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

Abstract

Prior retrospective and prospective evidence have suggested a potential survival benefit of adding metastasis-directed therapy (MDT) to standard of care systemic therapy for oligometastatic breast cancer. This has led to the increased utilization of MDT in this setting despite the lack of randomized evidence to support this approach. Furthermore, the recent presentation of NRG-BR002 has questioned the value of MDT. Thus, we evaluated whether the addition of MDT to systemic therapy improves PFS in oligometastatic breast cancer. EXTEND (NCT03599765) is a phase II randomized basket trial for multiple solid tumors testing whether the addition of MDT improves PFS. The primary endpoint was pre-specified to be independently assessed and reported for the breast basket when a minimum of 6 months of follow-up had been reached. Patients with ≤5 metastases were randomized to standard of care systemic therapy with or without MDT. The choice of systemic therapy was at the discretion of the treating medical oncologist. Number of metastatic lesions and prior lines of systemic therapy for metastatic disease were used as stratification variables pre-randomization. The primary endpoint was progression-free survival (PFS) defined as time to randomization to date of clinical or radiographic progression or death. The study was designed to have 80% power to detect an improvement in median PFS from 18 to 36 months, with a type I error of 0.1. Between September 2018 to July 2022, 43 patients were randomized. 22 patients were assigned to the MDT arm, and 21 patients to the no MDT arm. Three patients were not evaluable. The MDT arm patients were older vs the no-MDT arm patients (median 61.5 years vs 48 years, p = 0.01). Otherwise, the arms were well-balanced. Overall, 8 patients had triple negative disease (18.6%), and 12 patients (30%) had de novo metastatic disease. Of those patients with de novo presentation randomized to MDT, all except one had the primary tumor treated with surgery and radiation. At a median follow-up of 19.4 months, 20 events were observed. Among the 40 evaluable patients, there were 5 deaths (3 in the MDT arm and 2 in the no MDT arm). There was no difference in PFS between the MDT and no MDT arms (median 15.6 v 24.9 months, p = 0.66). Similarly, there was no difference in the secondary endpoint of time to new metastatic lesion appearance between the MDT and no MDT arms (median 15.6 months vs not reached, p = 0.09). Two grade 3 toxicities were observed in the MDT arm, and 1 in the no MDT arm. Further analysis of correlative translational biomarkers, including immune markers and ctDNA, are ongoing. The addition of MDT to standard of care systemic therapy did not improve PFS or time to new metastatic lesion in patients with oligometastatic breast cancer. This data coupled with the recently presented NRG-BR002 results, suggests there is no benefit to MDT in an otherwise unselected oligometastatic breast cancer population.