FDA, EMA Say Olaratumab Should Not Be Given to New Patients With Soft Tissue Sarcoma


No new patients with advanced soft tissue sarcoma should be treated with the combination of olaratumab plus doxorubicin, according to a statement from the FDA.

No new patients with advanced soft tissue sarcoma (STS) should be treated with the combination of olaratumab (Lartruvo) plus doxorubicin, according to a statement from the FDA.1

The FDA has made the recommendation based on negative findings from the phase III ANNOUNCE trial, which were announced in January 2019.1The combination of olaratumab with doxorubicin missed the ANNOUNCE trial’s primary endpoint of overall survival (OS) and did not confirm a clinical benefit for patients with advanced or metastatic STS compared with standard doxorubicin.2The OS endpoint in the leiomyosarcoma subpopulation was also not met.

"In light of this information, the FDA recommends that patients who are currently receiving Lartruvo should consult with their healthcare provider about whether to remain on the treatment," the FDA stated in a press release. "The FDA also recommends that Lartruvo should not be initiated in new patients outside of an investigational study."

The European Medicines Agency (EMA) also 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.3

The statements from both the FDA and EMA recommended 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 (NCT02451943), which was the confirmatory trial for the FDA approval of olaratumab in this setting, showed 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. Eli Lilly and Company, the manufacturer of olaratumab, will present the full findings at an upcoming medical meeting and will be published at a later date.

The company stated in a previous press release that the phase III data do not support starting patients on the therapy outside of a clinical trial.

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/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 November 2016, the European Commission approved the PDGFRα antagonist 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).3In 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 PDGFR&alpha;. 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).


  1. FDA grants accelerated approval to new treatment for advanced soft tissue sarcoma. FDA. Published October 19, 2016. Updated January 24, 2019. https://bit.ly/2CO8eVd. Accessed January 24, 2019.
  2. Lilly Reports Results of Phase 3 Soft Tissue Sarcoma Study of LARTRUVO&reg;. Eli Lilly and Company. Published January 18, 2019. https://bit.ly/2RXHz1W?rel=0" . Accessed January 18, 2019.
  3. No New Patients Should Start Treatment With Lartruvo After Study Shows Cancer Medicine Does Not Prolong Life. European Medicines Agency. Published January 23, 2019. https://bit.ly/2sIbrkP. Accessed January 24, 2019.
  4. Tap WD, Jones RL, Van Tine BA, et al. Olaratumab and doxorubicin versus doxorubicin alone for treatment of soft-tissue sarcoma: an open-label phase 1b and randomised phase 2 trial.Lancet. 2016;388(10043):488-497.
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