FIGITUMUMAB FOR EWING SARCOMA

December 29, 2009 — An experimental agent has demonstrated antitumor activity in Ewing's sarcoma, according to results of a preliminary study published in the December 24 online issue of the Lancet Oncology.

Figitumumab, developed by Pfizer, was shown to be safe for both adult and pediatric patients with sarcoma and also showed single-agent antitumor activity in different subtypes of the disease.

Of 28 patients who were assessed for a response to figitumumab, 2 patients with Ewing's sarcoma experienced objective responses — 1 complete response and 1 partial response. In addition, 8 other patients had disease stabilization (6 with Ewing's sarcoma, 1 with synovial sarcoma, and 1 with fibrosarcoma) that lasted 4 months or longer.

Possible Benefit From Insulin-Like Growth-Factor-1 Receptor Inhibitors

Figitumumab is a fully human immunoglobulin G2 monoclonal antibody that targets the insulin-like growth-factor-1 receptor (IGF-1R). The IGF-1R signaling pathway is involved in sarcomagenesis and regulates cellular growth, proliferation, survival, and transformation, and plays a critical role in the growth of tumor cells, the study authors note. IGF-1R has also specifically been implicated in the growth, metastasis, and angiogenesis in Ewing's sarcoma, with early reports showing antitumor activity of IGF-1R-targeting drugs in these conditions.

However, although there is reason for optimism regarding use of IGF-1R inhibitors in patients with Ewing's sarcoma, it is also crucial to identify the subset of patients who are most likely to respond to this therapy, notes an accompanying editorial.

"Despite the strong preclinical evidence that suggests a universal benefit with inhibiting IGF-1R, the progressive disease seen in some patients indicates that not all tumors are addicted to IGF-1R signaling or develop rapid resistance," write Jeffrey A. Toretsky, MD, from Georgetown University, Washington, DC, and Richard Gorlick, MD, from the Albert Einstein College of Medicine of Yeshiva University, Bronx, New York.

Because many drug makers are currently developing IGF-1R inhibitors, there could be "ample opportunity to optimize clinical benefit from IGF-1R blockade, although the development of these antibodies may be complicated," they explain. "Five-drug chemotherapy is routine in the treatment of Ewing's sarcoma; therefore, improvement in outcome for these patients will likely require demonstration of the feasibility of combining the antibody with standard chemotherapy."

Well Tolerated and Responses Seen

The phase 1 study was conducted by Johann S. de Bono, MBBS, PhD, of the Institute for Cancer Research, Sutton, United Kingdom, and the Royal Marsden NHS Foundation Trust, Sutton, United Kingdom, and colleagues. Between January 2006 and August 2008, a total of 29 patients with refractory, advanced sarcomas were separated into 2 groups within the same trial: the first cohort (n = 15) included patients 18 years or older with multiple subtypes of sarcoma, and the second group (n = 14) consisted of patients 9 years or older with refractory Ewing's sarcoma.

All patients received intravenous figitumumab 20 mg/kg and continued with their treatment until disease progression or unacceptable toxicity. The primary endpoint of the study was to assess the safety and tolerability of figitumumab, and secondary endpoints included pharmacokinetic profiling and preliminary antitumor activity.

For all patients in this study, the rate of nonprogression at 3 months was 34% (95% confidence interval [CI], 10% - 58%) and at 6 months was 28% (95% CI, 5% - 51%). The authors observed objective antitumor activity in patients with Ewing's sarcoma. One patient had a complete response that has lasted 21.5 months to date, whereas a second patient had a partial response that has lasted 11.4 months. Both are still continuing to receive treatment, the authors note. In addition, disease stabilization has lasted more than 9 months in 4 patients (range, 9.8 - 16.1 months), and 2 of these patients also are continuing to receive this treatment.

Apart from the 2 patients who had a response, 5 other patients with Ewing's sarcoma experienced shrinkage of the target tumor lesions, and the authors observed small reductions in tumor size among some patients with chondrosarcoma, fibrosarcoma, and synovial sarcoma.

Figitumumab was well tolerated in this population, and adverse events were primarily mild to moderate in severity and were reversible. Grade 3 events included deep venous thrombosis (n = 1), vomiting (n = 1), and back pain (n = 1). Grade 3/4 laboratory abnormalities were seen in 2 patients, and grade 1 hyperglycemia occurred in 4 patients. A delayed onset of puberty was noted in 1 prepubertal male patient who is still receiving treatment.

The researchers conclude that figitumumab is well tolerated and has antitumor activity in Ewing's sarcoma, thus warranting further investigation. "Phase 2 studies of figitumumab and other anti-IGF-R agents in Ewing's sarcoma and other sarcoma subtypes are now completing accrual and rational combinations with other treatments are also being pursued," they write.

Pfizer Global Research and Development funded the study. Several of the study authors have received research funding from, have served in a consultant or advisory role, are employees, own stock, or received honoraria for Pfizer Oncology, as detailed in the original article.

Lancet Oncol. Published online December 24, 2009.