The FDA has granted an biologics license application for olaratumab a priority review for use in combination with doxorubicin as a treatment of patients with advanced soft tissue sarcoma who are not good candidates for radiotherapy or surgery.
The BLA for olaratumab was based on data from the phase II JGDG trial, in which combining olaratumab with doxorubicin reduced the risk of death by 54% versus doxorubicin alone in patients with STS (HR, 0.46; 95% CI, 0.30-0.71;P= .0003). The median overall survival (OS) in the intent-to-treat population (n = 129) was 11.8 months higher with the olaratumab combination versus doxorubicin alone.
The FDA previously granted olaratumab a breakthrough therapy designation in STS. Under the priority review designation, the FDA will review the BLA for olaratumab within 6 months compared with the standard 10-month review.
“We are encouraged that the FDA has granted priority review for olaratumab as a potential treatment for advanced soft tissue sarcoma,” Richard Gaynor, MD, senior vice president, Product Development and Medical Affairs, for Lilly Oncology, said in a statement. “We are hopeful that, if approved, olaratumab will provide a meaningful addition to the limited treatment options for this rare and difficult-to-treat disease."
The pivotal, open-label phase II JGDG study included 133 patients with advanced STS that was not amenable to surgery or radiotherapy. Eligible patients had to have an ECOG PS <2 and available tumor tissue to determine PDGFRα status. Patients could not have received prior anthracyclines, but previous treatment was allowed. Patients were stratified by PDGFRα status, lines of prior treatment, ECOG PS, and disease histology. Patient characteristics were well balanced between the arms. By a small margin, there were more females who received the combination.
Patients were randomized 1:1 to receive 75 mg/m2of doxorubicin on day 1 for 8 cycles (21 days; n = 67) or the combination of the same doxorubicin regimen with 15 mg/kg of olaratumab on days 1 and 8 for 8 cycles (21 days; n = 66). Patients could receive dexrazoxane during cycles 5 through 8 at the investigator’s discretion prior to doxorubicin on day 1.
Following 8 cycles, patients on the doxorubicin arm were able to receive olaratumab monotherapy after progression, while patients on the combination arm received the olaratumab monotherapy until progression.
The primary outcome measure was progression-free survival (PFS), with secondary endpoints including OS, objective response rate (ORR), and PFS at 3 months.
The addition of olaratumab reduced the risk of disease progression by 33% versus doxorubicin alone (HR, 0.67; 95% CI, 0.44-1.02;P= .0615). Median PFS was 6.6 versus 4.1 months, respectively. Median OS was 26.5 months with the combination versus 14.7 months with doxorubicin alone. ORR was 18.2% in the combination arm compared with 11.9% in the doxorubicin arm (P= .34).
There were 6 grade 3 adverse events (AEs) that were observed in at least 5% of the population: neutropenia, anemia, febrile neutropenia, fatigue, thrombocytopenia, and infections. Three of these AEs occurred at a significantly higher rate in the combination arm compared with the doxorubicin arm: neutropenia (51.5% vs 33.8%), anemia (12.5% vs 7.7%), and fatigue (9.4% vs 3.1%).
Based on the positive phase II data, the olaratumab/doxorubicin combination is being compared with doxorubicin alone in the ongoing phase III ANNOUNCE trial (NCT02451943).
Tap WA, Jones R, Chmielowski B, et al. A randomized phase 1b/2 study evaluating the safety and efficacy of doxorubicin (Dox) with or without olaratumab (IMC-3G3), a human anti-platelet-derived growth factor α (PDGFRα) monoclonal antibody, in advanced soft tissue sarcoma (STS). Presented at: 2015 CTOS Annual Meeting; November 4-7, 2015; Salt Lake City, UT. Abstract 020.