SARC041: A phase 3 randomized double-blind study of abemaciclib versus placebo in patients with advanced dedifferentiated liposarcoma.
Abstract
LBA2 Background: Dedifferentiated liposarcoma (DDLS) remains a difficult disease to treat with limited systemic therapy options. Approved drugs offer modest benefit such as trabectedin (median progression-free survival [mPFS] 2.2 months [m]) or eribulin (mPFS 2.0m). The Cyclin-dependent kinase 4 (CDK4) oncogene is ubiquitously amplified in DDLS and is a rational therapeutic target. In single-arm phase 2 studies, treatment with selective CDK4 inhibitors resulted in mPFS 4.2m with palbociclib and mPFS 7.7m with abemaciclib. We hypothesized that treatment with abemaciclib would improve PFS compared to placebo in patients with recurrent or metastatic DDLS. Methods: SARC041 was a phase 3 randomized double-blind study of abemaciclib versus placebo. The study was open at 9 academic medical centers in the USA. Eligible patients (pts) had recurrent or metastatic DDLS (purely well-differentiated liposarcoma excluded), progression of disease by RECIST 1.1 in the 6 months prior to study entry, any number of prior systemic therapies, and adequate organ function and performance status. Pts were stratified by prior lines of therapy (0 vs 1 or more) and randomized 1:1 between abemaciclib 200 mg PO twice a day or matching placebo. Scans were every 6 weeks (every 12 weeks after week 36) and pts with progression of disease on placebo could cross over to open label abemaciclib. The primary endpoint was PFS. The design provided 80% power with two-sided 10% significance level to detect a hazard ratio of 0.6 by log-rank test. Secondary endpoints were overall response rate (ORR), PFS and response rate after crossover, and overall survival (OS). Data cutoff was March 1, 2026. Results: In total, 108 pts were randomized to receive abemaciclib (n = 54) or placebo (n = 54). Demographic/baseline characteristics were generally similar across treatment arms. Abemaciclib demonstrated a statistically significant improvement in PFS at 9.67m vs placebo at 1.52m (hazard ratio [HR] 0.39; 95% confidence interval [CI], 0.25–0.59; p < 0.001). ORR was 9.3% for abemaciclib vs 0% for placebo (p = 0.057). mOS was not reached with abemaciclib vs 25.45m with placebo (HR 0.55; 95% CI, 0.28–1.07; p = 0.077). mPFS after crossover from placebo to abemaciclib was 3.44m (95% CI 2.66, 6.84). ORR after crossover was 4.3% (95% CI 0.53%, 15%). mOS after crossover was 24.03m (95% CI: 11.7, NA). Grade 3 or higher adverse event rates were similar in both arms (p > 0.99). No new safety signals were observed. Conclusions: Abemaciclib demonstrated a statistically significant improvement in PFS vs placebo in pts with dedifferentiated liposarcoma, with an encouraging OS trend. These results support abemaciclib as a new treatment option for dedifferentiated liposarcoma. Clinical trial information: NCT04967521 .
Article Details
Journal Info
Journal of Clinical Oncology
Lippincott Williams & Wilkins
Authors (13)
Mark A. Dickson
Memorial Sloan Kettering Cancer Center, New York, NY
Karla V. Ballman
From the Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda (A.B.A., N.S., S.N., L.L., L.C.), the Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore (J.H.-C.), and the Investigational Drug Branch, Cancer Therapy Evaluation Program, National Cancer Institute, National Institutes of Health, Rockville (H.S., E.S.) — all in Maryland; the Alliance Statistics and Data Management Center, Mayo Clinic, Rochester, MN (K.V.B., M.O., C.M., G.P.B.); AdventHealth Cancer Institute and the University of Central Florida, Orlando (G.S.); Dana–Farber/Harvard Cancer Center, Boston (S.B., B.M.); UNC Lineberger Comprehensive Cancer Center, Chapel Hill (W.Y.K.), and Duke University Medical Center and Duke Cancer Institute, Durham (J.H., S.H.) — both in North Carolina; the University of Kansas Cancer Center, Westwood (R.P.); Memorial Sloan Kettering Cancer Center, New York (M.Y.T., M.J.M., J.E.R.), and Roswell Park Comprehensive Cancer Center, Buffalo (G.C.) — both in...
