CLL11 Study: 5-Year Results Confirm Obinutuzumab plus Chemotherapy as Front-Line Therapy for Patients with Chronic Lymphocytic Leukemia
In older patients with chronic lymphocytic leukemia (CLL) and comorbidities, the use of immunotherapy with obinutuzumab (Gazyva) plus chemotherapy with chlorambucil (Leukeran) as front-line therapy was supported by the findings of the CLL11 clinical trial final analysis.
“CLL is a disease that primarily affects older people, and the purpose of that trial was to improve treatment for these elderly CLL patients with comorbidities by introducing immunochemotherapy,” said Valentin Goede, MD, German CLL Study Group, Center of Integrated Oncology, University Hospital, Cologne, Germany, at the 2018 European Hematology Association Congress press briefing.
Chemotherapy alone was the standard treatment for patients with CLL when the CLL11 study was launched in 2009, and obinutuzumab, a glycoengineered type 2 CD20-antibody immunotherapy, was still an investigational agent. The FDA approved obinutuzumab, in combination with chlorambucil, for the treatment of patients with CLL in November 2013.
Obinutuzumab versus Rituximab
A further goal of CLL11, Dr Goede said, was to compare obinutuzumab and rituximab (Rituxan), a monoclonal antibody, in a head-to-head efficacy and safety study in 781 patients (median age, approximately 73 years) with untreated CLL and comorbidities.
Earlier analyses of CLL11 had established the superiority of obinutuzumab or rituximab plus chlorambucil over chlorambucil alone.
An updated 2015 analysis of the study revealed that at a median of 39 months, the median progression-free survival (PFS) was 28.7 months with obinutuzumab plus chlorambucil versus 15.7 months with rituximab plus chlorambucil (hazard ratio [HR], 0.46; 95% confidence interval [CI], 0.38-0.55; P <.0001).
The median time to next treatment was 51.1 months in the obinutuzumab plus chlorambucil arm and 38.2 months in the rituximab plus chlorambucil arm (HR, 0.57; 95% CI, 0.44-0.74; P <.0001). The median overall survival (OS) had not been reached in either arm, and no new safety concerns were observed.
At a median of 59.4 months, Dr Goede and colleagues’ final analysis added approximately 2 years to the follow-up time, and included 333 patients who received obinutuzumab plus chlorambucil and 330 receiving rituximab plus chlorambucil.
The median PFS was 28.9 months in the obinutuzumab arm and 15.7 months in the rituximab arm (P <.0001). The secondary analysis showed a median time to next treatment of 56.4 months versus 34.9 months for the obinutuzumab and rituximab arms, respectively (P <.0001).
The median OS was not reached in the obinutuzumab arm versus 73.1 months in the rituximab arm (HR, 0.76; 95% CI, 0.60-0.97; P = .0245). The 5-year OS rate was 66% and 57%, respectively. The OS advantage for obinutuzumab plus chemotherapy was generally consistent across subgroups, Dr Goede noted. Disease progression—the main cause of death—was 10% in the obinutuzumab arm and 15% in the rituximab arm.
Grade 3 to 5 adverse events were reported in 72% of patients in the obinutuzumab arm and 60% of patients in the rituximab arm. Grade 5 adverse event rates were 7% and 10%, respectively.
Secondary malignancy rates were identical (4%) for each arm, as were infection rates (<1%). Late-onset adverse event rates (ie, prolonged neutropenia, late-onset neutropenia, second malignancy, squamous-cell carcinoma, and basal-cell carcinoma) were all low and similar between the 2 groups. No new late-onset toxicities were detected.
“After a median observation time of about 5 years, obinutuzumab plus chlorambucil provided a meaningful improvement in PFS and OS, while prolonging time to next treatment relative to rituximab plus chlorambucil by about 1.5 years, and attaining an absolute treatment-free duration of about 4 years,” Dr Goede said.
“We consider these results clinically meaningful and also remarkable in the context of the long follow-up of the trial,” he added.
Although the study findings suggest obinutuzumab as the preferred anti-CD20 antibody in combination regimens for CLL, the data are also reassuring regarding the use of obinutuzumab with chlorambucil as comparators in newer clinical trials, with the combination of ibrutinib (Imbruvica) plus obinutuzumab and the triplet regimen of adding venetoclax (Venclexta) to ibrutinib plus obinutuzumab.
“We can expect these to be positive trials for PFS,” Dr Goede concluded, noting that toxicity profiles in these chemotherapy-free regimens will be “of interest” and are characteristically different from the toxicity profiles of chemotherapy.