Reference Detail

Ref Type

Journal Article

PMID

(37883723)

Authors

Lee CK, Kim HS, Jung M, Kim H, Bae WK, Koo DH, Jeung HC, Park SR, Hwang IG, Zang DY, Lee HW, Park S, Nam CM, Chung HC, Rha SY

Title

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

Journal	Vol	Issue	Date	Pages	Journal Short Title
Journal of clinical oncology : official journal of the American Society of Clinical Oncology			2023 Oct 26	JCO2300971	J Clin Oncol

URL

Abstract Text

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 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.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).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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Molecular Profile	Treatment Approach

Gene Name	Source	Synonyms	Protein Domains	Gene Description	Gene Role

Therapy Name	Drugs	Efficacy Evidence	Clinical Trials

Drug Name	Trade Name	Synonyms	Drug Classes	Drug Description

Gene	Variant	Impact	Protein Effect	Variant Description	Associated with drug Resistance

Molecular Profile	Indication/Tumor Type	Response Type	Therapy Name	Approval Status	Evidence Type	Efficacy Evidence	References
PTEN loss	stomach cancer	no benefit	GSK2636771 + Paclitaxel	Phase II	Actionable	In a Phase II trial (K-Umbrella), GSK2636771 and Taxol (paclitaxel) combination therapy did not significantly improve median progression-free survival (2.8 vs 4.0 months) or median overall survival (7.0 vs 8.7 months) in patients with advanced ERBB2 (HER2)-negative gastric cancer harboring PTEN loss compared to standard of care in the control group (PMID: 37883723; NCT02951091).	37883723
CD274 positive	stomach cancer	no benefit	Nivolumab + Paclitaxel	Phase II	Actionable	In a Phase II trial (K-Umbrella), Opdivo (nivolumab) and Taxol (paclitaxel) combination therapy improved median overall survival (10.7 vs 8.7 months, p=0.046) but not median progression-free survival (3.9 vs 4.0 months) in patients with advanced ERBB2 (HER2)-negative gastric cancer that was MSI high, mismatch repair deficient, or PD-L1 (CD274)-positive compared to standard of care in the control group (PMID: 37883723; NCT02951091).	37883723

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