Jan van de Winkel, PhD
The EMA’s Committee for Medicinal Products for Human Use (CHMP) has recommended approval of ofatumumab (Arzerra) in combination with fludarabine and cyclophosphamide as a treatment for patients with relapsed chronic lymphocytic leukemia (CLL), according to Genmab, which codevelops the anti-CD20 antibody with Novartis.
The application for ofatumumab was based on data from the phase III COMPLEMENT-2 study, in which the median progression-free survival (PFS) was 28.9 months with the addition of ofatumumab to chemotherapy compared with 18.8 months with fludarabine and cyclophosphamide alone (HR, 0.67; 95% CI, 0.51-0.88; P
= .0032). The overall response rate (ORR) with the triplet was 84% versus 68% in the control arm (P
= .0003), with complete response rates of 27% versus 7%, respectively.
The positive opinion has been sent to the European Commission, which usually issues its final approval decision within 2 to 3 months of the CHMP recommendation.
"We are very pleased with the CHMP's recommendation of Arzerra in this new indication and we hope that Arzerra will soon be available to a wider number of patients in Europe," Jan van de Winkel, PhD, Chief Executive Officer of Genmab, said in a statement.
In the phase III COMPLEMENT-2 study, 365 patients with relapsed CLL were randomized to receive ofatumumab plus fludarabine and cyclophosphamide (n = 183) or fludarabine/cyclophosphamide alone (n = 182). Ofatumumab was administered at 300 mg on day 1 of the first cycle followed by 1000 mg on day 8. For subsequent cycles, the drug was administered at 1000 mg on day 1. The maximum number of cycles was 6 in each arm. The chemotherapy agents were given at standard doses.
The median age of patients in the trial was 61 years, with 7% over the age of 75. A third of patients had high Rai stage CLL (34%) and 69% were IGHV unmutated. Seventy-five percent of patients had a chromosomal aberration. The primary endpoint of the study was PFS. Secondary outcome measures focused on overall survival (OS), response, and safety.
Duration of response was 29.6 months versus 24.9 months in the ofatumumab versus control arms, respectively (HR, 0.77; 95% CI, 0.56-1.05; P
= .0878). Time to progression was also improved with the triplet, at 42.1 months versus 26.8 months (HR, 0.63; 95% CI, 0.45-0.87; P
The time to next cancer therapy was 48.1 months with ofatumumab versus 40.1 months in the control arm (HR, 0.73; 95% CI, 0.51-1.05; P
= .073). Additionally, there was a numerical improvement in median OS with ofatumumab at 56.4 months versus 45.8 months with chemotherapy alone; however, the result was not statistically significant (HR, 0.78; 95% CI, 0.56-1.09; P
The adverse event (AE) profile for ofatumumab was similar to what has been reported in other trials with the drug. Adverse events reported in ≥5% of patient in the ofatumumab arm included neutropenia, thrombocytopenia, anemia, nausea, leukopenia, vomiting, pyrexia, rash, fatigue, and pneumonia.
The rate of grade ≥3 AEs with the ofatumumab combination was 74%, compared with 69% in the control arm. Fifty-three percent of patients who received ofatumumab had grade ≥3 neutropenia versus 39% of patients who received chemotherapy alone. In the ofatumumab cohort, 4% of patients had grade 3/4 infusion-related reactions (IRRs) compared with <1% in the control group. There were no fatalities associated with IRRs.
Robak T, Grosicki S, Warzocha K, et al. Ofatumumab in combination with fludarabine and cyclophosphamide (FC) versus FC in patients with relapsed chronic lymphocytic leukemia (CLL): results of the phase III study COMPLEMENT 2. Presented at: 20th Congress of the European Hematology Association (EHA); June 11-14, 2015; Vienna, Austria. Abstract 5782.