The primary endpoint of overall survival benefit with the combination of olaratumab plus doxorubicin was not met for patients with advanced or metastatic soft tissue sarcoma in the phase III ANNOUNCE clinical trial.
The primary endpoint of overall survival (OS) benefit with the combination of olaratumab (Lartruvo) plus doxorubicin was not met for patients with advanced or metastatic soft tissue sarcoma (STS) in the phase III ANNOUNCE clinical trial. The combination did not confirm clinical benefit compared to standard doxorubicin, announced Eli Lilly and Company, the manufacturer of olaratumab.1Additionally, the leiomyosarcoma subpopulation did not meet the OS endpoint.
ANNOUNCE was the confirmatory trial for the FDA approval of olaratumab in this setting. These data showed no difference in OS between the 2 arms. In terms of safety, the drug was well tolerated with no new safety signals. The findings will be presented at an upcoming medical meeting and published at a later date.
“As ANNOUNCE did not confirm clinical benefit, Lilly is working with global regulators to determine the appropriate next steps for Lartruvo,” the company stated in a press release. “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.”
For patients who have not previously received olaratumab, Eli Lilly added that the phase III data do not support starting this therapy in patients with STS outside of a clinical trial.
“At this time, Lilly is suspending promotion of Lartruvo,” the company stated in the release.
The double-blind, phase III ANNOUNCE trial (NCT02451943) randomized approximately 460 patients to receive olaratumab in combination with doxorubicin, followed by olaratumab alone, compared with doxorubicin plus placebo followed by placebo in patients with advanced or metastatic STS. Olaratumab was given at a loading dose of 20 mg/kg on days 1 and 8 of cycle 1 and 15 mg/kg on days 1 and 8 of all subsequent cycles, combined with doxorubicin at 75 mg/m2administered on day 1 of each cycle. Placebo was given in combination with doxorubicin for 8 cycles, while olaratumab was continued as a single agent until disease progression.
To be eligible for enrollment, patients had to have locally advanced, unresectable or metastatic STS not amenable to curative treatment and could have had any prior number of therapies, as long as they did not previously receive an anthracycline. Secondary endpoints of the study were safety, progression-free survival (PFS), objective response rate (ORR), and patient-reported outcomes.
In October 2016, the FDA granted an accelerated approval to the PDGFRα antagonist olaratumab in combination with doxorubicin for the treatment of patients with advanced STS who are ineligible for radiotherapy or surgery.
The approval was based on data from the phase II JGDG study, which demonstrated a 48% reduction in the risk of death with olaratumab and doxorubicin versus doxorubicin alone (HR, 0.52; 95% CI, 0.34-0.79,P<.05).2In the 133-patient, randomized, US trial, the median OS in the intent-to-treat population (n = 129) was 26.5 months with olaratumab/doxorubicin versus 14.7 months with doxorubicin alone.
Of those enrolled, 129 received at least 1 dose of treatment (64, olaratumab/doxorubicin; 65, doxorubicin).
Patient characteristics were well balanced between the arms. The median age of patients in the combination arm was 58.5 years, and most had an ECOG performance status of 0 to 1 (94%). Additionally, 88% of patients were positive for PDGFRα. Thirty-six percent and 40% of patients had leiomyosarcoma, in the combination and monotherapy arms, respectively. Other common histologies in the olaratumab and control arms, respectively, included undifferentiated pleomorphic sarcoma (15% vs 21%, respectively) and liposarcoma (12% vs 22%).
Additional results showed that, by blinded independent review, the median PFS was 8.2 months versus 4.4 months for olaratumab/doxorubicin and doxorubicin alone, respectively (HR, 0.67; 95% CI, 040-1.12;P= .1208). By investigator assessment, median PFS was 6.6 months with olaratumab plus doxorubicin versus 4.1 months with doxorubicin alone (HR, 0.67; 95% CI, 0.44-1.02;P= .0615).
By independent assessment, there was an 18.2% ORR in the combination arm versus 7.5% in the doxorubicin arm. The complete response (CR) rate to the olaratumab combination was 4.5% and the partial response rate was 13.6%; the CR rate was 1.5% in the doxorubicin arm.
Regarding safety, the most commonly reported all-grade adverse events (AEs) in the olaratumab group versus chemotherapy, respectively, were nausea (73% vs 52%), fatigue (69% vs 69%), musculoskeletal pain (64% vs 25%), mucositis (53% vs 35%), vomiting (45% vs 19%), diarrhea (34% vs 23%), and headache (20% vs 9%). The most common all-grade hematologic AEs were lymphopenia (77% vs 73%), neutropenia (65% vs 63%), thrombocytopenia (63% vs 44%), and hyperglycemia (52% vs 28%). Febrile neutropenia was experienced by 13% of patients treated with olaratumab versus 12% of those in the doxorubicin alone group.
Olaratumab is currently being evaluated in the ongoing, international, double-blind, placebo-controlled, randomized phase II ANNOUNCE 2 trial in combination with gemcitabine and docetaxel in patients with advanced STS (NCT02659020).
Lilly expects to incur a charge, which has not yet been determined, in the first quarter of 2019 related to olaratumab. However, it is estimated to be in the range of $70 million to $90 million (pre-tax), or approximately $0.10 per share (after tax). Moreover, the company expects this update to have an impact of an estimated $0.17 per share on their 2019 earnings per share guidance.