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FDA Grants Priority Review to Maintenance Ofatumumab in CLL

Silas Inman @silasinman
Published: Monday, Sep 21, 2015

Jan van de Winkel, PhD

Jan van de Winkel, PhD

The FDA has granted a priority review designation to ofatumumab (Arzerra) as a maintenance therapy for 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 application for 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 29.4 versus 15.2 months with observation, representing a 50% reduction in the risk of progression (HR, 0.50; 94% CI, 0.38-0.66; P <.0001). Additionally, the time to next therapy was 6.9 months longer with ofatumumab compared with observation.

Data from the PROLONG trial, which were published in Lancet Oncology and presented at the 2014 ASH Annual Meeting, were also submitted to the European Medicines Agency in early July 2015 by Novartis, which acquired ofatumumab from GlaxoSmithKline as part of a multi-billion-dollar product exchange. Under the priority review designation, the FDA will make a decision on the application by January 21, 2016.

"We are very pleased that the FDA has granted priority review for ofatumumab, which means ofatumumab could potentially be available as a maintenance therapy for patients suffering from relapsed CLL relatively soon," Jan van de Winkel, PhD, chief executive officer of Genmab, said in a statement. "We look forward to receiving FDA's feedback on the application."

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 6 years. Those in the observation arm had been diagnosed with CLL 5 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 31.1 months with observation (HR, 0.66; 95% CI, 0.47-0.92; = .011). The independent review committee found a median PFS of 30.4 months with ofatumumab compared with 14.8 months with observation (HR, 0.55; 95% CI, 0.42-0.72; P <.0001). After a median follow-up of 19.1 months, a substantial difference in median overall survival was not yet observed between the two arms (HR, 0.85; 95% CI, 0.52-1.37; P = .4877).

The most common grade ≥3 adverse events for ofatumumab versus observation were neutropenia (24% vs 10%) and infections (13% vs 8%). The most common grade 3/4 AEs, for ofatumumab versus observation, were neutropenia (24% vs 9%) and pneumonia (7% vs 5%). Eight percent of patients in the ofatumumab arm experienced an AE that resulted in treatment discontinuation.

“We are very pleased that this study of ofatumumab, the first phase III study to evaluate maintenance therapy for relapsed CLL, met the primary endpoint at the interim analysis," said van de Winkel, when the data were announced. "This result indicates the potential of ofatumumab in this setting where there are currently no approved treatments. We look forward to presenting the detailed data from this study at a future medical conference."

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.

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 maintenance versus observation in relapsed chronic lymphocytic leukaemia (PROLONG): an open-label, multicentre, randomised phase 3 study [Publish online ahead of print September 13, 2015]. Lancet Oncol. doi.org/10.1016/S1470-2045(15)00143-6



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