Adding Venetoclax to Obinutuzumab Prolongs Progression-Free Survival in Previously Untreated CLL

In a phase III trial of patients with previously untreated chronic lymphocytic leukemia (CLL) and co-existing comorbidities, a fixed-duration regimen of obinutuzumab plus venetoclax reduced the risk of disease progression and death by 65%, compared with obinutuzumab plus chlorambucil. The findings were presented at the 2019 American Society of Clinical Oncology annual meeting by lead author Kirsten Fischer, MD, of the University Hospital of Cologne in Germany.

Based on these results, venetoclax in combination with obinutuzumab was granted breakthrough therapy designation by the U.S. Food and Drug Administration, reviewed under the Real-Time Oncology Review pilot program, and subsequently approved for the treatment of previously untreated patients with CLL or small lymphocytic lymphoma.

“The standard of care for patients with CLL and coexisting conditions is fixed-duration chemoimmunotherapy or continuous and indefinite targeted therapy,” Dr. Fischer told ASH Clinical News. “As an answer to an unmet clinical need, we developed a new fixed-duration targeted treatment regimen.”

In preclinical models, venetoclax and obinutuzumab showed “impressive and additive effects” in combination, she added. Venetoclax induces apoptosis of CLL by selective inhibition of BCL2, while obinutuzumab attacks CLL by binding and destroying malignant CLL cells.

This randomized, open-label trial enrolled patients with previously untreated CLL and coexisting medical comorbidities who also had a Cumulative Illness Rating Scale (CIRS) score >6 and/or a creatinine clearance <70 mg/min. Participants were then randomized 1:1 to receive either obinutuzumab plus chlorambucil (n=216) or obinutuzumab plus venetoclax (n=216).

Patients received 12 cycles of treatment in the following schedules:

  • obinutuzumab (1,000 mg on days 1, 8, and 15 of cycle 1, then 1,000 mg on day 1 of cycles 2-6) plus venetoclax (a 5-week ramp-up period, then 400 mg/day until the end of cycle 12)
  • obinutuzumab (1,000 mg on days 1, 8, and 15 of cycle 1, then 1,000 mg on day 1 of cycles 2-6) plus chlorambucil (0.5 mg/kg on days 1 and 15 of cycles 1-12)

The authors noted that baseline characteristics were well balanced across the chlorambucil and venetoclax groups (median ages = 72 years and 71 years; median total CIRS scores = 9 and 8, respectively). A similar proportion of patients in both groups had a TP53 deletion, mutation, or both (12% in both groups).

After a median follow-up of 28.1 months (range not reported), the investigators found that patients who received obinutuzumab plus venetoclax had significantly higher rates of progression-free survival (PFS) at 24 months, compared with patients who received obinutuzumab plus chlorambucil: 88% vs. 64% (hazard ratio = 0.35; 95% CI 0.23–0.53; p<0.0001). Overall response rates also were higher in the venetoclax group (85% vs. 71%; p=0.0007).

The PFS benefit was observed in the venetoclax group, regardless of TP53 and IGHV status, the investigators added.

In addition, more patients in the venetoclax group achieved measurable residual disease (MRD) negativity, measured via polymerase chain reaction assay and next-generation sequencing, at three months following treatment:

  • MRD in peripheral blood: 76% vs. 35% (p<0.0001)
  • MRD in bone marrow: 57% vs. 17% (p<0.0001)

The researchers observed that MRD negativity rates appeared to occur earlier in venetoclax-treated patients and increased and deepened over time, compared with chlorambucil-treated patients. At 12-month follow-up, 81% of patients in the venetoclax group, versus 27% in the chlorambucil group, were MRD-negative (p value not reported).

They added that the safety profiles were similar between both groups; the most common grade 3/4 adverse events were blood and lymphatic system disorders, including:

  • neutropenia: 53% with venetoclax and 48% with chlorambucil
  • thrombocytopenia: 14% and 15%
  • anemia: 8% and 7%
  • febrile neutropenia: 5% and 4%

Dr. Fischer concluded that fixed-duration treatment of venetoclax plus obinutuzumab “achieves the highest rate of MRD-negative responses so far observed in a randomized prospective study.” However, the trial’s findings are potentially limited by its open-label design, which may have introduced bias.

The study authors reported relationships with AbbVie and Roche, which supported this study.

Reference

Fischer K, Al-Sawaf O, Bahlo J, et al. Effect of fixed-duration venetoclax plus obinutuzumab (VenG) on progression-free survival (PFS), and rates and duration of minimal residual disease negativity (MRD–) in previously untreated patients (pts) with chronic lymphocytic leukemia (CLL) and comorbidities. Abstract #7502. Presented at the 2019 American Society of Clinical Oncology Annual Meeting, June 4, 2019; Chicago, Illinois.

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