Effect of Doxorubicin Plus Olaratumab vs Doxorubicin Plus Placebo on Survival in Patients With Advanced Soft Tissue Sarcomas: The ANNOUNCE Randomized Clinical Trial

Abstract

Importance: Patients with advanced soft tissue sarcoma (STS) have a median overall survival of less than 2 years. In a phase 2 study, an overall survival benefit in this population was observed with the addition of olaratumab to doxorubicin over doxorubicin alone.

Objective: To determine the efficacy of doxorubicin plus olaratumab in patients with advanced/metastatic STS.

Design, setting, and participants: ANNOUNCE was a confirmatory, phase 3, double-blind, randomized trial conducted at 110 sites in 25 countries from September 2015 to December 2018; the final date of follow-up was December 5, 2018. Eligible patients were anthracycline-naive adults with unresectable locally advanced or metastatic STS, an Eastern Cooperative Oncology Group performance status of 0 to 1, and cardiac ejection fraction of 50% or greater.

Interventions: Patients were randomized 1:1 to receive doxorubicin, 75 mg/m2 (day 1), combined with olaratumab (n = 258), 20 mg/kg in cycle 1 and 15 mg/kg in subsequent cycles, or placebo (n = 251) on days 1 and 8 for up to 8 21-day cycles, followed by olaratumab/placebo monotherapy.

Main outcomes and measures: Dual primary end points were overall survival with doxorubicin plus olaratumab vs doxorubicin plus placebo in total STS and leiomyosarcoma (LMS) populations.

Results: Among the 509 patients randomized (mean age, 56.9 years; 58.2% women; 46.0% with LMS), all were included in the primary analysis and had a median length of follow-up of 31 months. No statistically significant difference in overall survival was observed between the doxorubicin plus olaratumab group vs the doxorubicin plus placebo group in either population (total STS: hazard ratio, 1.05 [95% CI, 0.84-1.30], P = .69, median overall survival, 20.4 months vs 19.7 months; LMS: hazard ratio, 0.95 [95% CI, 0.69-1.31], P = .76, median overall survival, 21.6 months vs 21.9 months). Adverse events of grade 3 or greater reported in 15% or more of total patients with STS were neutropenia (46.3% vs 49.0%), leukopenia (23.3% vs 23.7%), and febrile neutropenia (17.5% vs 16.5%).

Conclusions and relevance: In this phase 3 clinical trial of patients with advanced STS, treatment with doxorubicin plus olaratumab vs doxorubicin plus placebo resulted in no significant difference in overall survival. The findings did not confirm the overall survival benefit observed in the phase 2 trial.

Trial registration: ClinicalTrials.gov Identifier: NCT02451943.

