Ofatumumab Falls Short in DLBCL Trial

Jan van de Winkel, PhD

A phase III study exploring the chemotherapy regimen DHAP plus ofatumumab (Arzerra) failed to meet its primary endpoint of prolongation in progression-free survival (PFS) when compared with DHAP plus rituximab (Rituxan) for patients with relapsed or refractory diffuse large B-cell lymphoma (DLBCL).

The phase III ORCHARRD trial included 447 patients with CD20-positive DLBCL or grade 3b follicular lymphoma (FL) who had relapsed or were refractory to first-line treatment with rituximab plus chemotherapy. Patients were randomized in a 1:1 ratio to receive ofatumumab or rituximab in combination with DHAP (dexamethasone, cytarabine, and cisplatin) for 3 cycles. Patients who responded received high-dose chemotherapy and autologous stem cell transplant.

Overall, both treatments demonstrated similar efficacy and adverse events in the study. A higher rate of dose interruptions and delays were observed in the ofatumumab arm compared with the rituximab arm, primarily due to infusion reactions and increased serum creatinine. Findings from the head-to-head trial were announced in a press release by the company's co-developing the drug, GlaxoSmithKline and Genmab. Full data are being analyzed and will be presented at an upcoming medical meeting.

"We plan to submit detailed data from the ofatumumab ORCHARRD study in DLBCL for presentation at a medical conference later this year, which we hope will provide further clarity on today's headline results. Based on today's results we are unlikely to move forward with a regulatory filing," Jan van de Winkel, PhD, CEO of Genmab, said in a release.

In the phase II study that preceded ORCHARRD, treatment with ofatumumab plus either ICE (ifosfamide, carboplatin, and etoposide) or DHAP demonstrated promising results in 61 patients with relapsed or refractory DLBCL, grade 3b FL, or transformed FL. For all patients in the trial, the overall response rate (ORR) was 61%, with a complete response (CR) rate of 37%.

For evaluable patients receiving DHAP (n = 26), 69% experienced an ORR compared with 55% for those receiving ICE (n = 33). By histology, patients with DLBCL (n = 21) and grade 3b FL (n = 27) experienced an ORR of 67% with DHAP versus 48% with ICE. The ORR for the entire population for both regimens was 56%.

In this analysis, the response to first-line therapy correlated with the outcomes from second-line ofatumumab. In patients relapsing following a remission of greater than 1 year on prior rituximab therapy, the ORR was 83% with a CR rate of 67%. In patients with early relapse or primary refractory disease, the ORR was 55% with a CR rate of 30%. Only 1 patient with primary progressive disease on rituximab responded to ofatumumab.

“We are disappointed that the ORCHARRD study did not meet its primary endpoint. We will further analyze these results to better understand the findings and how they add to our collective knowledge of this disease,” Rafael Amado, MD, Head of Oncology R&D at GlaxoSmithKline, said in a release.

Both rituximab and ofatumumab target CD20 on the surface of normal and malignant B-cells. This process induces cell death through antibody-dependent cell-mediated toxicity, complement-dependent cytotoxicity, and apoptosis. Earlier research has suggested that ofatumumab may be a suitable replacement for rituximab across several blood cancers though research has yet to prove this theory.

The FDA first approved ofatumumab in October 2009 for the treatment of patients with chronic lymphocytic leukemia (CLL) who no longer respond to chemotherapy. In mid-April, the FDA approved ofatumumab plus chlorambucil for previously untreated patients with CLL who were considered inappropriate for treatment with the chemotherapy fludarabine.