Addition of metastasis-directed therapy to standard-of-care systemic therapy for oligometastatic pancreatic ductal adenocarcinoma (EXTEND): Results of a multicenter, randomized phase II trial.
Authors: Ludmir Ethan B. , Sherry Alexander Dean , Fellman Bryan M. , Liu Suyu , Bathala Tharakeswara , Haymaker Cara L. , Medina-Rosales Marina N. , Holliday Emma B. , Smith Grace L. , Lee Michael Sangmin , Zhao Dan , Smaglo Brandon George , Taniguchi Cullen M. , Koay Eugene Jon , Katz Matthew H. G. , Wolff Robert A. , Das Prajnan , Pant Shubham , Koong Albert C. , Tang Chad 
Published: January 2024

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Background: Standard treatment of oligometastatic pancreatic ductal adenocarcinoma (PDAC) consists of multi-agent chemotherapy, although outcomes remain poor. We tested the hypothesis that the addition of comprehensive metastasis-directed therapy (MDT) to standard-of-care systemic therapy would improve progression-free survival (PFS) compared with systemic therapy alone. Methods: The External Beam Radiation to Eliminate Nominal Metastatic Disease (EXTEND) trial is a multicenter phase II basket trial randomizing patients with ≤ 5 solid tumor metastases 1:1 to MDT plus systemic therapy versus systemic therapy alone. Each histology-specific basket was pre-specified and independently powered for the primary endpoint of PFS; here we present results of the pancreatic cancer basket. Progression was defined by radiographic criteria (RECIST v1.1), clinical events, or death. Patients were stratified at randomization by number of metastases (1-2 vs 3-5), number of prior lines of systemic therapy (0-1 vs 2+), and cancer antigen 19-9 (CA-19-9) level (<90U/ml vs ≥90U/ml). Exploratory endpoints included systemic immune response measures. The cutoff date for the primary analysis was September 1, 2023. ClinicalTrials.gov registration: NCT03599765. Results: Between March 2019 and February 2023, 41 patients with oligometastatic PDAC were randomized and 40 were eligible for PFS analysis (MDT arm: 19 patients; control arm: 21 patients). Baseline characteristics were well-balanced between arms. Thirty-one patients experienced progression or death; median follow-up time for censored patients was 9.9 months. The MDT arm had significantly longer PFS compared to the systemic therapy arm (median PFS 10.3 versus 2.5 months; log-rank p=0.006). After stratification, the estimated PFS hazard ratio was 0.43 (95% confidence interval: 0.20, 0.94; p=0.03) for MDT compared with systemic therapy. There were no grade 3 or greater adverse events with at least possible attribution to MDT, and only one grade 2 adverse event possibly related to treatment in the MDT arm occurred. Increased systemic T-cell stimulatory cytokines, CD8+ T-cell activation, CD8+ T-cell proliferation, and T-cell receptor clonal expansion following treatment were associated with the MDT arm compared with the control arm (all p<0.05). Conclusions: Among patients with oligometastatic PDAC, the combination of MDT plus systemic therapy was associated with improved PFS compared with systemic therapy alone. Further exploration in phase III trials is warranted, as is investigation into the potential therapeutic implications of systemic immune activation associated with MDT receipt. Clinical trial information: NCT03599765 .