Olaratumab (Lartruvo) failed to meet its primary endpoint in the phase III ANNOUNCE trial, , raising doubts about its continued role in treating advanced or metastatic soft-tissue sarcoma.
The combination of olaratumab plus standard care doxorubicin showed no overall survival (OS) improvement over doxorubicin alone for both the full study population or for those with leiomyosarcoma.
"As ANNOUNCE did not confirm clinical benefit, Lilly is working with global regulators to determine the appropriate next steps for Lartruvo," Lilly stated. "While these discussions are ongoing, patients who are currently receiving Lartruvo may, in consultation with their physician, continue their course of therapy if they are receiving clinical benefit."
But they noted that the trial results do not support treatment initiation with olaratumab for sarcoma patients who have not yet been treated with the drug, outside of participation in a clinical trial.
In 2016, the FDA to olaratumab in combination with doxorubicin for metastatic soft-tissue sarcomas that are not amenable to curative treatment with surgery or radiotherapy, and with a histologic subtype where an anthracycline-containing regimen would be indicated.
Accelerated approval was based on a randomized phase II trial that showed that adding olaratumab to doxorubicin improved the rate of overall response, progression-free survival (PFS), as well as OS. It was the first new drug approval for soft-tissue sarcoma in 40 years. Leiomyosarcoma was the most common sarcoma subtype (38%) in this trial, with 1.5% having synovial sarcoma and the remaining having one of 25 other histologies.
As a condition of the accelerated approval, Lilly was required to conduct a randomized trial to verify the benefit of olaratumab in these soft-tissue sarcoma patients.
"Lilly was surprised and disappointed that Lartruvo did not improve survival for patients with advanced soft-tissue sarcoma in this study," said Anne White, president of Lilly Oncology. "We will carefully study the detailed data in an effort to better understand the different results between the two trials."
In the phase II trial, the overall response rate in patients treated with the olaratumab-doxorubicin was 18% compared with 8% with doxorubicin alone. Median PFS was 8.2 months versus 4.4 months, respectively (HR 0.74, 95% CI 0.46-1.19), and median OS was 26.5 months versus 14.7 months, respectively (HR 0.52, 95% CI 0.34-0.79).
The most common adverse events (≥20%) with olaratumab in the phase II trial were abdominal pain, alopecia, diarrhea, decreased appetite, fatigue, headache, mucositis, musculoskeletal pain, nausea, neutropenia, neuropathy, and vomiting. Also, 13% of patients experienced infusion-related reactions. No new safety signals were found in the ANNOUNCE trial.