Addition of Metastasis-Directed Therapy to Systemic Therapy for Oligometastatic Pancreatic Ductal Adenocarcinoma (EXTEND): A Multicenter, Randomized Phase II Trial

Abstract

Purpose: The EXTEND trial tested the hypothesis that adding comprehensive metastasis-directed therapy (MDT) to chemotherapy would improve progression-free survival (PFS) over chemotherapy alone among patients with oligometastatic pancreatic ductal adenocarcinoma (PDAC).

Methods: EXTEND (ClinicalTrials.gov identifier: NCT03599765) is a multicenter, phase II basket trial randomly assigning patients with ≤five metastases 1:1 to MDT plus systemic therapy versus systemic therapy. Disease progression was defined by radiologic criteria (RECIST v1.1), clinical progression, or death. The primary end point was PFS in the per-protocol population, evaluated after all patients achieved at least 6 months of follow-up. Exploratory end points included systemic immune response measures.

Results: Between March 19, 2019, and February 13, 2023, 41 patients were randomly assigned and 40 were eligible for the primary analysis of PFS (19 patients in the MDT arm; 21 patients in the control arm). At a median follow-up time of 17 months, the median PFS time was 10.3 months (95% CI, 4.6 to 14.0) in the MDT arm versus 2.5 months (95% CI, 1.7 to 5.1) in the control arm. PFS was significantly improved by the addition of MDT to systemic therapy (P = .030 for stratified log-rank test) with a hazard ratio of 0.43 (95% CI, 0.20 to 0.94). No grade ≥3 or greater adverse events related to MDT were observed. Systemic immune activation events were associated with MDT and correlated with improved PFS.

Conclusion: This study supports the addition of MDT to systemic therapy for patients with oligometastatic PDAC. Induction of systemic immunity is a possible mechanism of benefit. These results warrant confirmatory trials to refine treatment strategy and provide external validation.

Figure 1.

CONSORT diagram of trial screening, randomization, and analysis.

Figure 2.

Kaplan-Meier curves comparing metastasis-directed therapy (MDT) plus systemic therapy versus systemic therapy alone for (A) progression-free survival and (B) overall survival.

Figure 3.

Swimmer plot showing patient-level outcomes after randomization for each group. Red squares denote progression; black squares denote death; black lines denote a transition to next-line systemic therapy; stars denote crossover to MDT.

Figure 4.

Changes over time in systemic immune features for the metastasis-directed therapy (MDT) plus systemic arm group and the systemic therapy alone arm. (A) Changes in systemic T cell populations from baseline in the MDT group (first column: end of radiotherapy vs baseline; second column: 3-month follow-up vs baseline) and the control group (third column: 3-month follow-up vs baseline). *p<0.05, Wilcoxon matched-pairs test. (B) Changes in systemic cytokine concentrations from baseline in the MDT group (first column: end of radiotherapy vs baseline; second column: 3-month follow-up vs baseline) and the control group (third column: 3-month follow-up vs baseline). *p<0.05, Wilcoxon matched-pairs test. (C) Number of T cell receptor clones exhibiting expansion (positive y-axis) and contraction (negative y-axis) between 3-month follow-up vs baseline for the MDT group and control group, defined by a beta-binomial model with multiple comparisons adjustment. Each set of positive/negative bars represent an individual patient. (D) T cell receptor clonal expansion and clonal contraction between end of radiotherapy vs baseline for the MDT group.

Figure 5.

Associations of systemic immune features with (A) progression-free survival (PFS) and (B) overall survival (OS) by Cox proportional hazard regression. Factors obtained at the end of radiotherapy (collected only in the MDT arm) were assessed in the MDT arm only. Factors obtained at 3-month follow-up (collected in both arms) were adjusted by using randomization arm as a covariate. Each immune feature was evaluated in its own regression model. Natural-killer type T cells are CD56⁺ CD3⁺ expressing T cells at the end of radiotherapy. Suppressed CD4⁺ T cells are CD73⁺ expressing cells dichotomized at the median at 3-month follow-up. Activated CD4⁺ T cells are PD1⁺ at 3-month follow-up. Activated CD8⁺ T cells are PD1⁺ at 3-month follow-up. Highly activated CD8⁺ T cells are CD25⁺ dichotomized at the median at 3-month follow-up. T cell chemotaxis signaling is the concentration of the cytokine interferon-gamma-induced protein-10 (IP-10) at the end of radiotherapy. Increasing T cell receptor repertoire diversity is the fold change between baseline and end of radiotherapy. Increasing T cell receptor repertoire motif richness is the fold change between baseline and 3-month follow-up.