Obinutuzumab Beats Rituximab in CLL

Roxanne Nelson

March 19, 2014

The new anti-CD20 antibody obinutuzumab (Gazya) performed better than the older product rituximab (Rituxan) when both were added to chemotherapy in previously untreated patients with chronic lymphocytic leukemia (CLL) and comorbidities.

The combination of obinutuzumab plus chlorambucil was associated with a higher complete response rate than rituximab plus chlorambucil (20.7% vs 7.0%), higher rates of molecular response, and longer progression-free survival (hazard ratio [HR], 0.39; P < .001).

Median progression-free survival was longer with obinutuzumab plus chlorambucil than with chlorambucil alone (26.7 vs 11.1 months; HR for progression or death, 0.18; P < .001). It was also longer with rituximab plus chlorambucil than with chlorambucil alone (16.3 vs 11.1 months; HR, 0.44; P < .001).

The results from the open-label 3-group study were published in the March 20 issue of the New England Journal of Medicine. They were previously presented at the 2013 American Society of Hematology annual meeting, and reported at that time by Medscape Medical News.

At the time, lead author Valentin Goede, MD, from University Hospital Cologne in Germany, said that the results were potentially practice-changing for this patient population.

Obinutuzumab has the potential to eventually replace rituximab for the care of CLL patients.

"While we will continue to evaluate these results through a longer follow-up period, these findings suggest that obinutuzumab has the potential to eventually replace rituximab for the care of CLL patients," he said.

The addition of rituximab to fludarabine and cyclophosphamide has been shown to prolong overall survival in physically fit patients with previously untreated CLL. But Dr. Goede and colleagues point out that randomized trials have not shown a similar benefit in CLL patients with coexisting conditions. Data from phase 2 trials, however, have suggested that combining rituximab with chlorambucil (an alkylating agent) might be a reasonable strategy in this population.

Actually, older patients with comorbidities are more typical of those seen in daily practice, Dr. Goede noted. For this group, the combination has an acceptable safety profile and prolonged overall survival.

Replacement for Rituximab?

As for whether or not obinutuzumab will replace rituximab in CLL, Dr. Goede noted that this is a "difficult question to address."

Both products are monoclonal antibodies specifically targeting the CD20 protein expressed on B-cells. However, obinutuzumab is a humanized antibody, whereas rituximab is a chimeric, and differences in immunogenic potential have been seen in preclinical testing. Both products are manufactured by Genentech/Roche, but rituximab is coming to the end of its product patent life.

In November 2013, obinutuzumab was approved by the US Food and Drug Administration (FDA) for use in combination with chlorambucil for the treatment of patients with previously untreated CLL.

It is the third anti-CD agent approved for use in CLL. The second one to come to market was ofatumumab (Arzerra, GlaxoSmithKline), which was approved last year with a breakthrough therapy designation.

"A head-to-head trial has not yet been conducted between ofatumumab and obinutuzumab," said Kanti R. Rai, MB, BS, from the Hofstra North Shore–LIJ School of Medicine in New York City. "And ofatumumab has not been approved for frontline therapy, although ongoing trials are looking at that now."

"Until we get those results, we have to make do with today's reality, and that is rituximab vs obinutuzumab," said Dr. Rai, who authored an accompanying editorial. "Obinutuzumab clearly wins. Progression-free survival is clearly better, and there is also a hint of increased life expectancy."

It is difficult to say whether obinutuzumab will eventually replace rituximab, Dr. Rai told Medscape Medical News.

However, "in the short run, meaning in the next 3 to 5 years, I feel that obinutuzumab might start to replace rituximab," he said. "In the same context, clinicians may decide to replace off-label chlorambucil with another type of chemotherapy."

The reason for this, he continued, is that chlorambucil has not been widely accepted. "It might be used, however, according to the FDA approval, for patients who are elderly, frail, and/or have comorbidities, because it is felt that chlorambucil is much better tolerated than classic chemotherapy."

For this patient population, Dr. Rai said that the combination of obinutuzumab and chlorambucil will probably become the frontline treatment. But for other patient populations with CLL, obinutuzumab plus another type of chemotherapy might become more frequently used.

"Whether it will totally replace rituximab or ofatumumab is not clear," he said.

Cost might play into it. "There may be a clear cut consideration of the cost of these drugs," Dr. Rai added. Rituximab's patent will expire in the United States in 2015, and lower-priced biosimilar versions could soon become widely available.

Study Details

In their study, Dr. Goede and colleagues randomized 781 patients with previously untreated CLL into 1 of 3 treatment groups: chlorambucil alone, obinutuzumab plus chlorambucil, and rituximab plus chlorambucil.

Median age of the patients was 73 years (but almost 40% were older than 75 years), creatinine clearance was 62 mL/min, and baseline Cumulative Illness Rating Scale score was 8 (range, 0 to 56).

The primary end point was investigator-assessed progression-free survival.

The most recent assessment of overall survival showed a significant survival benefit with obinutuzumab plus chlorambucil, compared with chlorambucil monotherapy (HR for death, 0.41; P = .002). Mortality rates were 9% and 20%, respectively.

Conversely, there was no significant benefit with rituximab plus chlorambucil, compared with chlorambucil alone (HR, 0.66; P = .11), and death rates were 15% and 20%, respectively.

In addition, there was no significant benefit with obinutuzumab plus chlorambucil, compared with rituximab plus chlorambucil (HR, 0.66; P = .08), and death rates were 8% and 12%, respectively. Overall survival medians were not reached in this study.

At the end of treatment, the number of patients with negative blood samples was more than 10-fold higher with obinutuzumab than with rituximab for minimum residual disease in both bone marrow (19.5% vs 2.6%) and blood (37.7% vs 3.3%).

More adverse events were observed in patients using the anti-CD agents than those using chlorambucil alone. Infusion-related reactions and neutropenia were more common with obinutuzumab plus chlorambucil than with rituximab plus chlorambucil, but the risk for infection was no higher.

The incidence of grade 3 or 4 neutropenia was highest with obinutuzumab plus chlorambucil and was lowest with chlorambucil alone. Rates of grade  to 5 infection ranged from 11% to 14%, and did not differ significantly among the treatment groups. The percentage of patients who died from an adverse event was lower with obinutuzumab plus chlorambucil (4%) than with rituximab plus chlorambucil (6%) or chlorambucil alone (9%).

The study was supported by F. Hoffmann–La Roche.

N Engl J Med. 2014;370:1101-1110, 1160-1162. Abstract, Editorial


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