The U.S. Food and Drug Administration granted Lartruvo (olaratumab), a PDGFRα antagonist, an accelerated approval in combination with doxorubicin for the treatment of patients with advanced soft tissue sarcoma (STS) who are not good candidates for radiotherapy or surgery.
The biologics license application (BLA) for Lartruvo was based on data from the phase 2 JGDG trial, in which combining Lartruvo 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 Lartruvo combination versus doxorubicin alone.
"For these patients, Lartruvo, added to doxorubicin, provides a new treatment option," Richard Pazdur, M.D., director of the Office of Hematology and Oncology Products in the FDA’s Center for Drug Evaluation and Research and acting director of the FDA’s Oncology Center of Excellence, said in a statement. "This is the first new therapy approved by the FDA for the initial treatment of soft tissue sarcoma since doxorubicin’s approval more than 40 years ago."
The human IgG1 monoclonal antibody Lartruvo 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 under 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 in a 1-1 ratio 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 Lartruvo 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 Lartruvo monotherapy after progression, while patients on the combination arm received the Lartruvo 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.
Evaluable patients in the Lartruvo arm (64 patients) received a median of seven infusions of doxorubicin (range, 1-8), 16.5 infusions of Lartruvo (range, 1-83), and five infusions of Lartruvo monotherapy post-combination (range, 1-68). Patients on the doxorubicin arm who were evaluable (65 patients) received a median of four infusions (range, 1-8). In total, 30 patients on this arm received Lartruvo post-progression and received a median number of four infusions (range, 1-60).
The addition of Lartruvo reduced the risk of disease progression by 33 percent versus doxorubicin alone. Median PFS was 8.2 versus 4.4, 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 Lartruvo /doxorubicin combination is being compared with doxorubicin alone in the ongoing phase 3 ANNOUNCE trial (NCT02451943