The FDA granted olaratumab a priority review for some people with advanced soft tissue sarcoma (STS).
Olaratumab, a PDGFRα antagonist, was granted a priority review by the FDA for use in combination with doxorubicin for patients not eligible for radiotherapy or surgery with advanced soft tissue sarcoma (STS).
The biologics license application (BLA) for olaratumab was based on data from the phase 2 JGDG trial, in which combining olaratumab with doxorubicin reduced the risk of death by 54 percent versus doxorubicin alone in patients with STS. The median overall survival (OS) in the intent-to-treat population (129 patients) 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 designation, the BLA for olaratumab will be reviewed by the FDA within six 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, senior vice president, Product Development and Medical Affairs, for Lilly Oncology, the manufacturer of the drug, 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 human IgG1 monoclonal antibody olaratumab binds to PDGFRα and blocks the PDGF-AA, PDGF-BB, and PDGF-CC ligands from binding to the receptor, according Lilly.
The pivotal, open-label phase 2 JGDG study included 133 patients with advanced STS that was not amenable to surgery or radiotherapy. Eligible patients had to have an ECOG performance status less than two 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/m2 of doxorubicin on day one for eight cycles (21 days; 67 patients) or the combination of the same doxorubicin regimen with 15 mg/kg of olaratumab on days one and eight for eight cycles (21 days; 66 patients). As in the phase 1 trial, patients could receive dexrazoxane during cycles five through eight at the investigator’s discretion prior to doxorubicin on day one.
Following eight 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 three months.
Evaluable patients in the olaratumab arm (64 patients) received a median of seven infusions of doxorubicin (range, one through eight), 16.5 infusions of olaratumab (range, one through 83), and five infusions of olaratumab monotherapy post-combination (range, one through 68). Patients on the doxorubicin arm who were evaluable (65 patients) received a median of four infusions (range, one through eight). In total, 30 patients on this arm received olaratumab post-progression and received a median number of four infusions (range, one through 60).
The addition of olaratumab reduced the risk of disease progression by 33 percent versus doxorubicin alone. 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 percent in the combination arm compared with 11.9 percent in the doxorubicin arm.
There were six grade 3 adverse events (AEs) that were observed in at least 5 percent 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 percent vs 33.8 percent), anemia (12.5 percent vs 7.7 percent) and fatigue (9.4 percent vs 3.1 percent).
Based on the positive phase 2 data, the olaratumab/doxorubicin combination is being compared with doxorubicin alone in the ongoing phase 3 ANNOUNCE trial (NCT02451943).