Imbruvica-Venclexta Combo Superior to Chlorambucil-Obinutuzumab for CLL

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The combination of Imbruvica with Venclexta significantly reduced the risk for progression or death by 78% compared with chlorambucil plus obinutuzumab.

First-line treatment with Imbruvica (ibrutinib) and Venclexta (venetoclax) improved progression-free survival compared with chlorambucil plus obinutuzumab in patients with chronic lymphocytic leukemia (CLL).

Findings from this analysis were presented at the European Hematology Association 2021 Virtual Congress.

In particular, Imbruvica is an oral BTK inhibitor administered once per day and has shown to provide a survival benefit in patients with previously untreated CLL. Venclexta is an oral BCL-2 inhibitor given once per day with demonstrated progression-free survival (time during and after treatment without disease worsening) benefit in patients with previously untreated CLL when given with an anti-CD20 antibody during a 12-week regimen.

“The expectation (was) that combining (Imbruvica) with (Venclexta) would lead to deeper, durable responses and enable treatment-free periods,” Dr. Arnon P. Kater, leader of tumor immunology at the Cancer Center Amsterdam, said during the presentation.

In this study, researchers aimed to evaluate the efficacy and safety of fixed-duration Imbruvica plus Venclexta compared with chlorambucil plus obinutuzumab in patients with previously untreated CLL. Researchers enrolled 211 patients with previously untreated CLL who were 65 years or older, or between ages 18 to 64. Moreover, these patients had a cumulative illness rating scale (a measurement of medical and psychiatric impairment of patients 65 years and older) score greater than six or creatinine clearance less than 70 mL/min (an indication of serious kidney damage.

Patients were randomly assigned one of the following treatments:

  • 420 mg daily of Imbruvica for three cycles followed by Imbruvica plus Venclexta for 12 cycles, or
  • 0.5 mg/kg of chlorambucil on days one and 15 for six six cycles plus 1,000 mg of obinutuzumab on days one to two, eight and 15 of the first cycle and day one of cycles two through six.

The primary focus of this study was progression-free survival, with other areas of interest including undetectable minimal residual disease (a very small number of cancer cells in the body after treatment) in bone marrow, the rate of complete response (disappearance of all cancer signs from treatment), overall response rate (percentage of patients with a partial or complete response to treatment), overall survival (OS, the time when patients with the disease are still alive after diagnosis or treatment) and safety.

In total, 106 patients were randomized to Imbruvica plus Venclexta (median age, 71 years; 55.7% men) and 105 were randomized to chlorambucil plus obinutuzumab (median age, 71 years; 60% men).

“Overall, (the) study population was elderly and unfit,” Kater explained. “The majority of patients had a CIRS score greater than six, and thereby, the study population was unfit than other (Imbruvica) first-line studies including RESONATE 2 and ILLUMINATE.”

After a median follow-up of 28 months, the combination of Imbruvica plus Venclexta significantly improved progression-free survival compared with chlorambucil plus obinutuzumab. Therefore, Imbruvica plus Venclexta was superior to chlorambucil plus obinutuzumab and reduced the risk for progression or death by 78%. This benefit was consistent across subgroups including comorbidities, age and underlying biology such as IGHV and del(11q) status.

Patients who were treated with Imbruvica plus Venclexta had deeper and more durable responses compared with chlorambucil plus obinutuzumab.

“This is likely related to the synergistic mechanism of action of (Imbruvica plus Venclexta),” Kater said.

The rate of complete response was significantly higher in patients treated with Imbruvica plus Venclexta compared with chlorambucil plus obinutuzumab (38.7% vs. 11.4%). Most responders to Imbruvica plus Venclexta (90%) had a maintained response after two years compared with 41% in patients who responded to chlorambucil plus obinutuzumab.

Treatment with Imbruvica plus Venclexta also led to significantly higher undetectable minimal residual disease rates compared with chlorambucil plus obinutuzumab as assessed in bone marrow (51.9% vs. 17.1%) and peripheral blood (54.7% vs. 39%). At one year after end of treatment, 85% of patients with undetectable minimal residual disease at the end of treatment with Imbruvica plus Venclexta sustained their undetectable minimal residual disease status.

The median exposure to Imbruvica plus Venclexta was 13.8 months compared with 5.1 months for chlorambucil plus obinutuzumab.

“Safety profiles for both arms were as expected given the known safety profiles of (Imbruvica, Venclexta) and chlorambucil plus obinutuzumab when used to treat (an) older comorbid CLL patient population,” Kater said.

Data on OS are immature, Kater said, with 11 deaths occurring in the Imbruvica plus Venclexta arm and 12 deaths in the chlorambucil plus obinutuzumab arm. Causes of deaths in both study arms were similar, with the most common causes being infections and cardiac events.

“If you take this GLOW data together with CAPTIVATE in the unfit population, we now experienced across a broad spectrum more than 400 CLL patients treated with (Imbruvica plus Venclexta) in this first-line setting,” Kater concluded.

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