Evaluation of Ofatumumab, a Novel Human CD20 Monoclonal Antibody, as Single Agent Therapy in Rituximab-Refractory Follicular Lymphoma.

Abstract 935 Introduction: Patients with follicular lymphoma (FL) who are refractory to rituximab-based therapy have a need for new non-cytotoxic treatment options. Ofatumumab targets a unique small-loop epitope on CD20 and elicits rapid and efficient in vitro cell lysis via complement-dependent cytotoxicity, even in rituximab-resistant B cells that express high levels of complement inhibitory proteins. Ofatumumab as single agent showed activity in relapsed/refractory FL, including in some patients previously exposed to rituximab (Hagenbeek et al, Blood 2008). Here we report preliminary results from an international, single-arm trial assessing ofatumumab monotherapy in patients with rituximab-refractory FL. Methods: Eligible patients (aged ≥18 years), with Grade 1 or 2 CD20+ FL considered refractory to rituximab alone or in combination with chemotherapy, were enrolled between Sept 2006 and Sept 2008 (N=116). Refractoriness to rituximab (at least 4 doses) was defined as failure to achieve at least a partial response, disease progression during rituximab treatment, or disease progression following a response within 6 months of last treatment with rituximab-containing regimens. Patients received 8 weekly infusions of ofatumumab (Dose 1, 300 mg; Doses 2–8, 500 or 1000 mg); glucocorticoid premedication was required before infusions 1 and 2, and acetaminophen and antihistamine were administered before every infusion. The primary endpoint was objective response (International Working Group criteria) in the 1000 mg dose group over 6 months from the start of treatment, as assessed by an Independent Endpoint Review Committee. Secondary endpoints included duration of response, progression-free survival (PFS) and adverse events (AEs). Results: Table 1 summarizes the baseline characteristics; 90% of patients received all 8 ofatumumab doses. The median follow-up time on the study was 4.7 months overall and 5.5 months for the 1000 mg group. The overall response rate (ORR) in the 1000 mg group was 10% (95% CI: 4, 17%), including 1 complete response. Stable disease was observed in 50% of patients. In the 1000 mg group, the median duration of response was 6.0 months (95% CI: 2.8, upper limit not estimable) and median PFS was 6.0 months (95% CI: 4.9, 9.1). The ORR in the total population was 11% (95% CI: 5, 17%). Among patients who were refractory to prior rituximab monotherapy (n=27), the ORR was 22% (95% CI: 7, 38%). The ORR among patients who were refractory to rituximab maintenance therapy (n=44) and rituximab combined with chemotherapy (n=45) was 9% (95% CI: 1, 18%) and 7% (95% CI: 0, 14%), respectively. During treatment and up to 30 days following the last dose, the most common AEs (>10% of patients) included rash (15%), urticaria (14%), fatigue (14%), pruritis (13%), nausea (12%), pyrexia (11%) and cough (11%); grade 3–4 infusion-related reactions occurred in only 3 patients (all grade 3 events), none of which were considered serious events; grade 3–4 hematologic AEs included neutropenia in 5% of patients, anemia in 3% and thrombocytopenia in 1%; grade 3 infections (sepsis, febrile neutropenia) occurred in 2 patients. Conclusions: The majority of patients with rituximab-refractory FL in this study were heavily pretreated, were also refractory to chemotherapy and had high-risk FLIPI scores. Although response rates were low with single-agent ofatumumab in patients refractory to rituximab-chemotherapy, a higher response rate was observed in patients who were refractory to rituximab monotherapy, indicating activity despite being refractory to single-agent rituximab. Ofatumumab was well tolerated in this heavily-pretreated population. Infusion reactions were manageable and no unexpected toxicities were observed. Further investigations with ofatumumab are warranted, including in combination with other therapies in patients with FL. | | 500 mg (n=30) | 1000 mg (n=86) | Total (N=116) | |:--------------------------------------- | ------------- | -------------- | -------------- | | Age, years | | | | | Median (range) | 60 (39-78) | 60 (37-82) | 60 (37-82) | | Duration of FL, years | | | | | Median (range) | 5 (0.6-16.7) | 4.1 (0.5-16.4) | 4.3 (0.5-16.7) | | FLIPI scores, % | | | | | 0-1 (low) | 23 | 22 | 22 | | 2 (intermediate) | 33 | 26 | 28 | | 3-5 (high) | 40 | 51 | 47 | | Number of prior FL therapies | | | | | Mean | 4.7 | 3.9 | 4.1 | | Median (range) | 4 (1-15) | 4 (1-12) | 4 (1-15) | | Qualifying R-refractory regimen, % | | | | | R-chemotherapy | 47 | 35 | 38 | | R-maintenance | 33 | 38 | 37 | | R-monotherapy | 20 | 24 | 23 | | Refractory to any prior chemotherapy, % | 67 | 64 | 66 | | Refractory to last chemotherapy, % | 53 | 48 | 49 | | R=rituximab | | | | Table 1. Baseline characteristics Disclosures: Hagenbeek: Roche, Bayer Schering Pharma, Genmab: Advisory roles. Off Label Use: Ofatumumab is an investigational anti-CD20 monoclonal antibody, currently under development for the treatment of B-cell malignancies (chronic lymphocytic leukemia, diffuse large B-cell lymphoma, Waldenstroms macroglobulinemia and follicular lymphoma) as well as autoimmune diseases (rheumatoid arthritis and multiple sclerosis). Fayad: GlaxoSmithKline, Genmab: Research Funding. Rossi: GlaxoSmithKline: Investigator on trial funded by GSK. Kuliczkowski: GlaxoSmithKline: Investigator on trial funded by GSK. Link: Genentech: Advisory Board, Research Funding; Genmab, GlaxoSmithKline: Research Funding. Radford: GlaxoSmithKline: Equity Ownership. Hellmann: Novartis, BMS: Consultancy, Honoraria. Gupta: GlaxoSmithKline: Employment. Arning: GlaxoSmithKline: Employment, Equity Ownership. Begtrup: Genmab: Employment, Equity Ownership. Schultz: Genmab: Employment. Bang: Genmab: Employment. Russell: Genmab: Employment, Equity Ownership. Czuczman: GlaxoSmithKline: Advisory Board, Honoraria, Research Funding; Genmab: Advisory Board, Research Funding.