FDA Approval Sought for Maintenance Ofatumumab in CLL

Jan van de Winkel, PhD

A supplemental biologics license application (sBLA) has been submitted to the FDA for ofatumumab (Arzerra) as a maintenance therapy in patients with relapsed chronic lymphocytic leukemia (CLL) following a response to second- or third-line therapy, according to a statement from Genmab, the company co-marketing the CD20 inhibitor with Novartis.

The sBLA for maintenance ofatumumab is based on a near doubling in progression-free survival (PFS) seen with the treatment compared with observation in the phase III PROLONG trial. In the open-label study, maintenance ofatumumab demonstrated a median PFS of 28.6 versus 15.2 months with observation, representing a 52% reduction in the risk of progression (HR = 0.48; P <.0001). Additionally, the time to next therapy was 10.6 months longer with ofatumumab compared with observation (HR = 0.63; P = .0076).

Data from the PROLONG trial, which were presented at the 2014 ASH Annual Meeting, were also submitted to the European Medicines Agency in early July 2015. Novartis completed the applications in both countries.

“The submission of the application to expand the label to use ofatumumab as a maintenance therapy for patients with relapsed CLL in the US follows closely behind the marketing application for this indication in Europe," Jan van de Winkel, PhD, chief executive officer of Genmab, said in a statement. "We are looking forward to the response from both the US and European regulatory authorities, and hope that ofatumumab will soon become available for maintenance therapy of patients with relapsed CLL."

In the PROLONG trial, 474 patients who experienced a partial or complete response with either second- or third-line therapy were randomized to ofatumumab (n = 238) or observation (n = 236). In the first cycle, ofatumumab was administered at an initial dose of 300 mg followed 1 week later by a 1000 mg dose. For subsequent cycles, the 1000 mg dose was administered every 8 weeks for up to 2 years.

Baseline characteristics were balanced between the two arms. The median time since diagnosis in the treatment arm was 5.24 years. Those in the observation arm had been diagnosed with CLL 4.59 years prior to enrollment in the trial. Across both arms, the majority of responses to prior therapy were partial responses (~80%). The primary endpoint was PFS, with secondary endpoints focused on duration of response, overall survival, and safety.

The median duration of treatment with ofatumumab was 12.5 months. The median time to next therapy with ofatumumab was 38.0 versus 27.4 months with observation (HR = 0.63; P = .0076). After a median follow-up of 26.1 months in the ofatumumab arm and 24 months in the observation arm, a substantial difference in median overall survival was not observed between the two arms (HR = 0.92; P = .74).

All-grade adverse events (ARs) were seen in 86% of patients in the ofatumumab arm compared with 72% in the observation group. Grade 3/4 adverse events occurred in 25% of patients with ofatumumab versus 17% with observation. The most common grade 3/4 AEs, for ofatumumab versus observation, were neutropenia (22% vs 9%) and pneumonia (7% vs 4%). Eight percent of patients in the ofatumumab arm experienced an AE that resulted in treatment discontinuation.

"The interim results of this study show that ofatumumab maintenance therapy significantly extended the amount of time the patients in the study lived without their CLL symptoms getting worse," van de Winkel said when the data were announced.

Ofatumumab was initially approved as a treatment for patients with CLL who had received all other available therapies in October 2009. This indication was extended to include previously untreated patients with CLL who were ineligible for fludarabine-based therapy in April 2014, based an on extension in PFS for patients treated in the COMPLEMENT-1 study.

In the phase III COMPLEMENT 2 study, ofatumumab in combination with fludarabine and cyclophosphamide was found to reduce the risk of progression by 33% compared with fludarabine and cyclophosphamide alone. The median PFS was 28.9 months with the addition of ofatumumab compared with 18.8 months with chemotherapy alone (HR = 0.67; 95% CI, 0.51-0.88; P = .0032). A regulatory application based on this data is anticipated.

Ofatumumab continues to be assessed across a variety of settings in clinical trials. A phase III study is comparing the CD20 inhibitor with rituximab (Rituxan) for patients with indolent B-cell non-Hodgkin lymphoma following relapse on a rituximab containing-regimen. This study was initiated in 2010 and continues to enroll patients, with a goal of accruing 516 participants (NCT01200589).

van Oers MHJ, Kuliczkowski K, Smolej L, et al. Ofatumumab (OFA) Maintenance Prolongs PFS in Relapsed CLL: Prolong Study Interim Analysis Results. Presented at: the 56th Annual Meeting of the American Society of Hematology; December 6-9, 2014; San Francisco, California. Abstract 21.