Richard Gaynor, MD
The Committee for Medicinal Products for Human Use (CHMP) has recommended approval of the PDGFRα antagonist olaratumab for use in combination with doxorubicin for patients with advanced soft tissue sarcoma (STS) who are not good candidates for radiotherapy or surgery.
The application for olaratumab was based on data from the phase II JGDG trial, in which combining the agent 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 positive opinion has been sent to the European Commission, which usually issues its final approval decision within 2 to 3 months of the CHMP recommendation.
“Patients with advanced soft tissue sarcoma have been seeking new treatment options that can potentially extend lives, so they can have more time with their families and loved ones,” Richard Gaynor, MD, senior vice president of Product Development and Medical Affairs for Lilly Oncology, the manufacturer of olaratumab, said in a statement. “Advanced soft tissue sarcoma is a rare disease that is difficult to treat, and this milestone brings us one step closer to providing physicians in Europe with a new option that they can offer to their patients.”
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 to Lilly.
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 performance status <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/m2 of 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). As in the phase I trial, 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.
Evaluable patients in the olaratumab arm (n = 64) received a median of 7 infusions of doxorubicin (range, 1-8), 16.5 infusions of olaratumab (range, 1-83), and 5 infusions of olaratumab monotherapy post-combination (range, 1-68). Patients on the doxorubicin arm who were evaluable (n = 65) received a median of 4 infusions (range, 1-8). In total, 30 patients on this arm received olaratumab post-progression and received a median number of 4 infusions (range, 1-60).
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%).
In May, the FDA granted a priority review to olaratumab for use in combination with doxorubicin in this setting. The priority review followed an FDA breakthrough designation for the drug.
Based on the positive JGDG trial data, the olaratumab/doxorubicin combination is being compared with doxorubicin alone in the ongoing phase III ANNOUNCE trial (NCT02451943). If olaratumab receives an accelerated approval from the FDA and/or conditional marketing authorization from the EC, Lilly will need to provide confirmatory results from the pivotal ANNOUNCE study to sustain the approvals.
- 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.