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<p>Pegenzileukin (SAR444245) is a pegylated recombinant human IL-2 variant designed to expand effector T cells and NK cells without stimulating regulatory T cells. This study evaluated pegenzileukin with pembrolizumab or cetuximab for treating advanced gastrointestinal cancers. A total of 138 patients with advanced gastric cancer (GC), colorectal carcinoma, esophageal squamous cell carcinoma (ESCC), and hepatocellular carcinoma (HCC) were enrolled across seven cohorts in this phase 2 study. Patients received pegenzileukin (24&#xa0;µg/kg every 3&#xa0;weeks [Q3W]) with pembrolizumab (200&#xa0;mg Q3W) or cetuximab (initially 400&#xa0;mg/m<sup>2</sup> and then 250&#xa0;mg/m<sup>2</sup> weekly). The primary endpoint was the objective response rate (ORR). The secondary endpoints were time to response, response duration, clinical benefit rate, progression-free survival (PFS), and safety. Exploratory biomarker analyses assessed immune cell expansion and cytokine levels. The ORR varied across the cohorts, with the highest in ESCC cohort (1/5; 20.0%) and the lowest in GC Cohort 2 and the HCC cohort (1/19; 5.3% and 1/20; 5.0%, respectively). The median PFS was consistent across the cohorts (1.9–2.1&#xa0;months). The most common treatment-emergent adverse events were asthenia (Pegenzileukin + pembrolizumab) and infusion-related reactions (Pegenzileukin + cetuximab). The biomarker analyses demonstrated robust expansion of CD8<sup>+</sup> T cells, CD8<sup>+</sup> Ki67<sup>+</sup> T cells, NK cells, and NK Ki67<sup>+</sup> cells without significant modulation of regulatory T cells. Pegenzileukin with pembrolizumab or cetuximab demonstrated limited efficacy, with a manageable safety profile in advanced GI cancers. The biomarker data supported the mechanism of action involving the upregulation of CD8<sup>+</sup> T cells and NK cells. ClinicalTrials.gov Identifier: NCT05104567.</p>

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Evaluating pegenzileukin (SAR444245/THOR-707) in combination with pembrolizumab or cetuximab in advanced metastatic gastrointestinal cancer: the PEGATHOR phase 2 study

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年6月22日

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  • William P. Harris,
  • Pilar García-Alfonso,
  • Jean Phillipe Metges,
  • Antonio Cubillo-Gracian,
  • Aziz Zaanan,
  • Lopez Lopez Carlos,
  • Monica Ronzoni,
  • Mariano Ponz-Sarvise,
  • Adyb Baakili,
  • Asma Kefsi,
  • Laurent Andrieu,
  • Maria Agrawal,
  • Wenting Wang,
  • Tobias Paehler,
  • Giovanni Abbadessa,
  • Eric Van Cutsem

摘要

Pegenzileukin (SAR444245) is a pegylated recombinant human IL-2 variant designed to expand effector T cells and NK cells without stimulating regulatory T cells. This study evaluated pegenzileukin with pembrolizumab or cetuximab for treating advanced gastrointestinal cancers. A total of 138 patients with advanced gastric cancer (GC), colorectal carcinoma, esophageal squamous cell carcinoma (ESCC), and hepatocellular carcinoma (HCC) were enrolled across seven cohorts in this phase 2 study. Patients received pegenzileukin (24 µg/kg every 3 weeks [Q3W]) with pembrolizumab (200 mg Q3W) or cetuximab (initially 400 mg/m2 and then 250 mg/m2 weekly). The primary endpoint was the objective response rate (ORR). The secondary endpoints were time to response, response duration, clinical benefit rate, progression-free survival (PFS), and safety. Exploratory biomarker analyses assessed immune cell expansion and cytokine levels. The ORR varied across the cohorts, with the highest in ESCC cohort (1/5; 20.0%) and the lowest in GC Cohort 2 and the HCC cohort (1/19; 5.3% and 1/20; 5.0%, respectively). The median PFS was consistent across the cohorts (1.9–2.1 months). The most common treatment-emergent adverse events were asthenia (Pegenzileukin + pembrolizumab) and infusion-related reactions (Pegenzileukin + cetuximab). The biomarker analyses demonstrated robust expansion of CD8+ T cells, CD8+ Ki67+ T cells, NK cells, and NK Ki67+ cells without significant modulation of regulatory T cells. Pegenzileukin with pembrolizumab or cetuximab demonstrated limited efficacy, with a manageable safety profile in advanced GI cancers. The biomarker data supported the mechanism of action involving the upregulation of CD8+ T cells and NK cells. ClinicalTrials.gov Identifier: NCT05104567.