On October 19, 2016, the U.S. Food and Drug Administration granted accelerated approval to olaratumab (LARTRUVO, Eli Lilly and Company) for the treatment of patients with soft tissue sarcoma (STS) not amenable to curative treatment with radiotherapy or surgery and with a histologic subtype for which an anthracycline-containing regimen is appropriate.
Approval was based on data from a randomized, active-controlled, clinical trial involving 133 patients with metastatic STS. Patients were required to have STS not amenable to curative treatment with surgery or radiotherapy, and a histologic type of sarcoma for which an anthracycline-containing regimen was appropriate, but had not been administered.
Patients were randomized (1:1) to receive the combination of olaratumab plus doxorubicin or doxorubicin as a single agent. Olaratumab was administered at 15 mg/kg as an intravenous (IV) infusion on days 1 and 8 of each 21-day cycle. All patients received doxorubicin 75 mg/m2 as an IV infusion on day 1 of each 21-day cycle for maximum of eight cycles and were permitted to receive dexrazoxane on cycles 5 to 8. Single-agent olaratumab was offered to patients in the doxorubicin alone arm at the time of disease progression. Sixty-six patients were randomized to the combination treatment and 67 to doxorubicin alone. Sixty-five percent of patients had no prior chemotherapy (excluding adjuvant and neoadjuvant therapy), 38% had leiomyosarcoma, 1.5% had synovial sarcoma, and 61% had other histologies (over 25 different STS histologies). All patients had metastatic disease and were enrolled in the United States.
Patients who received the combination treatment had a statistically significant improvement in overall survival (OS) compared to those receiving doxorubicin alone. Patients receiving the combination treatment had a median OS of 26.5 months (95% CI: 20.9, 31.7) compared to 14.7 months (95% CI: 9.2, 17.1) for those receiving doxorubicin alone (HR=0.52 [95% CI: 0.34, 0.79]).
The median progression-free survival (independent review) was 8.2 months (95% CI: 5.5, 9.8) for patients who received the combination treatment and 4.4 months (95% CI: 3.1, 7.4) for those receiving doxorubicin alone (HR=0.74 [95% CI: 0.46, 1.19]). The overall response rate (independent review) was 18% (95% CI: 9.8, 29.6) in the combination arm and 8% (95% CI: 2.5, 16.6) in the doxorubicin alone arm.
The most common (greater than or equal to 20%) side effects of treatment with olaratumab are nausea, fatigue, neutropenia, musculoskeletal pain, mucositis, alopecia, vomiting, diarrhea, decreased appetite, abdominal pain, neuropathy, and headache. Infusion-related reactions were seen in 13% of patients.
The recommended dose and schedule of olaratumab is 15 mg/kg administered as an IV infusion over 60 minutes on days 1 and 8 of each 21-day cycle until disease progression or unacceptable toxicity. For the first eight cycles, olaratumab is administered with doxorubicin.
FDA granted olaratumab fast track and breakthrough therapy designation, priority review status, and accelerated approval for this indication. As a condition of the accelerated approval, Eli Lilly and Company is required to conduct a randomized, controlled trial to verify and further describe the clinical benefit of olaratumab given with doxorubicin in patients with STS. Olaratumab also received orphan drug designation. A description of these expedited programs is in the Guidance for Industry: Expedited Programs for Serious Conditions-Drugs and Biologics, available at: http://www.fda.gov/downloads/drugs/guidancecomplianceregulatoryinformation/guidances/ucm358301.pdf.