Conflict of interest statement

Conflict of Interest Disclosures: Dr Tap reported receiving a standard budget from Eli Lilly and Company for site participation for this trial. Apart from the submitted work, Dr Tap reported receiving personal fees from Eli Lilly and Company, EMD Serono, Novartis, Eisai, Janssen, Immune Design, Adaptimmune, Daiichi Sankyo, Blueprint, Loxo, GlaxoSmithKline, Agios Pharmaceuticals, and NanoCarrier. In addition, Dr Tap reported having a patent pending to MSKCC/SKI for Companion Diagnostic for CDK4 inhibitors 14/854,329; participating on an advisory board for and having stock ownership of both Certis Oncology Solutions and Atropos Therapeutics; and consulting for Daiichi Sankyo’s FDA Oncologic Drugs Advisory Committee meeting on pexidartinib. All research at Memorial Sloan Kettering is supported in part by a grant from the National Institutes of Health, National Cancer Institute (No. P30 CA008748). Dr Wagner reported receiving grants and personal fees from Eli Lilly and Company for participation in this trial. Apart from the submitted work, Dr Wagner reported receiving personal fees and grants from Daiichi Sankyo and Five Prime Therapeutics; personal fees from Novartis, Deciphera, NanoCarrier, and Epizyne; and grants from Karyopharm, Aadi Bioscience, Plexxikon, and Celldex. Dr Schöffski reported grants to Leuven Cancer Institute from Eli Lilly and Company for participation in this trial. Apart from the submitted work, Dr Schöffski reported payments to Leuven Cancer Institute for consulting or advisory role from Eli Lilly and Company, Plexxikon, Eisai, Loxo, Blueprint Medicines, Ellipses Pharma, Deciphera, Merck, Servier, Genmab, Adaptimmune, Intellisphere, and Transgene and research funding to Leuven Cancer Institute from Eli Lilly and Company, Blueprint Medicines, Boehringer Ingelheim, CoBioRes NV, Eisai, Exelixis, G1 Therapeutics, Novartis, PharmaMar, and Plexxikon. Dr Martin-Broto reported receiving personal fees for consulting or an advisory role from Eli Lilly and Company, PharmaMar, Bayer, Roche, and Daichii; for speakers’ bureaus from PharmaMar; and for research from Novartis, PharmaMar, Eisai, Pfizer, and Bristol-Myers Squibb outside of this work. Dr Ganjoo reported receiving personal fees from Eli Lilly and Company for advisory board participation for this trial. Apart from the submitted work, Dr Ganjoo reported receiving personal fees from Daiichi Sankyo for advisory board participation. Dr Yen reported receiving grants and personal fees, in addition to grants to Taipei Veterans General Hospital and National Yang-Ming University School of Medicine, from Eli Lilly and Company for participation in this trial. Apart from the submitted work, Dr Yen reported receiving grants from Eli Lilly and Company, ONO, TLC, Eisai, and EffPha for clinical trial participation; personal fees from Merck, Deciphera, and Athenex; and personal fees for travel, accommodations, and other meeting expenses from Merck, Roche, ONO, and Eisai. Dr Abdul Razak reported receiving personal fees, in addition to grants to Princess Margaret Cancer Center, from Eli Lilly and Company for participation in this trial. Apart from the submitted work, Dr Abdul Razak reported providing expert testimony to Eli Lilly and Company. Dr Spira reported grants and provision of writing assistance, medicines, equipment, or administrative support to Virginia Cancer Specialists from Eli Lilly and Company for participation in this trial. Dr Spira also reported receiving grants from Eli Lilly during the conduct of the study and grants from Bristol-Myers Squibb, CytomX, Novartis, Roche, Trovagene, Arch, Merck, AbbVie, LAM Pharmaceuticals, Arcus, Loxo, and Amgen; grants, personal fees, and nonfinancial support from Takeda; and grants and personal fees from AstraZeneca outside the submitted work. Dr Kawai reported receiving personal fees for travel to meetings and participation in review activities from Eli Lilly and Company for this trial. Dr Kawai also reported receiving personal fees from Novartis and Eisai outside the submitted work. Dr Le Cesne reported receiving personal fees from Eli Lilly and Company for participation in this trial. Apart from the submitted work, Dr Le Cesne reported receiving personal fees for board membership and lectures from PharmaMar and for lectures from Pfizer, Eisai, and Bayer. Dr Van Tine reported receiving personal fees for travel expenses and study support for this trial from Eli Lilly and Company. Apart from the submitted work, Dr Van Tine reported receiving personal fees for consulting from Eli Lilly and Company, Epizyme, CytRx, Janssen, Bayer, Adaptimmune, Immune Design, Daiichi Sankyo, Plexxikon, and Pfizer; grants to Washington University in St Louis School of Medicine from Pfizer, Merck, and Tracon; personal fees for lectures from Eli Lilly and Company, Janssen, Caris, and Adaptimmune; and travel and research expenses from GlaxoSmithKline. Dr Naito reported receiving personal fees for advisory board participation for this trial from Eli Lilly and Company. Apart from the submitted work, Dr Naito reported receiving personal fees for advisory board participation from Daiichi Sankyo; research grants from Roche; personal fees for participation on speakers’ bureaus from Eli Lilly and Company, Pfizer, Chugai, Eisai, Merck Serono, Taiho, AstraZeneca, Nihon Kayaku, Fuji RI, Roche, Novartis, and Bayer; and personal fees from Mieji Seika. Dr Fedenko reported receiving personal fees for advisory board participation for this trial from Eli Lilly and Company. Apart from the submitted work, Dr Fedenko reported receiving personal fees for participation on speakers’ bureaus from Eli Lilly and Company, Eisai, Merck Serono, AstraZeneca, Roche, and Novartis. Ms Soldatenkova and Drs Shahir, Mo, and Wright are employees and stockholders of Eli Lilly and Company. In addition, Dr Mo reported receiving payment for a patent for dosing regimen assigned to ImClone LCC, a wholly owned subsidiary of Eli Lilly and Company. Dr Jones reported receiving personal fees for consulting apart from the submitted work from Eli Lilly and Company, Adaptimmune, Blueprint, Clinigen, Eisai, Epizyme, Daiichi Sankyo, Deciphera, Immunedesign, Merck, and PharmaMar and personal fees from UpToDate, as well as serving as an unpaid consultant for Tracon. No other disclosures were reported.

Figures

Figure 1.. Flow of Patient Disposition in the Total Soft Tissue Sarcoma Population

PDGFR indicates platelet-derived growth factor receptor. aIndividuals assessed for study eligibility were excluded prior to randomization for any reason other than those prespecified. bA total of 106 patients received 1 dose or more of olaratumab monotherapy. cStudy treatment in either group was discontinued for any reason other than those prespecified. dThe 245 patients who received postdiscontinuation follow-up includes the 1 patient who did not receive intervention due to worsening clinical status preceding death. eThe 236 patients who received postdiscontinuation follow-up includes the 2 patients who did not receive intervention due to worsening clinical status preceding death.

Figure 2.. Overall Survival and Progression-Free Survival in the Total Soft Tissue Sarcoma (STS) and Leiomyosarcoma (LMS) Populations

The curves stop when the number of patients was less than 15%. Tick marks on the curves denote censored observations. In the doxorubicin + placebo and doxorubicin + olaratumab treatment groups, respectively, the median overall survival (interquartile range [IQR]) was 19.7 months (IQR, 9.9-35.5) vs 20.4 months (IQR,10.4-not estimated) in the total STS population and 21.9 months (IQR, 10.8-32.3) vs 21.6 months (IQR, 11.2-not estimated) in the LMS population; the median progression-free survival was 6.8 months (IQR, 2.6-10.7) vs 5.4 months (IQR, 1.4-10.2) in the total STS population and 6.9 months (IQR, 3.1-9.8) vs 4.3 months (IQR, 1.4-11.1) in the LMS population. The median length of follow-up was 31 months in both treatment groups.

Figure 3.. Overall Survival in Prespecified Subgroups in the Total Soft Tissue Sarcoma (STS) Population

ECOG indicates Eastern Cooperative Oncology Group; PDGFR, platelet-derived growth factor receptor. Hazard ratios and 95% CIs (Wald) were estimated using stratified Cox model for overall and unstratified Cox models for subgroups.