Obinutuzumab Active in Elderly Chronic Lymphocytic Leukemia

Becky McCall

June 21, 2013

STOCKHOLM — Adding the investigational monoclonal antibody obinutuzumab (GA101, Genentech) to chlorambucil in elderly patients with chronic lymphocytic leukemia (CLL) more than doubled time to disease progression in a phase 3 trial.

"Effectively, this ends the era of chlorambucil monotherapy," study author Valentin Goede, MD, clinical scientist in the Department of Hematology at the University of Cologne, Germany, told Medscape Medical News.

Dr. Goede presented the first set of results from the CLL11 trial during the Presidential Symposium here at the 18th Congress of the European Hematology Association.

Obinutuzumab is a new monoclonal antibody directed against CD20, which is also targeted by rituximab (Rituximab, Genentech/Roche). However, obinutuzumab is a humanized antibody and has shown less propensity for immune reactions in preclinical testing than rituximab, which is a chimeric product.

The CLL11 trial is being conducted in collaboration with the German CLL Study Group, and is the first large phase 3 study to address first-line treatment for less-fit elderly patients with CLL. "We have been waiting for this because chlorambucil as a monotherapy is not a very effective regimen," Dr. Goede explained.

The CLL11 trial is distinctive because the trial cohort has a median age of 73 years. "One key aim was to improve the treatment of elderly patients with CLL because the majority of patients with this disease are elderly and many have comorbidities, which complicates treatment. Younger and fitter patients already have good standard treatment," Dr. Goede said.

"Many treatments are currently being used in this population without really good evidence," he emphasized.

Study Design

The first part of the CLL11 trial compared chlorambucil plus an anti-CD20 monoclonal antibody (either obinutuzumab or rituximab) with chlorambucil monotherapy in CLL patients with coexisting medical conditions.

Dr. Goede explained that results from a subsequent comparison of obinutuzumab plus chlorambucil with rituximab plus chlorambucil will likely be presented later in the year.

The 781 patients in the international multicenter study had previously untreated CLL and a range of pre-existing medical conditions, including hypertension, coronary heart disease, heart failure, diabetes, musculoskeletal problems, and renal impairment.

"We wanted to make sure that patients recruited had concurrent health problems typical of elderly populations," said Dr. Goede.

Patients received 1 of 3 treatment regimens: chlorambucil alone for 6 cycles; chlorambucil plus obinutuzumab (1000 mg on days 1, 8, and 15 of cycle 1 and on day 1 of cycles 2 to 6); or chlorambucil plus rituximab (375 mg/m² on day 1 of cycle 1 and 500 mg/m² on day 1 of cycles 2 to 6). Cycles were 28 days.

Significant Improvement in Progression-Free Survival

Investigator-assessed progression-free survival, the primary end point, was longer in the obinutuzumab group than in the chlorambucil monotherapy group (23.0 vs 10.9 months; hazard ratio, 14.0; 95% confidence interval, 0.09 - 0.21; <.0001).

"This finding suggests an 86% reduction in the risk for a progression, relapse, or death in the obinutuzumab arm," Dr. Goede pointed out.

He noted that these data, particularly the progression-free survival for the obinutuzumab group, might improve with time because the data are still immature.

Response to the therapy was also better in the obinutuzumab group than in the rituximab group in terms of the quantity of complete remissions (22.2% vs 8.3%). "That's quite a significant result," he said.

For molecular remissions, 31.1% of patients in the obinutuzumab group were negative for residual disease at the end of treatment. This is not seen in routine practice with rituximab, Dr. Goede noted.

Neutropenia was more frequent in the obinutuzumab and rituximab groups than in the chlorambucil monotherapy group, but Dr. Goede noted that these findings did not translate into infections. "This is probably due to better control of the disease itself in the monoclonal antibody arms. The transient nature of neutropenia is important in this elderly population."

Infusion-related reactions were higher in the obinutuzumab group, but only with the first infusion.

Table. Adverse Events in the 3 Groups

Adverse Event Obinutuzumab + Chlorambucil, % Rituximab + Chlorambucil Chlorambucil Monotherapy, %
Any grade ≥3 66.7 45.8 41.4
Infusion-related reaction 21.3 4.0
Neutropenia 34.2 25.3 14.7
Anemia 3.8 4.0 5.2
Thrombocytopenia 10.8 3.1 3.4
Infection 6.3 8.4 11.2

 

Although the results from the head-to-head comparison of the 2 monoclonal antibodies are not available yet, Dr. Goede said that they already "have implications for clinical practice. They show that elderly or unfit patients on chlorambucil treatment should also receive a monoclonal antibody. The evidence is very strong for benefits and the side effects do not offset these benefits."

Accumulation of Evidence for Chemoimmunotherapy

Robin Foà, MD, professor of hematology at University Sapienza in Rome, Italy, said that there is a primary unmet medical need in the elderly CLL population. He noted that most patients are older than 70 years at the start of treatment and, "as such, often have sizable comorbidities."

"The addition of obinutuzumab seems to be associated with a prolonged progression-free survival, although this will have to be confirmed with a longer follow-up and with more profound hematological and molecular remissions," he told Medscape Medical News.

Dr. Foà added that these results extend those from previous phase 2 studies conducted in Italy and the United Kingdom, which showed the benefit of adding rituximab to chlorambucil for elderly CLL patients or for patients unfit for fludarabine-based regimens. "It should be noted that the doses of chlorambucil used in the CLL11 trial are lower than those used in the Italian and British studies. Taken together, the results of these studies underline the role of anti-CD20-based chemoimmunotherapy for the management of CLL patients of all ages and physical conditions."

John Gribben, MD, consultant hematologist and medical oncologist from Barts and The London NHS Trust in the United Kingdom, said the CLL11 study is important because it provides data on the treatment of CLL in the elderly, in whom the disease is more prevalent.

"It is more than 50 years since chlorambucil was found to have activity in CLL, but no studies have shown improvement in outcome for these patients until now. The results show particularly impressive rates of complete remission for obinutuzumab plus chlorambucil, with 30% of patients achieving eradication of residual disease," Dr. Gribben noted.

"This randomized study changes the standard of care for less-fit patients with CLL and establishes increased activity for the new antibody obinutuzumab," he concluded.

Heading for Approval in Europe and the United States

Marketing applications have been submitted on the basis of the CLL11 data to regulatory authorities, including the European Medicines Association and the US Food and Drug Administration (FDA). A launch in the United States is expected by the end of this year.

The FDA has granted obinutuzumab breakthrough therapy designation. Genentech will open an expanded access program to provide obinutuzumab to people with CLL under certain circumstances in the meantime.

Dr. Goede reports receiving honoraria from Mundipharma and Roche. Dr. Foà reports conducting studies with rituximab (Roche) in the past, and serving as a speaker on CLL generally. Dr. Gribben reports receiving honoraria from and/or serving on advisory boards for Roche/Genentech, Celgene, Pharmacyclics, Janssen, and GSK.

18th Congress of the European Hematology Association (EHA): Abstract S567. Presented June 15, 2013.

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