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Open-Label, Multicenter, Randomized, Biomarker-Integrated Umbrella Trial for Second-Line Treatment of Advanced
Choong-Kun Lee1,2, Hyo Song Kim1,2, Minkyu Jung1,2
1Division of Medical Oncology, Department of Internal Medicine, Yonsei Cancer Center, Yonsei University College of Medicine, Seoul, South Korea.
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.
Insights
This study explored targeted agents for advanced gastric cancer (AGC) using an umbrella trial. While overall survival was similar to standard care, the approach proved feasible for screening novel therapies.
Area of Science:
- Oncology
- Clinical Trials
- Genomics
Background:
- Advanced gastric cancer (AGC) presents limited second-line treatment options.
- Biomarker-driven therapies offer potential for personalized treatment strategies.
Purpose of the Study:
- To evaluate targeted agents as second-line treatment for HER2-negative AGC within a standard-of-care (SOC) controlled umbrella trial.
- To assess the feasibility of IHC-based screening and patient allocation for novel targeted agents.
Main Methods:
- HER2-negative AGC patients were screened for druggable targets (EGFR, PTEN loss, PD-L1) using IHC and in situ hybridization.
- Patients were randomized 4:1 to a biomarker-directed targeted agent plus paclitaxel or SOC.
- Primary endpoint was progression-free survival (PFS); secondary endpoints included efficacy and safety.
Main Results:
- 318 patients were randomized; median follow-up was 35 months.
- The biomarker group (n=254) and control group (n=64) showed similar median PFS (3.7 vs 4.0 months) and overall survival (OS) (8.6 vs 8.7 months).
- Afatinib showed marginal PFS benefit in EGFR 3+ patients; nivolumab demonstrated a durable OS benefit (12.0 vs 7.6 months).
Conclusions:
- The biomarker-directed umbrella trial design was feasible for screening novel agents in AGC.
- While the overall biomarker group did not outperform SOC, specific targeted agents showed potential in selected patient subgroups.
- IHC-based screening facilitated effective early evaluation of targeted therapies for AGC.
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