The FDA has granted accelerated approval to the monoclonal antibody olaratumab, combined with doxorubicin, as first-line therapy for patients with inoperable soft-tissue sarcoma. In a randomized phase II trial, the median overall survival was 26.5 months for patients who received this combination, versus 14.7 months for those who received only doxorubicin.

The FDA has greenlighted the monoclonal antibody olaratumab (Lartruvo; Lilly Oncology), combined with doxorubicin, as first-line therapy for patients with inoperable soft-tissue sarcoma (STS). This combination is the only up-front treatment for STS to gain the agency's approval in 40 years—until now, doxorubicin has been the mainstay.

STS has multiple subtypes, making it difficult to diagnose and treat. Aberrant platelet-derived growth factor receptor (PDGFR) activity, a known occurrence in this disease, is implicated in tumor cell proliferation and migration. It also promotes the recruitment of fibroblasts that maintain a protumor microenvironment by producing angiogenic factors. Olaratumab was therefore designed to bind to and block PDGFRα, one of two PDGFR isoforms, with high specificity.

The FDA's nod was based on data from the phase II JGDG study, in which 133 patients with STS were randomly assigned to receive doxorubicin plus olaratumab, or doxorubicin alone. The objective response rates were 18.2% and 7.5%, respectively; the median progression-free survival was 8.2 months for patients given the combination and 4.4 months for those who received only the chemotherapy. Notably, the difference in median overall survival between the arms was sizeable: 26.5 months versus 14.7 months.

“Patients with leiomyosarcoma were highly represented in this study,” says lead investigator William Tap, MD, chief of the sarcoma medical oncology service at Memorial Sloan Kettering Cancer Center in New York, NY. “Olaratumab had very impressive activity in this subtype, but overall, many subtypes responded.” Nausea, musculoskeletal pain, and mucositis were among the most common side effects seen with this drug combination.

Tap notes that other, less specific PDGFR inhibitors have been evaluated in STS, including the multikinase inhibitor pazopanib (Votrient; GlaxoSmithKline), which was approved several years ago for patients with previously treated disease. Pazopanib blocks a variety of targets, including PDGFRα and PDGFRβ. Olaratumab is the first PDGFRα-selective inhibitor for STS, however, and “the fact that such a dramatic survival advantage was seen is very intriguing,” Tap says. “We need to more fully figure out olaratumab's mode of action—besides direct effects on the tumor, it may affect metastatic potential or even the immune microenvironment.”

A phase III trial to confirm the study's results is under way. Tap and his colleagues are also discussing olaratumab as possible adjuvant therapy for patients with localized STS at high risk of developing metastases. These patients are first treated with surgery and radiation, but metastatic disease often still follows, so “this would be a very important indication for olaratumab,” Tap says. –Alissa Poh

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©2016 American Association for Cancer Research.
2016
American Association for Cancer Research.