Adding Metastasis-Directed Therapy to Standard-of-Care Systemic Therapy for Oligometastatic Breast Cancer (EXTEND): A Multicenter, Randomized Phase 2 Trial

Abstract

Purpose: Prior evidence suggests a progression-free survival (PFS) benefit from adding metastasis-directed therapy (MDT) to standard-of-care (SOC) systemic therapy for patients with some oligometastatic solid tumors. Randomized trials testing this hypothesis in breast cancer have yet to be published. We sought to determine whether adding MDT to SOC systemic therapy improves PFS in oligometastatic breast cancer.

Methods and materials: External Beam Radiation to Eliminate Nominal Metastatic Disease is a multicenter phase 2 randomized basket trial testing the addition of MDT to SOC systemic therapy in patients with ≤5 metastases (NCT03599765). Patients were randomly assigned 1:1 to MDT (definitive local treatment to all sites of disease, plus SOC systemic therapy) or to SOC systemic therapy-only. Primary endpoint was PFS, and secondary endpoints included overall survival, time to subsequent line of systemic therapy, and time to the appearance of new metastases. Exploratory analyses included quality of life and systemic immune response measures.

Results: From September 2018 through July 2022, 22 and 21 patients were randomly assigned to the MDT and no-MDT arms, respectively. At a median follow-up of 24.8 months, PFS was not improved with the addition of MDT to SOC systemic therapy (median PFS 15.6 months MDT vs 24.9 months no-MDT [hazard ratio, 0.91; 95% CI, 0.34-2.48; P = .86]). Similarly, MDT did not improve overall survival, time to subsequent line of systemic therapy, or time to the appearance of new metastases (all P > .05). No significant differences were found in quality of life measures, systemic T-cell activation, or T-cell stimulatory cytokine concentration.

Conclusions: Among patients with oligometastatic breast cancer, the addition of MDT to SOC systemic therapy did not improve PFS. These findings suggest that MDT may have no systemic benefit in otherwise unselected patients with oligometastatic breast cancer, although this trial was limited by a heterogeneous and small sample size and overperformance of both treatment arms.

Fig. 1.

Trial Consolidated Standards of Reporting Trials diagram. Abbreviations: MDT = metastasis-directed therapy; OS = overall survival; PFS = progression-free survival.

Fig. 2.

Primary endpoint. (A) Progression-free survival stratified by randomization arm. (B) Swimmer plot denoting time to progression or death for each patient stratified by randomization arm. Abbreviation: MDT = metastasis-directed therapy.

Fig. 3.

Secondary endpoints. (A) Patterns of progression by treatment arm. (B) Overall survival stratified by randomization arm. (C) Time to subsequent line of systemic therapy stratified by randomization arm. (D) Time to appearance of new lesion stratified by randomization arm. Abbreviation: MDT = metastasis-directed therapy.

Fig. 4.

Immune cell profiling by flow cytometry, cytokine quantification, and T-cell receptor sequencing. Peripheral blood samples were compared at baseline and at initial 3-month follow-up. Asterisks indicate P < .05 for the Wilcoxon matched-pair test with sum of signed ranks (W) score shown. (A) Changes in CD4+ and CD8+ T-cell subpopulations by treatment arm. For flow cytometry gating, parent populations are the CD3+ population for both CD4+ and CD8+, the CD4+ population for markers on CD4+ cells, and CD8+ for markers on CD8+ cells. (B) Changes in circulatory cytokine levels by treatment arm. (C) Numbers of expanded and contracted peripheral T-cell receptor clones by treatment arm calculated using a beta-binomial model with a Benjamin-Hochberg correction. Abbreviations: MDT = metastasis-directed therapy; TCR = T-cell receptor.