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FDA Approves First-Line Ofatumumab for Fludarabine-Ineligible Patients With CLL

Silas Inman @silasinman
Published: Thursday, Apr 17, 2014

Dr. Paolo Paoletti

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, based on an improvement in progression-free survival (PFS) in a phase III trial.

In the trial, labeled COMPLEMENT 1, the combination of the anti-CD20 monoclonal antibody ofatumumab and chlorambucil demonstrated a 9.3-month improvement in PFS compared with chlorambucil alone. The overall response rate (ORR) with the combination was 82% versus 69% with chlorambucil alone. The approval comes following a Breakthrough Therapy designation for the drug in September 2013. The FDA first approved ofatumumab in October 2009 for the treatment of patients with CLL who no longer respond to chemotherapy.

“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. The median age of patients was 69 years with 82% ≥65 years and/or having ≥2 comorbidities. The majority of patients were Rai intermediate (51%) or high (40%).

Patients were enrolled in a 1:1 ratio to receive ofatumumab plus chlorambucil (n = 221) or chlorambucil alone (n = 226). Chlorambucil was administered orally at 10mg/m2 on days 1 through 7 of each 28-day cycle. Ofatumumab was administered intravenously at 300-mg on day 1 followed by 1000-mg on day 8 and day 1 of subsequent cycles. 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.

Ongoing studies are exploring ofatumumab as a treatment for patients with CLL. In the phase III RESONATE study, ofatumumab was compared with ibrutinib in 391 patients with relapsed or refractory CLL or small lymphocytic leukemia following treatment with one prior therapy. In January, this study was stopped early after demonstrating a significant improvement in the primary endpoint of PFS and the secondary endpoint of overall survival for patients treated with ibrutinib compared with ofatumumab.

Based on these results, a supplemental New Drug Application was submitted for ibrutinib in April 2014. Full data from this investigation have not yet been released.

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