chlorambucil/obinutuzumab. The investigator-assessed median PFS was not yet reached in either arm; however, the IRC assessment of PFS was consistent (HR, 0.33; 95% CI, 0.22-0.51; P < .001).
Similarly, the PFS benefit was observed across subgroups, including those with TP53 deletion, mutation, or both and in patients with unmutated IGHV.
The venetoclax/obinutuzumab group also demonstrated clinical benefit across secondary endpoints, including ORR (84.7% vs 71.3%; P < .001); CR (49.5% vs 23.1%; P < .001); and higher rates of MRD-negativity in the bone marrow (56.9% vs 17.1%; P <.001) and peripheral blood (75.5% vs 35.2%; P <.001) 3 months after treatment.
Regarding safety, the most common grade ≥3 AEs in the venetoclax/obinutuzumab group and chlorambucil/obinutuzumab groups were neutropenia (52.8% vs 48.1%, respectively) and infections (17.5% vs 15.0%). All-cause mortality occurred in 9.3% and 7.9% of patients, respectively; however, these differences were not significant.
Moreover, ≥1 any-grade AE occurred in 94.3% of patients in the venetoclax combination arm, with the most common grade 3/4 AEs being febrile neutropenia and infections. TLS occurred in 3 patients in the venetoclax plus obinutuzumab group, all of which occurred during treatment with obinutuzumab and before venetoclax.
In May 2019, the FDA approved the venetoclax and obinutuzumab combination for the treatment of previously untreated patients with CLL or small lymphocytic lymphoma, also based on results from the CLL14 trial.