The addition of olaratumab to doxorubicin dramatically improves survival in patients with advanced soft-tissue sarcoma, according to the results of a randomized phase Ib/II trial (abstract 10501) presented at the 2015 American Society of Clinical Oncology (ASCO) Annual Meeting, held May 29 to June 2, in Chicago.
“Olaratumab is the first agent added to doxorubicin to improve overall survival in advanced/metastatic soft-tissue sarcoma in a randomized trial,” said lead author William D. Tap, MD, chief, sarcoma medical oncology service at Memorial Sloan Kettering Cancer Center in New York.
Olaratumab is a human anti-platelet–derived growth factor α (PDGFRα) monoclonal antibody. “PDGFRα is genetically altered and overexpressed in multiple tumor types, including certain sarcomas, and the expression is associated with increased metastatic potential,” Tap said.
Doxorubicin remains the standard of care for most metastatic soft-tissue sarcomas, but doxorubicin combinations have yet to improve overall survival over doxorubicin alone. Olaratumab has demonstrated antitumor activity alone or in combination with doxorubicin in human sarcoma models, he said.
This phase II trial randomized 133 unresectable/metastatic soft-tissue sarcoma patients (median age 58 years) to receive up to 8 cycles of doxorubicin 75 mg/m2 with or without olaratumab 15 mg/kg. In the combination arm, olaratumab monotherapy continued after doxorubicin until disease progression. In the doxorubicin-alone arm, patients could cross over to olaratumab at progression.
The patient characteristics were well balanced, he said. The majority had ECOG status of 0 or 1. About one-third had leiomyosarcoma.
The primary endpoint of progression-free survival was met. The median progression-free survival was 6.6 months in the combination arm and 4.1 months in the doxorubicin-alone arm (hazard ratio [HR] = 0.67). Interim overall survival also favored the combination arm (25 months vs 14.7 months; HR = 0.44).
Similarly, objective response rates were higher in the combination arm (18.8%) as compared to the doxorubicin-alone arm (12.3%).
More grade 3 or higher adverse events occurred in combination arm, including neutropenia (51.5% vs 33.8%), anemia (12.5% vs 7.7%), fatigue (9.4% vs 3.1%), and thrombocytopenia (9.4% vs 7.7%). The doxorubicin-alone arm induced more grade 3 or higher febrile neutropenia (13.8 vs 12.5%) and infections (10.8 vs 6.3%), as well as more adverse events leading to discontinuations (22% vs 13%).
In conclusion, Tap said: “Olaratumab added to doxorubicin achieved a statistically significant improvement of 10.3 months in median overall survival over doxorubicin alone, without an increase in serious toxicity. Despite higher cumulative doxorubicin exposure, the olaratumab plus doxorubicin combination had an acceptable and monitorable safety profile, including cardiac safety.”
Based on these data, olaratumab has received Breakthrough Therapy Designation from the US Food and Drug Administration. A phase III study is planned, he said.
ASCO discussant Laurence Baker, DO, professor of medical oncology at the University of Michigan, noted the “dramatic difference in overall survival” seen with olaratumab, commenting that the PDGFRα monoclonal antibody “shows great promise,” and that he is excited a phase III trial is planned.