Survival Longer With Obinutuzumab Compared to Rituximab in CLL

Nancy A. Melville

June 20, 2018

STOCKHOLM — Final results from the phase 3 CLL11 trial confirm the superiority of the newer anti-CD20 monoclonal antibody drug obinutuzumab (Gazyva) compared to the older agent rituximab (Rituxan); both agents are from the same manufacturer, Roche, which sponsored the study.

In this study, conducted in patients with previously untreated chronic lymphocytic leukemia (CLL), the anti-CD20 agents were used together with chlorambucil (Leukeran, Aspen Global). The combinations were compared with each other and with chlorambucil alone.

The new study, which had follow-up period of approximately 5 years, shows that obintuzumab with chlorambucil was superior for both progression-free survival (PFS) and overall survival (OS).

"In this trial, use of a type 2 glycoengineered CD20 monoclonal (obinutuzumab) apparently resulted in lower risk of death compared with a type 1, nonglycoengineered CD20 antibody (rituximab)," first author Valentin Goede, MD, PhD, with the Department of Internal Medicine at the University Hospital of Cologne, Germany, told Medscape Medical News.

"This finding should have impact on international and national CLL treatment guidelines, which list chlorambucil-based chemoimmunotherapy as one option among others to treat patients with comorbidities (ie, unfit patients)," Goede said.

The study was presented here at the European Hematology Association (EHA) 2018 Congress.

The final analysis of the multinational trial, which started in 2010, included older patients (median age, 73 years) with previously untreated CD20-positive CLL and a high degree of comorbidities. The patients were treated with the obinutuzumab/chlorambucil combination (n = 333), a combination of rituximab and chlorambucil (n = 330), or chlorambucil alone (n = 238).

The mean observation time was 59.4 months. For patients treated with obinutuzumab/chlorambucil, median PFS was 28.9 months, compared to 15.7 months for the rituximab/chlorambucil combination group (hazard ratio [HR], 0.49; 95% confidence interval [CI], 0.41 - 0.58; P < .0001).

The median time to new treatment was substantially greater with obinutuzumab/chlorambucil (56.4 months vs 34.9 months; HR, 0.58; 95% CI, 0.46 - 0.73; P < .0001).

OS was also improved with obinutuzumab/chlorambucil. OS was not reached with obinutuzumab/chlorambucil; it was 73.1 months with rituximab/chlorambucil (HR, 0.76; 95% CI, 0.60 - 0.97; P = .0245).

"This difference is clinically meaningful and remarkable in the context of the long follow-up of these patients," Goede said.

Survival rates in the obinutuzumab/chlorambucil and rituximab/chlorambucil groups were 91% vs 84% at 2 years and 66% vs 57% at 5 years. There were significantly fewer deaths overall in the obinutuzumab/chlorambucil group (37% vs 45%).

In the comparison of obinutuzumab/chlorambucil to chlorambucil alone, median PFS was significantly greater for patients who received the combination treatment (n = 238) compared to those who received only chlorambucil (n = 118; 31.1 months vs 11.1 months; HR, 0.21; 95% CI, 0.16 - 0.28; P < .0001) during a period of 62.5 months.

OS was not reached in the obinutuzumab/chlorambucil group; it was 66.7 months with chlorambucil only (HR, 0.68; 95% CI, 0.49 - 0.94; P = .0196). For patients who received obinutuzumab/chlorambucil, the time to new treatment was 55.7, vs just 15.1 months for patients who received only chlorambucil (HR, 0.25; 95% CI, 0.19 - 0.35; P < .0001).

Each of the groups in the study received treatment in six 28-day cycles. Chlorambucil (0.5 mg/kg) was administered orally on days 1 and 15 of the six cycles.

Rituximab was administered intravenously at a dose of 375 mg/m2 on day 1 of cycle one and 500 mg/m2 on day 1 of cycles two through six.

Obinutuzumab (1000 mg) was administered intravenously on day 1 (dose split over 2 days; 100 mg on day 1, 900 mg on day 2), day 8, and day 15 of cycle 1, and on day 1 of cycles 2 through 6.

The median age of the patients was 73 years. The median total Cumulative Illness Rating Scale score was 8, and the median creatinine clearance was 62 mL/min.

No safety issues were identified that had not been previously reported. There were only marginal differences in rates of neutropenia across the three treatment arms.

There were also no significant differences in the rate of occurrence of second malignancies among the patients who received obinutuzumab and those who received rituximab. The rates were higher for both groups than for the chlorambucil group.

"These recent findings of the CLL11 study suggest that choice of the CD20 antibody during chlorambucil-based chemoimmunotherapy matters — obviously not just for progression-free and treatment-free, but also for overall survival," Goede said.

Obinutuzumab received approval from the US Food and Drug Administration for the treatment of CLL in 2013 after results from the CL11 trial, published in the New England Journal of Medicine, showed superiority of the chemoimmunotherapy over chemotherapy alone in PFS and OS.

"In the present treatment landscape of CLL, these data support the use of obinutuzumab and chlorambucil as a frontline therapy for CLL in patients who are old and have comorbidities," Goede said.

As treatment for CLL has evolved, newer agents and chemotherapy-free combinations with obinutuzumab have emerged. The phase 3 ILLUMINATE study has shown improved PFS in combination with ibrutinib (Imbruvica, AbbVie and Janssen Biotech) compared to obinutuzumab with chlorambucil.

Those unpublished results were reported by AbbVie and Janssen Biotech in May in a press release.

Venetoclax (Venclexta, AbbVie), a highly selective BCL2 inhibitor that has become important in the treatment of relapsed CLL, has shown antitumor activity in CLL in combination with obinutuzumab in a preliminary study, Goede noted.

"These are two examples of some encouraging combinations," he said.

Goede said the data show strong efficacy and safety of obinutuzumab/chlorambucilin for patients with previously untreated CLL who are older and who carry typical age-associated conditions, such as hypertension, diabetes, heart failure, chronic obstructive pulmonary disease, or renal impairment.

Notably, the data have shown obinutuzumab/chlorambucil to be effective in patients with mutated as well as unmutated IGHV, "however, presence of TP53 alteration should prompt alternative therapies," Goede said.

Improving OS

The final analysis underscores the emergence of the important measure of improved OS that is increasingly occurring with newer drugs, Anton Hagenbeek, MD, PhD, a professor of hematology at the University of Amsterdam, the Netherlands, told Medscape Medical News.

"For many years with CLL, we have seen new agents and combinations leading to a better progression-free survival, but now we are seeing more studies where the overall survival is also improved, like in this study," he said.

"So this is another example of a step forward in terms of improving overall survival in a way that is meaningful to the patient.

"While there are other treatments, this combination is going to be more appropriate for older patients who cannot tolerate a more aggressive treatment," Hagenbeek said.

The study was sponsored by F. Hoffmann-La Roche Ltd. Dr Goede has consulted for, has been a member of the advisory board of, and has received speaker honoraria and travel support from F. Hoffmann-La Roche Ltd, Janssen, Gilead and AbbVie. Dr Hagenbeek is an advisor for Takeda Oncology.

European Hematology Association (EHA) 2018 Congress. Abstract S151, presented June 15, 2018.

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