The European Medicines Agency’s Committee for Medicinal Products for Human Use has recommended that the conditional marketing authorization for olaratumab be revoked following results of the ANNOUNCE study, which did not demonstrate a survival benefit with the PDGFRα antagonist in combination with doxorubicin versus doxorubicin alone in patients with advanced or metastatic soft tissue sarcoma.
The European Medicines Agency’s Committee for Medicinal Products for Human Use (CHMP) has recommended that the conditional marketing authorization for olaratumab (Lartruvo) be revoked following results of the ANNOUNCE study, which did not demonstrate a survival benefit with the PDGFRα antagonist in combination with doxorubicin versus doxorubicin alone in patients with advanced or metastatic soft tissue sarcoma (STS).1
The CHMP made its conclusion following an assessment of the ANNOUNCE (NCT02451943) data, which also showed that the combination did not confirm a clinical benefit for patients with advanced or metastatic disease compared with standard doxorubicin.2 Moreover, the OS endpoint in the leiomyosarcoma subpopulation was also not met.
Full ANNOUNCE findings will be presented at the upcoming 2019 ASCO Annual Meeting and published in an upcoming journal.
The negative opinion follows a recent announcement by Eli Lilly and Company, the developer of olaratumab. The company stated that it would be withdrawing olaratumab from the market for this patient population in April 2019.
Additionally, Lilly will be establishing an access program for patients who can continue treatment with olaratumab with limited interruption following its withdrawal from the market. Those who are currently on olaratumab, following consult with their physicians on the agent’s associated risks, could continue therapy subject to local laws and regulations. No new patients will be permitted to undergo treatment with olaratumab outside of ongoing clinical trials. More information on the program will be disseminated to healthcare professionals in the upcoming weeks.
In January 2019, the FDA recommended that no new patients with advanced STS should be treated with the combination of olaratumab and doxorubicin.3 A similar recommendation was issued by the European Medicines Agency (EMA) based on the negative ANNOUNCE findings.4
Both the FDA and EMA made statements recommending that patients currently receiving olaratumab may continue to receive the treatment if they appear to be benefitting from it. Approximately 1100 patients in the European Union are currently treated with olaratumab.
In ANNOUNCE, which was the confirmatory trial for the FDA approval of olaratumab in this setting, results showed that there was no difference in OS between the 2 arms.5 The median OS was 20.4 months with olaratumab/doxorubicin and 19.7 months with doxorubicin (HR, 1.05). In the leiomyosarcoma subpopulation, the median OS was 21.6 months and 21.9 months for olaratumab/doxorubicin and doxorubicin, respectively.
Moreover, the median PFS with olaratumab/doxorubicin was 5.4 months and was 6.8 months with doxorubicin alone (HR, 1.23). Regarding safety, olaratumab was found to be well tolerated and no new safety signals were reported.
The double-blind ANNOUNCE trial 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/m2 administered 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, PFS, objective response rate (ORR), and patient-reported outcomes.
This 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).6 In 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 arms. The median age in the combination arm was 58.5 years, and most patients 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%).
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).
There was an 18.2% ORR in the combination arm versus 7.5% in the doxorubicin arm by independent assessment. 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.
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.