NEW ORLEANSObinutuzumab (GA101) plus chlorambucil significantly prolonged progression-free survival (PFS), with higher complete response and minimal residual disease (MRD) negativity rates compared with rituximab plus chlorambucil, in treatment-naïve patients with chronic lymphocytic leukemia (CLL) and co-existing medical conditions, final stage 2 results of the CLL11 trial reported at the 55th American Society of Hematology (AHS) Annual Meeting and Exposition.

In addition, the combination of the novel glycoengineered type II CD20 antibody, obinutuzumab, with chlorambucil demonstrated prolonged overall survival (OS) compared with chlorambucil alone in this population typically treated in daily practice, said Valentin Goede, MD, of the University Hospital Cologne, Cologne, Germany.

These results suggest that obinutuzumab “may be a stronger CD20 antibody than rituximab,” Dr. Goede said. “This could lead to a potential decrease in the total amount of chemotherapy required for an effective combination regimen, translating to less toxicity for the patient.”

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The phase 3 CLL11 trial randomly assigned 780 patients with CLL with a Cumulative Illness Rating Scale (CIRS) score higher than 6 and/or an estimated creatinine clearance (CrCl) less than 70 mL/min to chlorambucil alone (0.5 mg/kg orally day 1 and day 15 every 28 days, six cycles), obinutuzumab plus chlorambucil (100 mg intravenously day 1, 900 mg day 2, and 1,000 mg day 8 and 15 of cycle 1 and 1,000 mg day 1 cycles 2-6), or rituximab plus chlorambucil (375 mg/m2 intravenously day 1 cycle 1, 500 mg/m2 day 1 cycles 2-6).

Primary end point was investigator-assessed PFS. Response rates, MRD, and OS were key secondary efficacy end points.

At the preplanned interim analysis, the primary end point was met early and the results were released by the independent data monitoring board.

Dr. Goede presented data from the final stage 2 analysis of efficacy and safety results of the head-to-head comparison between obinutuzumab plus chlorambucil (n = 333) and rituximab plus chlorambucil (n = 330). Median observation time was 18.7 months. Both treatment arms were well balanced for baseline characteristics: median age was 73 years; CIRS score, 8; and CrCl 63 mL/min.

Overall response rate was 78% in the obinutuzumab plus chlorambucil arm versus 65% in the rituximab plus chlorambucil arm (P < 0.0001); complete response was 21% and 7%, respectively. Median PFS was 26.7 months in the obinutuzumab arm versus 15.2 months in the rituximab arm (hazard ratio [HR], 0.39; 95% CI: 0.31-0.49; P < 0.0001). Median OS was not reached in either arm (HR, 0.66; 95% CI: 0.41-1.06; P = 0.0849).

During treatment, the incidence of adverse events grade 3 or higher was 70% in the obinutuzumab arm (n = 336) and 55% in the rituximab arm (n = 55), including infusion-related reaction (20% vs. 4%; no deaths); neutropenia (33% vs. 28%; no deaths); and infection (12% vs. 12%).

The PFS benefit of obinutuzumab plus chlorambucil over rituximab plus chlorambucil was supported by all preplanned subgroup analyses (including the cytogenetic subgroups 17p-, 11q-, 12+, 13q-), Dr. Goede reported. The number of patients with MRD-negative blood samples at end-of-treatment was more than 10-fold higher with obinutuzumab plus chlorambucil compared with rituximab plus chlorambucil (87/231 [37.7%] vs. 8/243 [3.3%]; P < 0.0001). Grade 3/4 infusion-related reactions with obinutuzumab plus chlorambucil occurred at first infusion only.

Dr. Goede also presented an update of the stage 1 analysis, which compared obinutuzumab plus chlorambucil versus chlorambucil alone and rituximab plus chlorambucil versus chlorambucil alone. The median 23 months observation time showed that combining either obinutuzumab or rituximab with chlorambucil has superior efficacy to chemotherapy with chlorambucil alone.

Obinutuzumab plus chlorambucil or rituximab plus chlorambucil versus chlorambucil alone was associated with significant improvement in PFS (obinutuzumab plus chlorambucil vs. chlorambucil: HR, 0.18; 95% CI: 0.13-0.24; P < 0.0001; and rituximab plus chlorambucil vs. chlorambucil: HR, 0.44; 95% CI: 0.34-0.57; P < 0.0001).

The updated median PFS in obinutuzumab plus chlorambucil was 26.7 months; rituximab plus chlorambucil, 16.3 months; and chlorambucil alone, 11.1 months. Updated OS analysis demonstrated a benefit of obinutuzumab plus chlorambucil over chlorambucil (HR, 0.41; 95% CI: 0.23-0.74; P = 0.0022); OS analysis for rituximab plus chlorambucil over chlorambucil showed HR, 0.66, 95% CI 0.39-1.11, and P = 0.1129. At the data cut-off, 9% of the patients in the obinutuzumab plus chlorambucil arm had died, as had 15% in the rituximab plus chlorambucil arm and 20% in the chlorambucil arm.

“Overall, obinutuzumab plus chlorambucil is superior to rituximab plus chlorambucil and a highly active treatment in this typical CLL patient population,” Dr. Goede concluded, adding that the results suggest obinutuzumab “has the potential to eventually replace rituximab” for the care of patients with CLL.