Effect of doxorubicin plus olaratumab vs doxorubicin plus placebo on survival in patients with advanced soft tissue sarcomas: The ANNOUNCE randomized clinical trial Journal Article
| Authors: | Tap, W. D.; Wagner, A. J.; Schöffski, P.; Martin-Broto, J.; Krarup-Hansen, A.; Ganjoo, K. N.; Yen, C. C.; Abdul Razak, A. R.; Spira, A.; Kawai, A.; Le Cesne, A.; Van Tine, B. A.; Naito, Y.; Park, S. H.; Fedenko, A.; Pápai, Z.; Soldatenkova, V.; Shahir, A.; Mo, G.; Wright, J.; Jones, R. L.; for the ANNOUNCE Investigators |
| Article Title: | 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. © 2020 American Medical Association. All rights reserved. |
| Keywords: | adult; cancer survival; controlled study; aged; aged, 80 and over; middle aged; survival analysis; leukemia; young adult; major clinical study; overall survival; clinical trial; constipation; drug tolerability; fatigue; mortality; neutropenia; doxorubicin; placebo; advanced cancer; diarrhea; drug safety; hypertension; monotherapy; side effect; conference paper; comparative study; follow up; antineoplastic agent; edema; progression free survival; quality of life; drug eruption; multiple cycle treatment; anemia; leukopenia; mucosa inflammation; nausea; neuropathy; randomized controlled trial; thrombocytopenia; vomiting; antineoplastic combined chemotherapy protocols; proportional hazards models; dehydration; drug administration schedule; monoclonal antibody; abdominal pain; coughing; dizziness; dyspnea; febrile neutropenia; fever; lymphocytopenia; pruritus; sarcoma; alanine aminotransferase; hypokalemia; insomnia; antibodies, monoclonal; proportional hazards model; multicenter study; urinary tract infection; xerostomia; soft tissue sarcoma; sex difference; clinical effectiveness; headache; phase 3 clinical trial; age distribution; inoperable cancer; drug administration; leiomyosarcoma; antibiotics, antineoplastic; gamma glutamyltransferase; double blind procedure; double-blind method; dyspepsia; antineoplastic antibiotic; alopecia; upper respiratory tract infection; placebos; dysgeusia; decreased appetite; musculoskeletal pain; heart ejection fraction; olaratumab; platelet derived growth factor a; response evaluation criteria in solid tumors; infusion related reaction; very elderly; intention to treat analysis; humans; human; male; female; priority journal; oropharynx pain |
| Journal Title: | JAMA - Journal of the American Medical Association |
| Volume: | 323 |
| Issue: | 13 |
| ISSN: | 0098-7484 |
| Publisher: | American Medical Association |
| Date Published: | 2020-04-07 |
| Start Page: | 1266 |
| End Page: | 1276 |
| Language: | English |
| DOI: | 10.1001/jama.2020.1707 |
| PUBMED: | 32259228 |
| PROVIDER: | scopus |
| PMCID: | PMC7139275 |
| DOI/URL: | |
| Notes: | Article -- Export Date: 1 May 2020 -- Source: Scopus |
