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Phase 3 trial fails to confirm OS benefit of olaratumab in advanced soft tissue sarcoma
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CHICAGO — The randomized phase 3 ANNOUNCE trial failed to confirm the OS benefit of adding olaratumab to standard doxorubicin for patients with advanced soft tissue sarcoma, according to results presented during the plenary session at ASCO Annual Meeting.
The study outcomes appeared inconsistent with those of a phase 2 trial that showed improved OS and PFS with olaratumab (Lartruvo, Eli Lilly), which received accelerated FDA approval in October 2016 for use in combination with doxorubicin to treat adults with soft tissue sarcoma. Olaratumab went on to receive conditional, accelerated and full approvals in more than 40 countries before the phase 3 study results prompted initiation of the drug’s withdrawal from the market for this patient population.
“Sarcoma has represented an area of great unmet medical need,” William D. Tap, MD, chief of the sarcoma medical oncology service at Memorial Sloan Kettering Cancer Center, said during the presentation. “In the past 5 years, there has been a resurgence of phase 3 clinical trials in sarcoma, including several large first-line studies comparing combination therapies to doxorubicin. None have shown superiority.”
Doxorubicin serves as the current standard of care for patients with metastatic soft tissue sarcoma, among whom median OS ranges from 14 months to 19 months. Olaratumab, a fully human immunoglobin G class 1 monoclonal antibody targeting PDGFR-alpha, showed antitumor activity alone and with doxorubicin in human sarcoma xenograft models.
The combination demonstrated superior PFS and OS (26.5 months vs. 14.7 months; stratified HR = 0.46; 95% CI, 0.3-0.71) compared with doxorubicin and placebo among 129 patients in the phase 2 study.
In the phase 3 study to confirm the OS benefit, researchers randomly assigned 509 patients (median age, 57 years; 41.8% men) with locally advanced or metastatic soft tissue sarcoma to as many as eight 21-day cycles of doxorubicin (75 mg/m² on day 1) with either olaratumab (20 mg/kg on days 1 and 8 of cycle 1, 15 mg/kg on days 1 and 8 of subsequent cycles; n = 258) or placebo (n = 251).
Treatment with olaratumab or placebo continued until disease progression.
Almost half the patients in the study (46%) had leiomyosarcoma, whereas 17.9% had liposarcoma, 12.6% had pleomorphic sarcoma and 23.6% had other subtypes. Researchers stratified randomization by histology, prior systemic therapy ECOG performance score and geographic area.
OS in the intent-to-treat population and/or leiomyosarcoma subset of that population served as the primary endpoint. The study would be considered positive if either endpoint was met. Secondary endpoints included PFS, objective response rate, safety and pharmacokinetics.
The study failed to meet its primary endpoint, with median OS of 20.4 months in the olaratumab arm and 19.7 months in the placebo arm (HR = 1.05; 95% CI, 0.84-1.3) in the intent-to-treat population and 21.6 months vs. 21.9 months in the leiomyosarcoma subset (HR = 0.95; 95% CI, 0.69-1.31).
Patients who received olaratumab vs. placebo demonstrated shorter median PFS in both the intent-to-treat group (5.4 months vs. 6.8 months; HR = 1.23; 95% CI, 1.01-1.5) and the leiomyosarcoma subset (4.3 months vs. 6.9 months; HR = 1.22; 95% CI, 0.92-1.63). The ORR also was lower with olaratumab vs. placebo in both groups (intent-to-treat, 14% vs. 18.3%; leiomyosarcoma subset, 13.4% vs. 22.6%).
The olaratumab and placebo groups demonstrated similar rates of adverse events, including neutropenia (any grade, 55.3% vs. 57.8%; grade 3 or higher, 46.3% vs. 49%), nausea (any grade, 59.5% vs. 66.7%; grade 3 or higher, 2.7% vs. 2.4%) and anemia (any grade, 42.8% vs. 45.4%; grade 3 or higher, 13.6% vs. 12.4%).
“Lilly was surprised and disappointed that Lartruvo did not improve survival for patients with advanced soft tissue sarcoma in this study,” Anne White, president of Lilly Oncology at Eli Lilly and Co., said in a statement posted on the company’s website. “Lilly is committed to helping people who have soft tissue sarcoma and we will carefully study the detailed data in an effort to better understand the different results between the two trials. We are thankful for the patients and physicians who have participated in the ANNOUNCE study.”
Tap said that the phase 2 study may have had different results because of its small sample size and subtype-specific treatments that may have impacted OS rates.
“[This] was a well-controlled and conducted phase 3 trial which failed to meet its OS primary endpoint in all soft tissue sarcoma histologies or the leiomyosarcoma population,” Tap said. “After data readout, the trial sponsor and global regulatory agencies recommended that no new patients start olaratumab. Withdraw of olaratumab is already in progress.” – by John DeRosier
Reference:
Tap WD, et al. Abstract LBA3. Presented at: ASCO Annual Meeting; May 31-June 4, 2019; Chicago.
Disclosures: Tap reports stock ownership in Atropos Pharmaceuticals and Certis Oncology Solutions and consultant/advisory roles with and/or research funding from Agios, BioAtla, Blueprint Medicines, Daiichi Sankyo, Deciphera, Eisai, Eli Lilly, EMD Serono, GlaxoSmithKline, Immune Design, Janssen, Loxo Oncology, Nonocell, Novartis, Plexxikon and TRACON Pharmaceuticals. Please see the abstract for all other authors’ relevant financial disclosures.