Comprehensive molecular characterization of gastric cancer patients from phase II second-line ramucirumab plus
Seung Tae Kim1, Jason K Sa2, Sung Yong Oh3
1Division of Hematology-Oncology, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, 81 Irwon-ro, Gangnam-gu, Seoul, 06351, Republic of Korea.
Background:
Gastric cancer (GC) is a heterogenous disease consisted of several subtypes with distinct molecular traits. The clinical implication of molecular classification has been limited especially in association with treatment efficacy of ramucirumab or various targeted agents.
Methods:
We conducted a prospective non-randomized phase II single-arm trial of ramucirumab plus paclitaxel as second-line chemotherapy in 62 patients with metastatic GC who failed to respond to first-line fluoropyrimidine plus platinum treatment. For integrative molecular characterization, all patients underwent pre-ramucirumab treatment tissue biopsy for whole-exome/whole-transcriptome sequencing to categorize patients based on molecular subtypes. We also systematically performed integrative analysis, combining genomic, transcriptomic, and clinical features, to identify potential molecular predictors of sensitivity and resistance to ramucirumab treatment.
Results:
Sixty-two patients were enrolled in this study between May 2016 and October 2017. Survival follow-up in all patients was completed as of the date of cut-off on January 2, 2019. No patient attained complete response (CR), while 22 patients achieved confirmed partial response (PR), resulting in a response rate (RR) of 35.5% (95% CI, 23.6-47.4). According to TCGA molecular classification, there were 30 GS, 18 CIN, 3 EBV, and 0 MSI tumors. The RR was 33% in GS (10/30), 33% in CIN (6/18), and 100% in EBV-positive GC patients with significant statistical difference for EBV(+) against EBV(-) tumors (P = 0.016; chi-squared test). Moreover, responsive patients were marked by activation of angiogenesis, VEGF, and TCR-associated pathways, while non-responder patients demonstrated enrichments of sonic hedgehog signaling pathway and metabolism activity. Integrative multi-layer data analysis further identified molecular determinants, including EBV status, and somatic mutation in GNAQ to ramucirumab activity.
Conclusions:
Prospective molecular characterization identified a subset of GC patients with distinct clinical response to ramucirumab therapy, and our results demonstrate the feasibility of personalized therapeutic opportunities in gastric cancer.
Trial Registration:
The study was registered on ClinicalTrial.gov ( NCT02628951 ) on June 12, 2015.
Insights
Gastric cancer patients responding to ramucirumab therapy were identified through molecular profiling. This study highlights personalized treatment strategies for gastric cancer based on molecular subtypes and biomarkers.
Area of Science:
- Oncology
- Genomics
- Molecular Biology
Background:
- Gastric cancer (GC) is a heterogeneous disease with distinct molecular subtypes.
- The clinical utility of molecular classification for predicting treatment efficacy, particularly for ramucirumab, remains limited.
Purpose of the Study:
- To investigate the efficacy of ramucirumab plus paclitaxel as second-line chemotherapy in metastatic gastric cancer.
- To perform integrative molecular characterization to identify predictors of response to ramucirumab treatment.
Main Methods:
- A prospective, single-arm, phase II trial involving 62 metastatic gastric cancer patients.
- Whole-exome and whole-transcriptome sequencing were performed on pre-treatment biopsies for molecular subtyping.
- Integrative analysis of genomic, transcriptomic, and clinical data was conducted to identify response predictors.
Main Results:
- The overall response rate (RR) was 35.5% (22/62 patients).
- EBV-positive gastric cancer patients showed a 100% response rate, significantly higher than EBV-negative tumors (P=0.016).
- Responsive patients exhibited activated angiogenesis and VEGF pathways; non-responders showed enriched sonic hedgehog signaling and metabolism pathways. GNAQ mutations were also identified as a determinant.
Conclusions:
- Prospective molecular characterization identified distinct patient subsets with varying responses to ramucirumab.
- The findings support the feasibility of personalized therapeutic strategies in gastric cancer based on molecular profiling.
