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Open-Label, Multicenter, Randomized, Biomarker-Integrated Umbrella Trial for Second-Line Treatment of Advanced Gastric Cancer: K-Umbrella Gastric Cancer Study

Purpose: This study aimed to screen targeted agents as second-line treatment with a standard-of-care (SOC) controlled umbrella trial design in advanced gastric cancer (AGC).

Patients and methods: Patients with HER2-negative AGC from eight Korean cancer centers were screened for druggable targets using immunohistochemistry (IHC) and in situ hybridization, and randomly assigned to the biomarker versus control group at a 4:1 ratio. In the biomarker group, patients were treated with specific targeted agent plus paclitaxel: pan-ERBB inhibitor for epidermal growth factor receptor (EGFR) 2+/3+ patients (afatinib; EGFR cohort), PIK3Cβ inhibitor for phosphatase and tensin homolog (PTEN) loss/null patients (GSK2636771; PTEN cohort), and anti-PD-1 inhibitor for PD-L1+, deficient mismatch repair/microsatellite instability-high, or Epstein-Barr virus-related cases (nivolumab; NIVO cohort). NONE cohort in the biomarker group without predefined biomarkers and control group received SOC (paclitaxel with or without ramucirumab). The primary end point was progression-free survival (PFS), and the secondary end points were efficacy and safety.

Results: A total of 318 patients were randomly assigned into the control (n = 64) and biomarker (n = 254; EGFR, n = 67; PTEN, n = 37; NIVO, n = 48; NONE, n = 102) groups. Median follow-up was 35 months. Median PFS and overall survival (OS) were 3.7 (95% CI, 3.1 to 4.1) and 8.6 (95% CI, 7.6 to 9.8) months in the biomarker group and 4.0 (95% CI, 3.0 to 4.6) and 8.7 (95% CI, 7.1 to 9.9) months in the control group. Afatinib addition led to marginal survival benefits to patients with EGFR 3+ compared with SOC (PFS, 4.0 v 2.2 months; P = .09), but GSK2636771 did not prolong the survival of patients with PTEN loss. Addition of nivolumab showed a durable survival benefit (median OS, 12.0 v 7.6 months; P = .08).

Conclusion: Although biomarker group did not show better survival than the control group, IHC-based screening and allocation of patients with AGC to the second-line treatment in an umbrella design were feasible for effective early screening of novel agents.

 

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**Title:** Early Screening of Targeted Agents in Advanced Gastric Cancer: A Controlled Umbrella Trial

**Abstract:**

**Background:** Advanced gastric cancer (AGC) poses significant challenges in terms of treatment options. This study aimed to assess the efficacy and safety of targeted agents as second-line treatment alongside standard-of-care (SOC) in AGC patients through a controlled umbrella trial design.

**Methods:** HER2-negative AGC patients from eight Korean cancer centers were screened for druggable targets using immunohistochemistry (IHC) and in situ hybridization. Patients were randomly assigned to either the biomarker group (receiving specific targeted agents based on biomarkers) or the control group (receiving SOC). The biomarker group was further divided into subgroups: EGFR cohort (treated with afatinib for EGFR 2+/3+ patients), PTEN cohort (treated with GSK2636771 for PTEN loss/null patients), NIVO cohort (treated with nivolumab for PD-L1+, deficient mismatch repair/microsatellite instability-high, or Epstein-Barr virus-related cases), and NONE cohort (without predefined biomarkers). Progression-free survival (PFS) was the primary endpoint, and secondary endpoints included efficacy and safety.

**Results:** A total of 318 patients were assigned to the control (n = 64) and biomarker (n = 254) groups. Median follow-up was 35 months. In the biomarker group, median PFS was 3.7 months, and overall survival (OS) was 8.6 months. In the control group, median PFS was 4.0 months, and OS was 8.7 months. Afatinib demonstrated marginal survival benefits for EGFR 3+ patients compared to SOC. GSK2636771 did not significantly prolong survival for PTEN loss patients. Nivolumab addition showed a durable survival benefit.

**Conclusion:** While the biomarker group did not exhibit superior survival compared to the control group, the study demonstrated the feasibility of IHC-based screening and patient allocation in an umbrella design. This approach allowed for early screening of novel agents in AGC, offering valuable insights into the potential of targeted therapies in this challenging disease.

Related Products

Cat.No. Product Name Information
S8002 GSK2636771 GSK2636771 is a potent, orally bioavailable and selective inhibitor of PI3Kβ with >900-fold selectivity over PI3Kα/PI3Kγ and >10-fold over PI3Kδ. Sensitive to PTEN null cell lines.

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