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Ref Type Journal Article
PMID (30592991)
Authors Bang YJ, Kang YK, Ng M, Chung HC, Wainberg ZA, Gendreau S, Chan WY, Xu N, Maslyar D, Meng R, Chau I, Ajani JA
Title A phase II, randomised study of mFOLFOX6 with or without the Akt inhibitor ipatasertib in patients with locally advanced or metastatic gastric or gastroesophageal junction cancer.
Journal European journal of cancer (Oxford, England : 1990)
Vol 108
Issue
Date 2019 02
URL
Abstract Text Akt activation is common in gastric/gastroesophageal junction cancer (GC/GEJC) and is associated with chemotherapy resistance. Treatment with ipatasertib, a pan-Akt inhibitor, may potentiate the efficacy of chemotherapy in GC/GEJC.In this randomised, double-blind, placebo-controlled, multicentre, phase II trial, patients with locally advanced or metastatic GC/GEJC not amenable to curative therapy were randomised 1:1 to receive ipatasertib or placebo, plus mFOLFOX6 (modified regimen of leucovorin, bolus and infusional 5-fluorouracil [5-FU], and oxaliplatin). The co-primary end-point was progression-free survival (PFS) in the intent-to-treat (ITT) population and in phosphatase and tensin homolog (PTEN)-low patients. Secondary end-points included PFS in patients with PI3K/Akt pathway-activated tumours; overall survival, investigator-assessed objective response rate and duration of response in the ITT population; and safety assessments.In 153 enrolled patients, the median PFS (ITT) was 6.6 months (90% confidence interval [CI], 5.7-7.5) with ipatasertib/mFOLFOX6 versus 7.5 months (90% CI, 6.2-8.1) with placebo/mFOLFOX6 (hazard ratio, 1.12; 90% CI, 0.81-1.55; P = 0.56). No statistically significant PFS benefit was observed in biomarker-selected patient subgroups (PTEN-low and PI3K/Akt pathway-activated tumours) with ipatasertib/mFOLFOX6 versus placebo/mFOLFOX6. Other secondary end-points did not favour the ipatasertib/mFOLFOX6 treatment arm. The percentages of patients with ≥1 adverse event (AE, 100% versus 98%) and grade ≥3 AEs (79% versus 74%) were similar between arms. Higher rates of AEs leading to treatment withdrawal (16% versus 6%) and serious AEs were reported in the ipatasertib arm (54% versus 43%). Thirty-nine and 29 deaths occurred in the ipatasertib and placebo arms, respectively.Ipatasertib/mFOLFOX6 compared with placebo/mFOLFOX6 did not improve PFS in unselected or biomarker-selected patients. No unexpected safety concerns were observed.ClinicalTrials.gov (NCT01896531).

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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 dec exp gastroesophageal cancer no benefit Fluorouracil + Ipatasertib + Leucovorin + Oxaliplatin Phase II Actionable In a Phase II trial, the combination of Ipatasertib (GDC-0068) and mFOLFOX6 did not improve median progression-free survival (7.1 vs 7.4 months; HR=1.07, p=0.86) compared to placebo plus mFOLFOX6 in patients with advanced gastroesophageal junction or gastric cancer harboring decreased PTEN expression (IHC=0 in >10% of tumor cells) (PMID: 30592991; NCT01896531). 30592991
PTEN dec exp stomach cancer no benefit Fluorouracil + Ipatasertib + Leucovorin + Oxaliplatin Phase II Actionable In a Phase II trial, the combination of Ipatasertib (GDC-0068) and mFOLFOX6 did not improve median progression-free survival (7.1 vs 7.4 months; HR=1.07, p=0.86) compared to placebo plus mFOLFOX6 in patients with advanced gastric or gastroesophageal junction cancer harboring decreased PTEN expression (IHC=0 in >10% of tumor cells) (PMID: 30592991; NCT01896531). 30592991