Ofatumumab Misses PFS Endpoint in Bulky CLL

Jan van de Winkel, PhD

Ofatumumab (Arzerra) failed to meet its primary endpoint of improvement in progression-free survival (PFS) in a phase III study of the drug versus physicians’ choice for bulky fludarabine-refractory chronic lymphocytic leukemia (CLL), according to an announcement from GlaxoSmithKline (GSK) and Genmab, the companies developing the agent.

The OMB114242 study was conducted to meet the requirements from the EU Commission for the conditional approval of ofatumumab as a treatment for patients with CLL refractory to fludarabine and alemtuzumab, the companies noted in a release. At this point, ofatumumab is not indicated as a treatment for patients with bulky CLL. In the US, ofatumumab is approved in combination with chlorambucil as a frontline treatment for fludarabine-ineligible patients with CLL and for patients with CLL refractory to fludarabine and alemtuzumab.

“Although ofatumumab performed broadly in-line with previous data, today’s result is disappointing. Based on this result, we do not anticipate applying for a label expansion for ofatumumab in this specific refractory CLL population,” Jan van de Winkel, Ph.D., Chief Executive Officer of Genmab, said in a statement.

The phase III, open-label OMB114242 study randomized 122 patients with bulky fludarabine-refractory CLL in a 2:1 ratio to ofatumumab or physicians’ choice. Patients in the ofatumumab arm received an initial dose of 300 mg followed 1 week later by 2,000 mg weekly for 7 weeks. Four weeks after this initial induction period, ofatumumab was administered at 2,000 mg every 4 weeks for a total treatment duration of 6 to 12 months. Patients in the physicians’ choice arm received a treatment regimen chosen by a physician for up to six months.

In early results released from the phase III study, PFS was 5.36 months for ofatumumab and 3.61 months for physicians’ choice (HR=0.79, P = .267). The secondary objectives of the study were to evaluate response, overall survival, safety, tolerability and health-related quality of life of subjects treated with ofatumumab versus physicians’ choice of treatment. A full analysis of these endpoints is underway and will be completed in the coming months.

“It was our priority to share this result with the scientific community as soon it became available. We will now work to further analyze the data and to better understand the totality of the efficacy and safety findings,” Rafael Amado, MD, Head of Oncology R&D at GSK, said in a release. “We are very grateful to the CLL patients who participated in this trial.”

In a previous study, 138 patients with fludarabine/alemtuzumab refractory (n = 59) and fludarabine-refractory with bulky lymphadenopathy (n = 79) CLL received eight weekly infusions of ofatumumab followed by four monthly infusions during a 24-week period (dose 1 = 300 mg; doses 2 to 12 = 2,000 mg).

The results showed overall response rates of 58% in the fludarabine/alemtuzumab refractory group and 47% in bulky fludarabine-refractory group. The median PFS was 5.7 months and the median overall survival (OS) was 13.7 months in the fludarabine/alemtuzumab refractory. In the bulky fludarabine refractory patients, the median PFS was 5.9 months and the median OS was 15.4 months.

The most common adverse events during the study were infusion reactions and infections, which were primarily grade 1 or 2 events. Hematologic events during treatment included anemia and neutropenia.

Ofatumumab has faced many ups and downs in recent months. Earlier this year, the FDA extended the indication for the drug to include patients in the frontline setting. However, last month GSK announced that ofatumumab failed to meet its primary endpoint of prolongation in PFS when compared with DHAP plus rituximab (Rituxan) for patients with relapsed or refractory diffuse large B-cell lymphoma.