Addition of Metastasis-Directed Therapy to Standard of Care for Oligometastatic Disease: Primary Aggregated Analysis of All Baskets from the Phase II Randomized EXTEND Trial
Abstract
PURPOSE We tested the hypothesis that adding metastasis-directed therapy (MDT) to standard-of-care (SOC) systemic therapy improves progression-free survival (PFS) among patients with oligometastatic disease. METHODS EXTEND was a multicenter randomized phase II trial. Patients with 1-5 metastases were randomly assigned to MDT + SOC versus SOC in one of the six baskets (breast, pancreas, kidney, two prostate baskets, and an other basket) with basket-specific stratification and powering. PFS, the primary end point, was prespecified in the per-protocol set within each basket, across all baskets, and across all baskets excluding the prostate baskets. Exploratory end points included circulating tumor DNA (ctDNA) and immune profiling. RESULTS From 2018 through 2023, 521 patients were screened, 350 were randomly assigned, and 334 were analyzed per protocol (MDT + SOC, n = 166; SOC, n = 168). Radiotherapy was used as MDT for 98% of metastases (370/379). Overall, after a median follow-up of 53 months, PFS was improved with MDT + SOC (hazard ratio [HR], 0.54 [95% CI, 0.41 to 0.72], P < .001). Similarly, PFS was improved when excluding the prostate baskets (HR, 0.60 [95% CI, 0.40 to 0.89]). Within each basket, PFS superiority was identified for the pancreas, prostate, and other baskets, whereas the breast and kidney baskets were inconclusive. At enrollment, detectable ctDNA correlated with shorter PFS and survival; by contrast, ctDNA clearance 3 months postenrollment correlated with improved survival. MDT + SOC-induced systemic immune activation was most pronounced among baskets demonstrating PFS superiority. CONCLUSION The phase II EXTEND trial supports the addition of MDT to SOC for oligometastatic disease. Histology-specific efficacy signals were identified for phase III testing. Translational insights suggest the potential for optimizing the definition of oligometastasis using ctDNA and point to systemic immune responses as a possible mechanism of benefit from MDT.
Article Details
Journal Info
Journal of Clinical Oncology
Lippincott Williams & Wilkins
Authors (30)
Alexander D. Sherry
Noah S. Meimoun, BA, Division of Radiation Oncology, Department of Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX; Alexander D. Sherry, MD, Department of Radiation Oncology, The Mayo Clinic, Rochester, MN; Ethan B. Ludmir, MD, Division of Radiation Oncology, Department of Gastrointestinal Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX; and Timothy A. Lin, MD, MBA, Division of Radiation Oncology, Department of Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX
Cara Haymaker
Shuqi Wang
Suyu Liu
3Department of Biostatistics, The University of Texas MD Anderson Cancer Center, Houston, TX
Tharakeswara K. Bathala
Marina N. Medina-Rosales
Department of Translational Molecular Pathology, Division of Pathology and Laboratory Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX
Aaron Seo
Department of Radiation Oncology, Division of Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX
Kieko Hara
Department of Translational Molecular Pathology, Division of Pathology and Laboratory Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX
Jay Reddy
University of Nebrsaka-Lincoln
Stephen G. Chun
Department of Radiation Oncology, Division of Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX
Lauren L. Mayo
Department of Radiation Oncology, Division of Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX
Gary Walker
Shubham Pant
M.D. Anderson Cancer Center, Houston
Dan Zhao
Craig A. Kovitz
Department of General Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX
David Ramirez
Department of Breast Medical Oncology, Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX
Chul S. Ha
Department of Radiation Oncology, The University of Texas Health Science Center at San Antonio, San Antonio, TX
Benjamin D. Smith
Department of Physics, University of Alberta 1 , Edmonton, Alberta T6G 2E1,
Daniel Gomez
Lorenzo Cohen
Albert C. Koong
Department of Gastrointestinal Radiation Oncology, Division of Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX
Alexandre Reuben
Nizar Tannir
Department of Genitourinary Medical Oncology, Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX
Paul G. Corn
Department of Genitourinary Medical Oncology, Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX
Phuoc T. Tran
Bilal A. Siddiqui
Sumit K. Subudhi
Pavlos Msaouel
Ethan B. Ludmir
Noah S. Meimoun, BA, Division of Radiation Oncology, Department of Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX; Alexander D. Sherry, MD, Department of Radiation Oncology, The Mayo Clinic, Rochester, MN; Ethan B. Ludmir, MD, Division of Radiation Oncology, Department of Gastrointestinal Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX; and Timothy A. Lin, MD, MBA, Division of Radiation Oncology, Department of Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX
Chad Tang
Department of Genitourinary Medical Oncology The University of Texas MD Anderson Cancer Center Houston Texas USA