Eli Lilly and Company has announced that it is withdrawing its PDGFRα antagonist olaratumab from the market for the treatment of patients with advanced soft tissue sarcoma.
Eli Lilly and Company has announced that it is withdrawing its PDGFRα antagonist olaratumab (Lartruvo) from the market for the treatment of patients with advanced soft tissue sarcoma (STS), following the disappointing findings of the phase III ANNOUNCE trial.1
In the study, the combination of olaratumab and doxorubicin missed the primary endpoint of overall survival (OS) nor did it confirm a clinical benefit for patients with advanced or metastatic STS compared with standard doxorubicin.2 Moreover, the OS endpoint in the leiomyosarcoma subpopulation was also not met. Full data from the ANNOUNCE trial (NCT02451943) will be presented at an upcoming 2019 ASCO Annual Meeting and published in an upcoming journal.
Additionally, Lilly is in the midst of establishing an access program for patients who can continue treatment with olaratumab with limited interruption following its withdrawal from the market. Patients 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.
Further information on the program will be disseminated to healthcare professionals in the upcoming weeks.
"Lilly wants to ensure that patients and physicians feel supported during this important time," said Anne White, president of Lilly Oncology, in a press release. "Advanced soft tissue sarcoma is a rare and difficult-to-treat cancer. Establishing this program will give patients who are currently taking Lartruvo the opportunity to continue their treatment program uninterrupted."
The announcement follows a January 2019 statement from the FDA, in which the agency recommended that no new patients with advanced STS should be treated with the combination of olaratumab plus doxorubicin.3
Additionally, the European Medicines Agency (EMA) issued a similar recommendation based on the negative findings of the confirmatory trial, stating that the combination of olaratumab and doxorubicin should not be administered in any new patients with advanced STS.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.
Results of ANNOUNCE, which was the confirmatory trial for the FDA approval of olaratumab in this setting, demonstrated that there was no difference in OS between the 2 arms. 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.
In November 2016, the European Commission approved olaratumab in combination with doxorubicin for the treatment of patients with advanced STS who are ineligible for radiotherapy or surgery; this was contingent on the results of a confirmatory trial. The FDA approved olaratumab for the same indication in October 2016.
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).3 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 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.
However, 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).