Mia C. Weiss
Division of Medical Oncology, Washington University, St. Louis, MO
Steven Attia
avin Ratan, MD, MEd, Division of Cancer Medicine, Department of Sarcoma Medical Oncology, University of Texas, MD Anderson Cancer Center, Houston, TX; Bernd Kasper, MD, PhD, Sarcoma Unit, Mannheim University Medical Center, Mannheim Cancer Center, University of Heidelberg, Mannheim, Germany; Thierry Alcindor, MD, MS, Dana Farber Cancer Institute, Harvard Medical School, Boston, MA; Patrick Schöffski, MD, Department of General Medical Oncology, University Hospitals Leuven, Leuven Cancer Institute, KU Leuven, Leuven, Belgium; Winette T. van der Graaf, MD, PhD, Department of Medical Oncology, Netherlands Cancer Institute, Amsterdam, the Netherlands; Noah Federman, MD, Departments of Pediatrics and Orthopedics, UCLA Jonsson Comprehensive Cancer Center, UCLA David Geffen School of Medicine, Los Angeles, CA; Nam Q. Bui, MD, Division of Oncology, Department of Medicine, Stanford University, Stanford, CA; Gina D'Amato, MD, Sylvester Comprehensive Cancer Center, University of Miami Health System, Miami, FL; Richard...
Michael J. Wagner
Seth M. Pollack
Department of Medicine, Division of Hematology and Oncology, Northwestern University, Chicago, IL
Edwin Choy
Massachusetts General Hospital, Boston, MA
Andrew J. Wagner
Fahima Dossa, MD, PhD, Department of Surgery, Cedars-Sinai Medical Center, Los Angeles, CA; Chandrajit P. Raut, MD, Department of Surgery, Mass General Brigham, Harvard Medical School, Boston, MA; Andrew J. Wagner, MD, PhD, Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA; Robin L. Jones, MD, Sarcoma Unit, The Royal Marsden NHS Foundation Trust and Institute of Cancer Research, London, United Kingdom; Rebecca A. Gladdy, MD, PhD, Department of Surgical Oncology, Mount Sinai Hospital and Princess Margaret Cancer Centre, University of Toronto, Toronto, ON, Canada; Abha A. Gupta, MD, Division of Medical Oncology, Princess Margaret Cancer Centre, University of Toronto, Toronto, ON, Canada; Kenneth Cardona, MD, Division of Surgical Oncology, Department of Surgery, Winship Cancer Institute, Emory University, Atlanta, GA; David E. Gyorki, MD, Division of Cancer Surgery, Peter MacCallum Cancer Centre, and Sir Peter MacCallum Department of Oncology, University of Melbourne, Melbourne, VIC, Au...
Breelyn A. Wilky
Lara E. Davis
Knight Cancer Institute, Oregon Health & Science University, Portland, OR
Richard F. Riedel
avin Ratan, MD, MEd, Division of Cancer Medicine, Department of Sarcoma Medical Oncology, University of Texas, MD Anderson Cancer Center, Houston, TX; Bernd Kasper, MD, PhD, Sarcoma Unit, Mannheim University Medical Center, Mannheim Cancer Center, University of Heidelberg, Mannheim, Germany; Thierry Alcindor, MD, MS, Dana Farber Cancer Institute, Harvard Medical School, Boston, MA; Patrick Schöffski, MD, Department of General Medical Oncology, University Hospitals Leuven, Leuven Cancer Institute, KU Leuven, Leuven, Belgium; Winette T. van der Graaf, MD, PhD, Department of Medical Oncology, Netherlands Cancer Institute, Amsterdam, the Netherlands; Noah Federman, MD, Departments of Pediatrics and Orthopedics, UCLA Jonsson Comprehensive Cancer Center, UCLA David Geffen School of Medicine, Los Angeles, CA; Nam Q. Bui, MD, Division of Oncology, Department of Medicine, Stanford University, Stanford, CA; Gina D'Amato, MD, Sylvester Comprehensive Cancer Center, University of Miami Health System, Miami, FL; Richard...
Andrew Koff
Memorial Sloan Kettering Cancer Center, New York, NY
William D. Tap
Memorial Sloan Kettering Cancer Center, New York, NY