Anti-CD20 Antibodies Continue to Improve Outlook in CLL

Kanti Rai, MD

The FDA approval of two anti-CD20 antibodies— ofatumumab (Arzerra) and, recently, obinotuzumab (Gazvya)—has greatly advanced the outlook for managing chronic lymphocytic leukemia (CLL), noted Kanti Rai, MD, who discussed the treatments at the 2013 Chemotherapy Foundation Symposium.

“We are in an era of anti-CD20 monoclonal antibodies as the backbone of treatment of CLL and other chronic lymphoid malignancies,” said Rai, a professor of Medicine and Molecular Medicine at Hofstra North Shore Long Island Jewish School of Medicine, Hempstead, New York. “There have been important advances in CLL. Both ofatumumab and obinotuzumab have a great future and an important place in the treatment of CLL.”

In 1997, Rituximab became the first anti-CD20 antibody to be approved for the treatment of hematologic malignancies and later became part of the armamentarium for the treatment of patients with CLL.

“Ofatumumab was approved a few years ago, and made slow but strong headway in the armamentarium for CLL. And [just recently], obinotuzumab was approved by the FDA, making it the newest entry in this exciting field,” said Rai.

All three drugs kill B cells via complement dependent toxicity, APC presenting.

In the pivotal phase II trial of singleagent ofatumumab, patients with CLL who were double refractory to fludarabine and alemtuzumab had excellent responses to treatment. The rate of partial response in these very poor prognosis patients was a “respectable” 58%, Rai said, and patients had a “reasonably long overall survival.” Median progression-free survival (PFS) was 5.7 months and median overall survival (OS) was 13.7 months.

On the heels of its single-agent activity, ofatumumab has moved on to studies of various combinations, with encouraging results.

GlaxoSmithKline and Genmab recently submitted an application to the FDA to market ofatumumab combined with alkylator-based therapy for treatment-naïve patients with CLL who are not eligible for fludarabinebased therapy. The submission is based on a phase III study in which ofatumumab plus chlorambucil improved PFS by 9.3 months versus chlorambucil alone in previously untreated patients with CLL.

Studies have also shown that ofatumumab can replace rituximab in the fludarabine/cyclophosphamide/ rituximab (FCR) regimen for CLL pioneered at MD Anderson Cancer Center. “There is clear-cut evidence that the combination of ofatumumab, fludarabine, cyclophosphamide [O-FC] is equivalent to FCR,” Rai said.

A phase II trial confirmed comparable high activity and safety of the O-FC regimen for previously untreated CLL. Investigators are moving forward with this regimen using a 1000-mg dosage of ofatumumab.

Phase III Data for Anti-CD-20 Antibody Obinutuzumab in CLL

Obinutuzumab Plus Chlorambucil

(n = 238)

Chlorambucil

(n = 118)

P

Median PFS (months)

23.0

11.1

<.0001

ORR (%)

75.9

32.1

-

Data are from the phase III CLL11 trial that lead to the FDA approval of obinutuzumab in CLL. Overall study also included a third arm in which patients received chlorambucil plus rituximab.

Another attractive combination is ofatumumab plus the PI3K-inhibitor idelalisib versus idelalisib alone. This combination is in phase I/II testing.

Ofatumumab and lenalidomide have been studied as both frontline treatment of CLL and in previously treated CLL. This combination has been extremely effective, Rai said.

Obinutuzumab is the second of the newer anti- CD20 antibodies Rai reviewed. The pivotal CLL11 trial of obinutuzumab plus chlorambucil showed that the combination improved PFS by 11.9 months over chlorambucil alone (P <.0001). Overall response rate (ORR) was 75.9% in the obinutuzumab arm versus 32.1% in the control arm.

The most common grade 3/4 adverse events for patients treated with obinutuzumab plus chlorambucil were neutropenia (34%), infusion reactions (21%), and thrombocytopenia (11%).

In a third arm of the CLL11 study, patients received chlorambucil plus rituximab. Final data for the head-to-head comparison between the obinutuzumab and rituximab arms were presented at the 55th Annual ASH Meeting (View more >>>).

“Ofatumumab and obinutuzumab have each demonstrated good activity in CLL as single agents. Now ongoing trials are showing that combinations with each of these drugs are extremely promising,” said Rai.

Rai, K. Anti-CD20 monoclonal antibodies in therapy of CLL: obinutuzumab and ofatumumab. Presented at: 2013 Chemotherapy Foundation Symposium; November 6-8, 2013; New York City.