Safety and anti-tumor effects of vismodegib in patients with refractory advanced gastric cancer: A single-arm, phase-II trial

Ryul Kim, Jun Ho Ji, Jung Hoon Kim, Jung Yong Hong, Ho-Yeong Lim, Won Ki Kang, Jeeyun Lee, Seung Tae Kim, Ryul Kim, Jun Ho Ji, Jung Hoon Kim, Jung Yong Hong, Ho-Yeong Lim, Won Ki Kang, Jeeyun Lee, Seung Tae Kim

Abstract

This phase-II study (ClinicalTrials.gov identifier: NCT03052478) aimed to evaluate the efficacy and safety of vismodegib, an inhibitor targeting the Hedgehog signaling pathway, in patients with refractory advanced gastric cancer. Patients with refractory advanced gastric cancer, whose disease had progressed after undergoing standard therapies, were enrolled in this phase-II trial of vismodegib. Vismodegib (150 mg) was administered orally once a day for a 21-day cycle. The primary endpoint was objective response rate, and the secondary endpoints were overall survival and safety profile. Tumor biopsies were obtained before vismodegib treatment. We conducted whole-exome and transcriptome sequencing to analyze biomarkers. Twenty-three patients were enrolled in this study. Among 19 patients who were eligible for response evaluation, only one showed stable disease, yielding a disease control rate of 5.3%. Median overall survival was 74 days (95% confidence interval, 74-151 days). Treatment-related adverse events of any grade were reported in seven patients (31.8%), and most were grade 1 or 2. Whole transcriptome data showed that the Hedgehog signaling pathway was not enriched in patient samples. This is the first clinical trial demonstrating the clinical activity and safety of vismodegib monotherapy in refractory advanced gastric cancer patients. Further well-designed clinical trials should be conducted to select advanced gastric cancer patients who are likely to benefit from vismodegib.

Keywords: Advanced gastric cancer; Hedgehog pathway; Phase II clinical trial; SMO; Vismodegib.

Conflict of interest statement

Competing Interests: The authors have declared that no competing interest exists.

© The author(s).

Figures

Figure 1
Figure 1
Kaplan-Meier estimate of overall-survival.
Figure 2
Figure 2
Genomic characteristics of 13 advanced gastric cancer samples. A. Barplot illustrating each patient's exonic tumor mutational burden. B. Signatures of exonic somatic single-base substitutions (SBSs) delineated by COSMIC signatures. C. Genomic plot with segments highlighting significant amplification (red, above the horizontal line) and deletion (blue, below the horizontal line) regions. The G-score was assigned by the Genomic Identification of Significant Targets in Cancer algorithm (GISTIC; see Supplementary Methods) according to the amplitude of aberration and frequency of occurrence across samples. False Discovery Rate q-values were calculated for the aberrant regions, and regions with a q-value <0.10 were considered significant. Abbreviations: TMB, tumor mutational burden; SNV, single-nucleotide variation; SBS, single-base substitution.
Figure 3
Figure 3
Pathway enrichment in advanced gastric cancer samples. A. Volcano plot showing differentially activated pathways between tumor samples and matched normal blood samples. We performed Gene Set Variation Analysis (GSVA) to screen the most significantly activated or suppressed signaling pathways. B. Gene Set Enrichment Analysis plot showing downregulation of the SMO activation pathway.

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