Alessandro Riva, MD
Adding ofatumumab (Arzerra) to fludarabine and cyclophosphamide improved progression-free survival (PFS) by an absolute value of 54% in patients with relapsed chronic lymphocytic leukemia (CLL), representing a 33% reduction in the risk of progression, according to results from the phase III COMPLEMENT 2 study presented at the 20th Congress of the European Hematology Association.
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). Overall response rate (ORR) was also improved with the triplet versus the control, at 84% versus 68%, respectively (P
= .0003), with complete response rates of 27% versus 7%.
“The results from the COMPLEMENT 2 study validate the benefit of Arzerra treatment in combination with fludarabine and cyclophosphamide in certain patients with CLL,” said Alessandro Riva, MD, Global Head, Novartis Oncology Development and Medical Affairs, in a press release.
The open-label, international phase III COMPLEMENT 2 study randomized 365 patients with relapsed CLL to receive ofatumumab plus fludarabine and cyclophosphamide (n = 183) or fludarabine cyclophosphamide alone (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 six in each arm.
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 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
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
“These data showed that the addition of ofatumumab to fludarabine and cyclophosphamide extended the amount of time before a patient's CLL progressed, and further add to the body of evidence supporting the potential use of ofatumumab for these patients,” Tadeusz Robak, professor of Hematology, Department of Hematology, Medical University of Lodz and Copernicus Memorial Hospital, Lodz, Poland, said in the press release.
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.
Ofatumumab targets CD20 on the surface of both normal and malignant B-cells, which induces cell death through antibody-dependent cell-mediated toxicity, complement-dependent cytotoxicity, and apoptosis.
The drug is not currently approved for the indication explored in COMPLEMENT 2; however, Riva said that Novartis “looks forward to sharing the data with regulatory authorities.”
Ofatumumab was approved by the FDA in 2009 for previously treated patients with CLL that is no longer responding to chemotherapy. In April 2014, the FDA approved ofatumumab plus chlorambucil for previously untreated patients with CLL who were considered inappropriate for treatment with fludarabine, based on an improvement in PFS in the phase III COMPLEMENT 1 trial.
In the study, patients were randomized in a 1:1 ratio to receive ofatumumab plus chlorambucil (n = 221) or chlorambucil alone (n = 226). In the ofatumumab arm, 82% of patients received more than 6 cycles of therapy.
Median PFS by independent review was 22.4 months with ofatumumab plus chlorambucil compared with 13.1 months for chlorambucil alone (HR = 0.57; 95% CI, 0.45-0.73; P
< .001). ORR was 82% versus 69% with a complete response rate of 12% versus 1%, for ofatumumab plus chlorambucil compared with chlorambucil alone, respectively.