Novartis announced that the phase III data published in The Lancet showed that treatment with Arzerra (ofatumumab) plus chlorambucil, a chemotherapy, resulted in a statistically significant improvement in progression free survival (PFS) versus chlorambucil alone in treatment-naïve patients with chronic lymphocytic leukaemia (CLL) for whom fludarabine-based therapy was considered inappropriate, mainly due to advanced age or the presence of comorbidities.

CLL, the most commonly diagnosed adult leukaemia in Western countries, accounts for approximately 1 in 4 cases of all leukaemia. The average age at the time of diagnosis is approximately 71 years, and the majority of patients with CLL have at least one comorbidity such as hypertension, diabetes, heart disease or COPD.

"Finding effective treatments with clinically acceptable safety profiles for elderly patients with CLL and for those with co-existent chronic and potentially life-threatening conditions continues to be a challenge," said Prof. Peter Hillmen, St. James's University Hospital, Leeds, United Kingdom and lead study author. "The results published in The Lancet reinforce our understanding that the combination of ofatumumab plus chlorambucil provides this patient population a treatment option that improves clinical health outcomes in CLL."

The primary endpoint of the study was PFS according to the International Workshop for Chronic Lymphocytic Leukaemia (iwCLL) updated 2008 National Cancer Institute-sponsored Working Group (NCIWG) guidelines. In this clinical study, median PFS was improved by 71% in the group receiving ofatumumab plus chlorambucil compared to the chlorambucil alone group (22.4 months vs 13.1 months, respectively; HR 0.57 [95% CI 0.45, 0.72]; p<0.0001). Improvement in PFS was observed in most subgroups irrespective of age, gender, disease stage and prognostic factors. More patients in the group receiving ofatumumab plus chlorambucil (50%) experienced adverse events (AEs) of grade 3 or greater compared to chlorambucil alone (43%), with neutropenia being the most common adverse event (26% vs. 14%). Grade 3/4 infusion-related reactions (IRRs) were reported in 10% of patients receiving ofatumumab plus chlorambucil leading to drug withdrawal in 3% of patients and hospitalization in 2% of patients. No fatal IRRs were reported.

"The results presented in The Lancet demonstrate that the addition of Arzerra to chlorambucil resulted in a significant improvement in progression free survival, with an acceptable safety profile," said Alessandro Riva, M.D., Global Head, Novartis Oncology Development and Medical Affairs. "We are excited that Arzerra is now part of the Novartis Oncology portfolio of products, and look forward to building upon the body of evidence that supports the clinical benefit of Arzerra for appropriate patients with CLL."

These phase III data formed the basis for regulatory approvals in the United States (US) and European Union (EU) in 2014, as well as the recent inclusion of Arzerra plus chlorambucil in the National Comprehensive Cancer Network (NCCN) treatment guidelines.

This prospective, randomized, open-label, phase III study (COMPLEMENT 1, NCT00748189) included 447 patients with previously untreated CLL for whom fludarabine-based therapy was considered inappropriate.  Patients in the study were randomized 1:1 to treatment with up to twelve cycles of ofatumumab in combination with chlorambucil or up to twelve cycles of chlorambucil alone.

The primary endpoint of the study was PFS according to the iwCLL updated 2008 NCIWG guidelines, using a blinded independent endpoints review committee. Secondary endpoints included overall survival (OS), time to progression, overall response rate (ORR), complete response (CR) rate, time to response, duration of response, time to next therapy (TTNT), safety assessments, pharmacokinetics, pharmacogenetics, and quality of life.

Findings from the study showed a 71% improvement in median PFS in the group receiving ofatumumab plus chlorambucil compared to the group receiving chlorambucil alone (22.4 months vs 13.1 months, respectively; HR 0.57 [95% CI 0.45, 0.72]; p<0.0001). Patients in the group receiving ofatumumab plus chlorambucil [n=221] showed similar improvements in PFS across age groups compared to the chlorambucil alone [n=226]. Improvement in PFS was observed in most subgroups irrespective of age, gender, disease stage and prognostic factors.  

Additionally, patients in the combination arm also experienced significantly longer TTNT when compared to chlorambucil alone (39.8 months vs 24.7 months, respectively; HR 0.49 [95% CI: 0.36, 0.67]; p<0.0001). Patients in the combination arm had a higher ORR (82% of patients vs 69% of patients, respectively; odds ratio 2.16 [95% CI: 1.36-3.42]; p=0.001), with a better CR rate (14% of patients vs 1% of patients, respectively). Compared to those on chlorambucil alone, patients in the combination arm had a duration of response of 22.1 months versus 13.2 months (HR 0.56 [95% CI: 0.43, 0.74]; p<0.001).

More patients in the group receiving Arzerra plus chlorambucil (combination) experienced AEs of grade 3 or greater (50%) compared to chlorambucil alone (43%). The most common AEs (>=2%) reported were neutropenia, thrombocytopenia, anemia, infections, and infusion-related reactions. Overall, AEs leading to treatment withdrawal were similar in both groups (13% vs 13%). AE frequency with Arzerra plus chlorambucil was similar for older patient groups (>=65 years old) compared with chlorambucil alone. Neutropenia occurred more frequently in the combination group, but did not result in a higher rate of infection, and thrombocytopenia and anemia were more frequently observed in the chlorambucil alone group. The most common infections were respiratory tract infections (27% for combination vs 31% for chlorambucil alone) and there were similar frequencies of sepsis (3% vs 2%) and opportunistic infections (4% vs 5%) reported in the combination and chlorambucil alone groups, respectively.

Grade 3/4 IRRs were reported in 10% of patients receiving Arzerra plus chlorambucil leading to drug withdrawal in 3% of patients and hospitalization in 2% of patients. No fatal IRRs were reported. Deaths during treatment or within 60 days after the last dose were similar in both groups (3% vs 3%).

Arzerra (ofatumumab) is a human monoclonal antibody that is designed to target the CD20 molecule found on the surface of chronic lymphocytic leukemia (CLL) cells and normal B lymphocytes.

In the United States, Arzerra is approved for use in combination with chlorambucil for the treatment of previously untreated patients with CLL for whom fludarabine-based therapy is considered inappropriate. In the European Union, Arzerra is approved for use in combination with chlorambucil or bendamustine for the treatment of patients with CLL who have not received prior therapy and who are not eligible for fludarabine-based therapy. Arzerra is also approved for first-line use in Russia, Iceland, Norway, Luxembourg and Brazil.

In more than 50 countries worldwide, Arzerra is also indicated as monotherapy for the treatment of patients with CLL refractory to fludarabine and alemtuzumab.

Arzerra is marketed under a co-development and collaboration agreement between Genmab and Novartis, as successor in interest to GSK.