Novel Agent Fails to Show Sufficient Activity in Recurrent Osteosarcoma

The GPNMB-targeted agent known as glembatumumab vedotin was reasonably well tolerated and showed some activity in a phase II study of recurrent/refractory osteosarcoma, but this activity was not enough to continue the drug’s evaluation in this setting based on the study protocol.

Few treatment advances have been made in recurrent osteosarcoma in recent years. The GPNMB protein was considered an intriguing target due to its role in enhancing tumor growth and metastasis through cytokine release, angiogenesis promotion, and other mechanisms. “It is expressed extracellularly, making it an ideal target for an antibody–drug conjugate,” said Lisa M. Kopp, DO, MPH, of the University of Arizona in Tucson.

Kopp presented results of a phase II study of glembatumumab at the Connective Tissue Oncology Society (CTOS) 2017 Annual Meeting, held November 8–11 in Wailea, Hawaii. The study was designed to have two stages, with enrollment for stage 2 only beginning if sufficient responses or stable disease was seen in stage 1; it did not reach that threshold.

Stage 1 included 22 patients, with a median age of 20; there were 15 male patients and 7 female patients, and they had a median of 2 measurable lesions at enrollment. “These were heavily pretreated patients,” Kopp said.

There were two cases of stable disease, and one partial response, falling one short of the threshold required to move ahead with the trial.

The agent was generally well tolerated; the most frequent grade 3 adverse event was rash. There was one death that was deemed possibly related to glembatumumab, due to end organ failure relating to multiple toxicities; these were deemed to be not solely related to the study drug.

During a question-and-answer session following the presentation, the question was raised of why it wouldn’t be of interest to continue studying a drug that clearly has at least some activity in a difficult malignancy. Another expert involved with the Children’s Oncology Group, which conducted this study, noted that conducting randomized phase III trials in this malignancy in particular is extremely difficult; if the group can only do one such trial every 10 years or so, they aim to focus on agents with a strong, clear signal of activity in order to have the best chance of success.

“[Glembatumumab] did show some antitumor activity,” Kopp said, “including one patient with prolonged stable disease and a response, but neither of these warranted proceeding to stage 2.”