Obinutuzumab for CLL Approved in EU

Zosia Chustecka


July 29, 2014

Obinutuzumab (Gazyvaro, Roche) is now approved in Europe for the treatment of chronic lymphocytic leukemia (CLL), specifically for use in combination with chlorambucil in patients with previously untreated disease who have comorbidities making them unsuitable for intensive therapy (such as full-dose fludarabine-based therapy).

This indication was recommended for approval in the European Union in May and was approved in November 2013 in the United States, where the drug is marketed as Gazyva by Genentech.

Obinutuzumab is a monoclonal antibody that specifically targets the CD20 protein expressed on B-cells, and is seen as a successor to rituximab (Rituxan, Genentech; MabThera, Roche). Both drugs were developed by the same companies.

Rituximab was the first, and for a long time the only, anti-CD20 monoclonal antibody to gain approval for use in B-cell lymphomas and leukemias, and more recently also for rheumatoid arthritis; it became a best-selling product, with annual sales of nearly $7 million. However, it is now approaching the end of its patent life.

While rituximab is a chimeric human/murine product, obinutuzumab is a fully humanized product and has shown less propensity for immune reactions in preclinical testing, and has been associated with fewer severe adverse events in a head-to-head comparator trial. It has also shown superior efficacy, compared with rituximab, in the CLL11 trial, which was used as the basis for approval.

In the CLL111 trial, the combination of obinutuzumab plus chlorambucil met its primary end point by significantly reducing the risk of disease worsening or death by 61%, compared with the combination of rituximab plus chlorambucil. The mean progression-free survival was 26.7 months for the obinutuzumab group, compared with 15.2 months for those in the rituximab group (hazard ratio, 0.39; P < .001).

The CLL11 study also showed higher complete response rates (21% compared with 7%) and a 10-fold increase in the percentage of people achieving minimal residual disease negativity (37.7% compared with 3.3%), the company noted.

Clearly a Winner, But Will it Replace?

Obinutuzumab clearly wins. Progression-free survival is clearly better.

The CLL11 study was published earlier this year in the New England Journal of Medicine (2014;370:1101-1110), as reported by Medscape Medical News. At the time, coauthor of an accompanying editorial (N Engl J Med. 2014;370:1160-1162), Kanti R. Rai, MB, BS, from the Hofstra North Shore–LIJ School of Medicine in New York City, commented: "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.

"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.

Boxed Warning in the United States

When recommending approval, the European Medicines Agency noted that the safety profile is in accordance with what would be expected for a monoclonal antibody in this class. Infusion-related reactions, neutropenia, and infections were among the most common adverse events reported. Some rare but serious adverse events were reported; however, the toxicity profile was considered acceptable in view of its benefits, the European agency noted.

In the United States, the drug's labelling has a boxed warning about hepatitis B virus reactivation and the potential risk of inducing progressive multifocal leukoencephalopathy (PML). According to the FDA, these are known risks with other monoclonal antibodies in this class, and rare cases have been identified in clinical trials with obinutuzumab.

Roche told Medscape Medical News that in the European Union, the product labels in general do not have boxed warnings, and that in the European Union label for obinutuzumab, the information on hepatitis B reactivation and PML is included in the Special Warnings and Precaution for Use section and the Undesirable Effects section.

The company also said that it cannot comment on the cost of the new product, as pricing negotiations are still ongoing.


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