No Clinical Benefit for Ombrabulin, Cisplatin in Metastatic Soft-Tissue Sarcoma

Researchers recommend against the therapeutic use of the ombrabulin and cisplatin combination in the metastatic soft-tissue sarcoma setting

medwireNews: Treatment with ombrabulin plus cisplatin fails to demonstrate a clinical benefit in patients with metastatic soft-tissue sarcomas, research shows, despite a statistically significant improvement in progression-free survival (PFS) compared with placebo plus cisplatin.

In this double-blind, phase III trial, 355 patients with anthracycline- and ifosfamide-refractory disease were randomly assigned to receive cisplatin with either the tumour vascular-disrupting agent ombrabulin at a dose of 25 mg/m2 (n=176) or placebo (n=179).

After a median follow-up of 30.5 months and 27.9 months in the ombrabulin and placebo arms, respectively, median PFS was 1.54 months for patients treated with ombrabulin and 1.41 for those given placebo.

Although the difference between the groups was statistically significant, the absolute increase in PFS for ombrabulin-treated patients was small and thus not clinically meaningful, say Jean-Yves Blay, from University Claude Bernard Lyon I in France, and co-investigators.

When patients were stratified by histological subtype, ombrabulin treatment resulted in a nonsignificant increase in median PFS compared with placebo in the case of patients with liposarcoma (2.86 vs 1.31 months), leiomyosarcoma (2.73 vs 1.61 months) and other subtypes (1.48 vs 1.38 months), but not for those with high-grade undifferentiated pleomorphic sarcoma (1.35 vs 1.48 months).

Median overall survival did not vary between the arms, and neither did the likelihood of survival without disease progression at 3 months and 6 months.

Adverse events of grade 3 and 4 were experienced by more patients in the ombrabulin group than in the placebo group, with neutropenia and thrombocytopenia the most common toxicities, at 19% versus 8% and 8% versus 3%, respectively.

And mortality owing to adverse events was also more frequent in patients given ombrabulin compared with those given placebo, with rates of 10% and 7%, respectively.

The trial was based on a “compelling mechanism to target tumour vasculature”, say the researchers in The Lancet Oncology, adding that the combination, however, did not show a “sufficient clinical benefit” in this patient population to support its use as a therapeutic option.

In an accompanying commentary, Richard Quek, from National Cancer Centre Singapore, agrees that “ombrabulin is not ready to be used as a treatment for soft-tissue sarcoma.”

“Key efforts in development of alternative tumour vasculature-disrupting agents, and, by extension, drug development altogether in soft-tissue sarcoma, should be directed at increased understanding of the molecular basis of this disease and at Biomarker discovery”, he concludes.

References

Blay J-Y, Pápai Z, Tolcher AW, et al. Ombrabulin plus cisplatin versus placebo plus cisplatin in patients with advanced soft-tissue sarcomas after failure of anthracycline and ifosfamide chemotherapy: a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet Oncol; Advance online publication 9 April 2015. doi:10.1016/S1470-2045(15)70102-6

Quek R. Tumour vascular-disrupting agents in soft-tissue sarcoma. Lancet Oncol; Advance online publication 9 April 2015. doi:10.1016/S1470-2045(15)70139-7

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