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Authors Sun Young Rha, Choong-kun Lee, Hyo Song Kim, Minkyu Jung, Hyunki Kim, Bae Woo Kyun, Dong-Hoe Koo, Hei-Cheul Jeung, Sook Ryun Park, In Gyu Hwang, Dae Young Zang, Hyun Woo Lee, Sejung Park, Jung Mo Nam, Hyun Cheol Cheol Chung
Title The first report of K-Umbrella Gastric Cancer Study: An open label, multi-center, randomized, biomarker-integrated trial for second-line treatment of advanced gastric cancer (AGC).
Journal Journal of Clinical Oncology
Vol 40
Issue no. 16_suppl
Date June 01, 2022
Abstract Text Background: To explore proper agents for AGC patients as 2nd-line treatment based on optimal biomarker, we conducted K-Umbrella GC study with standard of care (SOC) controlled umbrella trial design. Methods: HER2-negative AGC patients from 6 Korean cancer centers were centrally screened for druggable targets by IHC and in situ hybridization. Patients were randomized to the biomarker vs. control group with SOC as 4:1 ratio. In the biomarker group, patients were treated with specific targeted agents in combination with weekly paclitaxel; 1) EGFR 2+/3+ patients for pan-ERBB inhibitor (afatinib; EGFR cohort), 2) PTEN loss/null (H-score <100) patients for PIK3Cβ inhibitor (GSK2636771; PTEN cohort), and 3) PD-L1+, dMMR/MSI-high, or EBV-related cases for anti-PD-1 inhibitor (nivolumab; NIVO cohort). Control group and NONE cohort in biomarker group without predefined biomarkers were treated with SOC (weekly Paclitaxel±Ramucirumab). Primary endpoint was PFS between control and biomarker groups. Secondary endpoints included efficacy and safety of each cohort. Results: Between Feb 2016 and Feb 2021, total 722 patients were centrally screened. 329 patients were enrolled and randomized to control group (n=63) or biomarker group (n=266; EGFR cohort n=67; PTEN cohort n=42; NIVO cohort n=54; NONE cohort n=103). With a median follow-up of 35 months (95%CI 26.1-55.3), median PFS and OS were 3.8 (95%CI 3.2-4.3) and 8.9 (95%CI 7.8-10.1) months for biomarker group and 4.1 (95%CI 3.0-4.8) and 8.7 months (95%CI 7.2-10.2) for control group. In control group, PTEN loss/null was poor prognostic marker; patients with PTEN loss/null (n=12) showed worse survival compared to PTEN intact patients (n=51) (mPFS, 2.8 vs 4.3 months, P=0.03; mOS, 8.7 vs 9.1 months), where other biomarkers showed similar prognosis. Afatinib for EGFR cohort or GSK2636771 for PTEN cohort did not show significant survival benefit compared to control group (Table). Among patients with immune-related biomarkers, addition of nivolumab showed durable survival benefit (mOS 12.0 vs 7.6 months, P=0.08) compared to SOC. Conclusions: Considering the characteristics of umbrella design with multiple biomarkers having different biological roles, biomarker group did not show the improved survival over control arm with these 3 drugs. For optimal biomarker-driven targeted agent applications, NGS-based biomarker driven K-Umbrella GC-2 study is ongoing. Clinical trial information: NCT02951091.


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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 (2.9 vs 4.1 months) or median overall survival (7.4 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 (Journal of Clinical Oncology 40, no. 16_suppl (June 01, 2022) 4001; NCT02951091). detail...