LBA 11 - Addition of Metastasis-Directed Therapy to Standard of Care: Primary Aggregate Analysis and Immunologic Correlatives of the Phase II Randomized EXTEND Trial

02:50pm - 03:00pm PT

Room 22/23

Presenter(s)

Alexander Sherry, MD - Mayo Clinic Rochester, Rochester, MN

A. D. Sherry^1,2, C. Haymaker³, S. Wang⁴, S. Liu⁴, T. Bathala⁵, M. Medina-Rosales³, A. Reuben⁶, A. Seo¹, C. S. Ha⁷, J. P. Reddy⁸, S. G. Chun¹, D. Zhao⁹, D. Ramirez¹⁰, N. Tannir¹¹, P. G. Corn¹¹, B. A. Siddiqui¹¹, S. Subudhi¹¹, P. Msaouel^3,11, E. B. Ludmir^4,12, and C. Tang^3,13; ¹Department of Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, ²Department of Radiation Oncology, Mayo Clinic, Rochester, MN, ³Department of Translational Molecular Pathology, Division of Pathology and Laboratory Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, ⁴Department of Biostatistics, The University of Texas MD Anderson Cancer Center, Houston, TX, ⁵Department of Abdominal Imaging, Division of Diagnostic Imaging, The University of Texas MD Anderson Cancer Center, Houston, TX, ⁶Department of Thoracic-Head & Neck Medical Oncology, Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, ⁷University of Texas Health Science Center at San Antonio, San Antonio, TX, ⁸Department of Breast Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, ⁹Department of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, ¹⁰Department of Breast Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, ¹¹Department of Genitourinary Medical Oncology, Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, ¹²Department of Gastrointestinal Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, ¹³Department of Genitourinary Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX

Purpose/Objective(s): Response to metastasis-directed therapy (MDT) for oligometastatic disease varies across tumor histologies, yet few prospective data exist to assess such heterogeneity. EXTEND is a randomized phase II basket trial powered to detect benefits in progression-free survival (PFS) within independent histology-specific “baskets”. Here we present the pre-specified primary efficacy analysis combining all baskets with updated follow-up of previously reported baskets. We leverage the unique basket design and immune correlatives to assess the heterogeneity of the MDT effect.

Materials/Methods: EXTEND (NCT03599765) randomized patients with 1-5 metastases to standard of care (SOC) with or without MDT. Each basket was powered for PFS with a one-sided a of 0.10. Trial processes such as follow-up, response assessment, and collection of correlatives were homogenous between baskets. Peripheral T cell subsets were identified by multiparameter flow cytometry; T cell clonal expansion was defined by paired T cell receptor (TCR) sequencing.

Results: In 2018-2023, 521 patients were screened, 350 were randomized, and 334 were analyzed per-protocol (MDT+SOC, n=166; SOC, n=168). Data were locked on April 1, 2025, after a median follow-up of 53 months (IQR, 38 to 60). PFS was significantly improved in the aggregate population (HR 0.54, 95% CI 0.41 to 0.72) and in the pancreas, prostate, and “other” baskets; no significant differences were identified in the breast or renal baskets (Table). The MDT-related grade =3 toxicity rate was 6% (n=10/166). TCR expansion was greater after MDT+SOC vs SOC, but only among baskets demonstrating PFS improvement (Table). Linear mixed effect models identified interaction (P = 0.06) between activated CD8⁺ T cell dynamics (PD1^- Ki67⁺) with MDT+SOC vs SOC among the baskets meeting the primary endpoint; the induction of this cell subset was also associated with PFS (HR 0.10, 95% CI: 0.03 to 0.33; P < 0.001).

Conclusion: In the largest randomized trial of oligometastatic disease to date, EXTEND affirms the need for disease site-specific trials and identifies candidate tumor histologies meriting phase III evaluation. Translational work linked differences in efficacy signals with histology-specific immune stimulation, which may partly explain the observed differences in MDT efficacy.

Table. Summary of PFS Results and Biomarker Correlates.

Basket	HR (95% CI), P	P for TCR expansion: MDT+SOC vs SOC
Aggregate (N=334)	0.54 (0.41 to 0.72), <0.001	<0.0001
Aggregate without prostate (N=160)	0.60 (0.40 to 0.89), 0.01	0.03
Prostate intermittent ADT (N=87)	0.44 (0.25 to 0.77), 0.003	0.007
Prostate continuous ADT (N=87)	0.56 (0.28 to 1.09), 0.08	0.0002
Pancreas (N=40)	0.40 (0.19 to 0.84), 0.01	0.096
Breast (N=40)	0.73 (0.28 to 1.82), 0.5	0.4
Renal (N=40)	1.03 (0.46 to 2.33), 0.93	1
Other (N=40)	0.41 (0.17 to 0.99), 0.04	n/a