NEW ORLEANS – The glycoengineered CD20-antibody obinutuzumab is already being hailed as a breakthrough first-line therapy for chronic lymphocytic leukemia, and clinicians finally got to see the full data behind the accolades and its recent approval.
In the CLL11 study of older chronic lymphocytic leukemia (CLL) patients with coexisting medical problems, obinutuzumab (Gazyva) pushed the overall response rate to 78%, compared with 65% with rituximab (Rituxan) (P less than .0001). Both drugs were used in combination with chlorambucil chemotherapy.
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Complete remission occurred in 21% of patients given obinutuzumab, formerly known as GA101, and 7% on rituximab.
More patients receiving obinutuzumab also achieved minimal residual disease in bone marrow (19.5% vs. 2.6%) and blood (37.7% vs. 3.3%); both differences were statistically significant at P less than .0001), Dr. Valentin Goede reported during a plenary session at the annual meeting of the American Society of Hematology.
Obinutuzumab significantly extended the study’s primary endpoint of progression-free survival to 26.7 months from 15.2 months with combination rituximab (hazard ratio, 0.39; P less than .0001), and delivered a huge 15-month advantage in median progression-free survival over chlorambucil alone(11.1 months vs. 26.7 months; HR, 0.18; P less than .0001).
Overall survival data are still immature at about 18 months but look promising, with 28 deaths on obinutuzumab (8%) and 41 (12%) on rituximab (HR, 0.66; P = .08), said Dr. Goede of the German CLL Study Group and University Hospital Cologne, Germany.
During a press conference, he described the results of the CLL11 trial as practice-changing for older CLL patients, who comprise the bulk of patients clinicians see, but not for all patients with CLL.
"If we combine GA101 or rituximab with a weaker chemotherapy backbone, GA101 obviously is superior to rituximab in this setting, and will substitute for rituximab," he said. "It is more difficult to give an estimation for younger patients, where as you know, rituximab is combined with much more aggressive chemotherapy backbones. We know that these therapies are very effective in these patients and we don’t know how much GA101 adds to the efficacy when replacing rituximab."
Dr. Jennifer R. Brown, press briefing moderator and director of the chronic lymphocytic leukemia center at the Dana-Farber Cancer Institute in Boston, said there has been a great deal of skepticism prior to CLL11 that any CD20 antibody would beat rituximab so definitively in a head-to-head study.
Dr. Jennifer R. Brown
"The results are very impressive and in this patient population, obinutuzumab clearly beat rituximab. So going forward, it will be of great interest to study [obinutuzumab] in other contexts," she said.
Almost 40% of the 663 patients in the head-to-head comparison were older than 75 years (median age, 73 years) and all had common comorbidities such as cardiovascular disease, diabetes mellitus, dyslipidemia, and chronic obstructive pulmonary disease.
All 781 patients in the CLL11 study had previously untreated CLL and a total Cumulative Illness Rating Scale score of more than 6 and/or a creatinine clearance rate of less than 70 mL/min.
Results from the first stage of the phase III study comparing chlorambucil alone with obinutuzumab were reported earlier this year at the annual meeting of the American Society of Clinical Oncology.
Obinutuzumab was approved in November in combination with chlorambucil for the first-line treatment of CLL, and carries boxed warnings regarding the potential for hepatitis B reactivation and progressive multifocal leukoencephalopathy, which have been reported in rare cases in other obinutuzumab trials. These adverse events have not been seen so far in CLL11, but were added to the label because they are known risks with other monoclonal antibodies including rituximab, Dr. Goede said in an interview.
Overall grade 3/4 adverse events were more common with obinutuzumab than rituximab (70% vs. 55%), primarily driven by infusion-related reactions (20% vs. 4%). These reactions occurred only during the first infusion and should be managed with corticosteroid prophylaxis and a slow initial infusion rate, he said. Neutropenia was also increased (33% vs. 28%) but did not lead to an increase in infections.
Dr. Goede reported honoraria from Mundipharma and Hoffman-La Roche; several coauthors reported financial relationships including board membership and employment with Roche, parent company of Genentech, which makes obinutuzumab.