Jan van de Winkel, PhD
The European Medicines Agency’s Committee for Medicinal Products for Human Use (CHMP) issued a negative opinion to ofatumumab (Arzerra) regarding its potential use in the maintenance setting for patients with relapsed chronic lymphocytic leukemia (CLL).
The negative CHMP opinion will be sent to the European Commission (EC) for a final regulatory decision. The EC generally follows recommendations from the CHMP.
"We are disappointed that we did not receive a positive recommendation for Arzerra in the maintenance CLL setting in Europe. We will continue to work with Novartis to define the best path forward for Arzerra," said Jan van de Winkel, PhD, CEO of Genmab.
The CHMP based its decision on results from the phase III PROLONG trial, in which 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.
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 2 arms. The median patient age was 64.5 years (range, 33-87). Patients in the ofatumumab arm had received a median of 2 prior therapies (range, 2-5).
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; P
= .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
Overall, the most common (≥10%) adverse events (AEs) in patients treated with ofatumumab were infusion reactions, neutropenia, and upper respiratory tract infection. The most common grade 3/4 AEs for ofatumumab versus observation were neutropenia (22% vs 8%) and pneumonia (5% vs 3%).
Serious AEs were reported in 33% of patients in the ofatumumab arm. Pneumonia, pyrexia, and neutropenia were the most common serious AEs. Eight percent of patients in the ofatumumab arm experienced an AE that resulted in treatment discontinuation.
Ofatumumab, combined with chlorambucil or bendamustine, is approved in the EU for use in previously untreated patients with CLL who are not candidates for fludarabine-based therapy.
In the United States, ofatumumab is approved for use in in combination with chlorambucil in treatment-naive patients with CLL who are ineligible for fludarabine-based therapy and for the extended treatment of patients with recurrent or progressive CLL who are in complete or partial response following at least 2 lines of therapy.
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. Lancet Oncol. 2015;16(13):1370-1379.