Zosia Chustecka

December 12, 2011

December 12, 2011 (San Diego, California) — For more than a decade now, rituximab (Rituxan, Genentech) has reigned supreme as the only drug of its kind — a monoclonal antibody specifically targeting the CD20 protein expressed on B cells. This activity has secured a role for rituximab in a range of B-cell lymphomas and leukemias, and has more recently also been used for rheumatoid arthritis.

Now comes a challenger, in the form of a new product with the same specific action: obinutuzumab, which also comes from Genentech. This is a humanized antibody, whereas rituximab is a chimeric product, and the new product showed less propensity for immune reactions in preclinical testing.

The drug is in phase 3 clinical trials. Data from phase 2 studies, presented here at the annual meeting of the American Society of Hematology, have stirred up considerable interest, particularly because preliminary results from the first head-to-head comparison with rituximab showed higher response rates with the new drug. In addition, in other phase 2 studies obinutuzumab elicited responses in patients who were refractory to rituximab.

Head-to-Head Comparison

The head-to-head comparator study was reported by Laurie Sehn, MD, MPH, clinical assistant professor in the Division of Medical Oncology at the University of British Columbia Center for Lymphoid Cancer in Vancouver, Canada.

This phase 2 trial was conducted in 175 patients with relapsed indolent non-Hodgkin's lymphoma (of whom 149 had follicular and 26 had nonfollicular disease) who had been treated with at least 2 prior therapies, including rituximab, and previously demonstrated a response to rituximab lasting 6 months or longer.

Patients were randomly assigned to receive 4 weekly infusions of rituximab (375 mg/m2) or obinutuzumab (1000 mg). Responses were assessed 28 to 42 days after the last dose, and patients without evidence of progression then continued to receive maintenance therapy at the same doses, given once every 2 months for up to 2 years. The primary efficacy analysis was conducted in the 149 patients with follicular lymphoma at the end of the indication phases. The overall response rate was higher for obinutuzumab than for rituximab (44.6% vs 33.3%), as was the complete remission rate (12.2% vs 5.3%).

The new drug was well tolerated, Dr. Sehn reported, although it was associated with a higher rate of infusion rate reactions and also cough, but both of these were considered to be mild. More severe adverse events were seen in the rituximab group (11% vs 6% receiving obinutuzumab), and more patients in the rituximab group discontinued therapy.

"We are encouraged to see higher response rates without appreciable differences in safety," Dr. Sehn commented. "Based on these data, phase 3 trials are warranted, and indeed are already underway," she added.

More Data From Phase 2 Trials

At the meeting, data were presented from 2 other phase 2 studies in a similar patient population of relapsed/refractory non-Hodgkin's lymphoma, and in 1 of the studies, the disease was described as "aggressive." Those researchers reported that obinutuzumab showed "encouraging activity" as monotherapy, and in both studies some responses were reported in patients who were refractory to rituximab.

Another phase 2 trial investigated the use of obinutuzumab in combination with chemotherapy in patients with relapsed or refractory follicular lymphoma. This trial, reported by John Radford, MD, from the Christie NHS Foundation Trust, Manchester, United Kingdom, used obinutuzumab in combination with fludarabine and cyclophosphamide (FC) or with the combination of cyclophosphamide/doxorubicin/vincristine/prednisone, also known as CHOP.

The results show that obinutuzumab can be combined safely with chemotherapy regimens used in the treatment of follicular lymphoma and that it demonstrates a high level of activity compared with historical controls, Dr. Radford concluded. The combination with CHOP could be delivered at the protocol-specified interval of every 3 weeks in most patients, although the combination with FC in a more heavily pretreated population showed worse tolerability, he commented.

Following these promising results, obinutuzumab is now being studied in combination with CHOP and other chemotherapies in a randomized phase 3 study against the standard of care, rituximab with CHOP chemotherapy, R-CHOP.

Dr. Sehn has disclosed no relevant financial relationships, but coauthors reported receiving research funding from Pharmacyclics, and 2 coauthors were company employees.

American Society of Hematology Annual Meeting. Abstracts 629 (Sehn et al.), 268, 270, and 3665, all presented December 12, 2011.

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