The approval was based on a near doubling in progression-free survival (PFS) seen with the treatment compared with observation in the phase 3 PROLONG trial.
The FDA has approved Arzerra (ofatumumab) for the extended treatment of patients with recurrent or progressive chronic lymphocytic leukemia (CLL) who are in complete or partial response following two or more lines of therapy. The approval was based on a near doubling in progression-free survival (PFS) seen with the treatment compared with observation in the phase 3 PROLONG trial.
In the open-label study, maintenance Arzerra demonstrated a median PFS of 29.4 versus 15.2 months with observation, representing a 50 percent reduction in the risk of progression. Additionally, the time to next therapy was 6.9 months longer with Arzerra compared with observation.
In the PROLONG trial, 474 patients who experienced a partial or complete response with either second- or third-line therapy were randomized to Arzerra (238 patients) or observation (236 patients). In the first cycle, Arzerra was administered at an initial dose of 300 mg followed one week later by a 1000-mg dose. For subsequent cycles, the 1000-mg dose was administered every eight weeks for up to two years.
Baseline characteristics were balanced between the two arms. The median patients age was 64.5 years (ranging from 33 to 87). Patients in the Arzerra arm had received a median of two prior therapies (ranging from two to five).
The median time since diagnosis in the treatment arm was six years. Those in the observation arm had been diagnosed with CLL five years prior to enrollment in the trial. Across both arms, the majority of responses to prior therapy were partial responses (about 80 percent). The primary endpoint was PFS, with secondary endpoints focused on duration of response, overall survival and safety.
The median duration of treatment with Arzerra was 12.5 months. The median time to next therapy with Arzerra was 38.0 versus 31.1 months with observation. The independent review committee found a median PFS of 30.4 months with Arzerra compared with 14.8 months with observation. After a median follow-up of 19.1 months, a substantial difference in median overall survival was not yet observed between the two arms.
Overall, the most common (at least 10 percent) adverse events (AEs) in patients treated with Arzerra were infusion reactions, neutropenia, and upper respiratory tract infection. The most common grade 3/4 AEs for Arzerra versus observation were neutropenia (22 vs 8 percent) and pneumonia (5 vs 3 percent).
Serious AEs were reported in 33 percent of patients in the Arzerra arm. Pneumonia, pyrexia and neutropenia were the most common serious AEs. Eight percent of patients in the Arzerra arm experienced an AE that resulted in treatment discontinuation.
Arzerra 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.
Commenting on the new maintenance indication, Jan van de Winkel, CEO of Genmab, which codevelops Arzerra with Novartis, said, "The approval of Arzerra in the United States as extended treatment provides patients with relapsed CLL with a new treatment option that can help delay disease progression."
Arzerra continues to be assessed across a variety of settings in clinical trials. A phase 3 study is comparing the CD20 inhibitor with Rituxan (rituximab) for patients with indolent B-cell non-Hodgkin lymphoma following relapse on a Rituxan 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 [published online ahead of print September 13, 2015]. Lancet Oncol. doi.org/10.1016/S1470-2045(15)00143-6.