Robatumumab shows efficacy in Ewing sarcoma, fails primary endpoint

The novel antibody robatumumab did not exhibit significant benefit as a single agent for patients with metastatic osteosarcoma, according to phase 2 study results.

However, the agent showed promising long-term benefit with a tolerable safety profile in patients with metastatic Ewing Sarcoma who responded to treatment.

Robatumumab (SCH717454, Merck) is a fully human antibody that binds to and inhibits the insulin-like growth factor receptor-1 (IGF-1R), which is a target for treatment in osteosarcoma and Ewing sarcoma.

Peter M. Anderson, MD, PhD, staff physician at Cleveland Clinic Pediatric Institute who served as professor in the department of pediatric patient care at The University of Texas MD Anderson Cancer Center during the conduct of this study, and colleagues evaluated the safety and efficacy of robatumumab in three distinct sarcoma populations.

Anderson and colleagues conducted a multicenter phase 2 study of 219 pediatric and adult patients (median age, 20 years; range, 9-79; 63% male) with metastatic resectable osteosarcoma (group 1; n = 68), metastatic unresectable osteosarcoma (group 2; n = 35) and metastatic Ewing Sarcoma (group 3; n = 116).

Researchers administered IV robatumumab every 2 weeks over the course of 60 minutes. Patients in group 1 received a low dose of 0.3 mg/kg or a standard dose of 10 mg/kg; all patients in group 2 and group 3 received a 10-mg/kg dose.

Ki-67 tumor cell proliferation in group 1 patients served as the study’s primary endpoint.

The study closed early after the merger of Merck and Shering Plough, but responding patients were allowed to continue therapy at the discretion of the study investigators.

Ninety-four percent (n = 203) of patients experienced a treatment-emergent adverse event of any grade, and 50% (n = 107) experienced a grade 3 or worse adverse event. Slightly fewer group 1 patients assigned the 10-mg/kg dose experienced high-grade adverse events than those assigned 3 mg/kg (30% vs. 47%).

A total of 151 patients died on study (group 1, n = 35; group 2, n = 28; group 3, n = 88), largely due to disease progression (n = 121).

Disease progression also accounted for 80% (n = 176) of treatment discontinuation; 5% (n = 12) of patients discontinued due to adverse events.

The researchers did not have sufficient data to report conclusions about tumor proliferations, because only 16% (n = 11) of group 1 patients had complete Ki-67 data at baseline and endpoint.

Data on tumor response were available for 144 patients. Three patients in group 1 achieved a partial response (0.3 mg/kg, n = 1; 10 mg/kg, n = 2) and 17 patients had stable disease (0.3 mg/kg, n = 10; 10 mg/kg, n = 7). Eleven patients exhibited documented disease progression (0.3 mg/kg, n = 8; 10 mg/kg, n = 3).

No patients with unresectable osteosarcoma (group 2) experienced tumor response, although six patients had stable disease. Twenty-three patients had documented disease progression.

Among patients with Ewing sarcoma (group 3), six achieved partial responses and 23 achieved stable disease. Fifty-five patients had documented disease progression.

Although group 3 had a median OS of 6.9 months overall, the six responding patients continued to receive treatment after study closure and remain alive and healthy. Remissions in these patients have lasted longer than 4 years.

“This finding warrants further study to explore the potential benefits of combination therapy with anti–IGF-1R antibody treatment,” Anderson and colleagues wrote. – by Cameron Kelsall

Disclosure: Anderson reports no relevant financial disclosures. Please see the full study for a list of all other researchers’ relevant financial disclosures.