FDA Approves Frontline Ofatumumab for Select Patients With CLL

Paolo Paoletti, MD

The FDA has approved ofatumumab (Arzerra) plus chlorambucil for previously untreated patients with chronic lymphocytic leukemia (CLL) who are considered inappropriate for treatment with the chemotherapy fludarabine. The approval for the combination was based on the phase III COMPLEMENT 1 trial, which demonstrated a 9.3-month improvement in progression-free survival (PFS) for the combination compared with chlorambucil alone.

“CLL is the most common form of leukemia amongst adults in Western countries, many of whom are elderly with multiple health issues,” Paolo Paoletti, MD, President of Oncology at GSK, the company that co-developed the combination, said in a press release. “Today’s approval by the FDA for the use of Arzerra in the first-line setting means that appropriate patients with CLL have a new treatment option.”

The COMPLEMENT 1 study enrolled 447 patients with CLL who were considered inappropriate for fludarabine-based therapy due to advanced age and/or comorbidities. Patients were enrolled in a 1:1 ratio to receive ofatumumab plus chlorambucil (n = 221) or chlorambucil alone (n = 226). Patients received a median of 6 cycles of therapy in both arms of the trial. However, in the ofatumumab arm, 82% of patients received more than 6 cycles of therapy.

According to results presented at the 2013 ASH annual meeting, the median PFS by independent review was 22.4 months with ofatumumab plus chlorambucil compared with 13.1 months for chlorambucil alone (hazard ratio [HR] = 0.57; 95% CI, 0.45-0.73; P < .001). ORR was 82% versus 69% with a complete response rate of 12% versus 1%, for ofatumumab plus chlorambucil compared with chlorambucil alone, respectively.

Grade 3/4 adverse events occurred in 50% of patients treated with ofatumumab compared with 43% in the chlorambucil monotherapy arm. The most common grade 3/4 toxicity was neutropenia, which occurred in 26% of patients treated with ofatumumab compared with 14% for chlorambucil alone.

Grade 3/4 infusion-related adverse events were reported in 10% of patients treated with ofatumumab compared with none for those receiving chlorambucil alone. No fatal infusion reactions were reported. Infections rates were similar, at 15% and 14%, for ofatumumab plus chlorambucil versus chlorambucil alone.

“We are pleased that Arzerra has been shown to provide clinical benefit and will now be available in the first-line setting. Arzerra, the first approved therapeutic created by Genmab and developed in collaboration with GSK, is the only therapeutic CD20 antibody approved in combination with chlorambucil for first-line CLL and as a monotherapy for CLL refractory to fludarabine and alemtuzumab,” said Jan van de Winkel, PhD, the Chief Executive Officer of Genmab, the company that co-developed the drug.

Ofatumumab targets CD20 similarly to the well-established treatment rituximab. Targeting CD20 on the surface of both normal and malignant B-cells induces cell death through antibody-dependent cell-mediated toxicity, complement-dependent cytotoxicity, and apoptosis. The FDA first approved ofatumumab in October 2009 for the treatment of patients with CLL who no longer respond to chemotherapy.