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. (February 2019)

• Record Type: Journal Article
• Authors: Bang, Y.-J.; Kang, Y.-K.; Ng, M.; Chung, H.C.; Wainberg, Z.A.; Gendreau, S.; Chan, W.Y.; Xu, N.; Maslyar, D.; Meng, R.; Chau, I.; Ajani, J.A.
• Is Part Of: European journal of cancer. Volume 108(2019)
• Page Start: 17
• Page End: 24
• Publication Date: 2019-02
• Subjects: Ipatasertib -- Gastric cancer -- Gastroesophageal junction cancer -- mFOLFOX6 -- Akt inhibitor; Cancer -- Periodicals; Neoplasms -- Periodicals; Cancer -- Périodiques; Cancer; Tumors; Electronic journals; Periodicals; Electronic journals; 616.994
• DOI: 10.1016/j.ejca.2018.11.017
• Languages: English
• ISSNs: 0959-8049

Abstract

Abstract: Background: 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. Patients and methods: 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. Results: 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. Conclusions: Ipatasertib/mFOLFOX6 compared with placebo/mFOLFOX6 did not improve PFS in unselected or biomarker-selected patients. No unexpected safety concerns were observed. Trial registration: ClinicalTrials.gov (NCT01896531). Highlights: Ipatasertib + mFOLFOX6 did not improve PFS in patients with GC/GEJC. PFS benefit was not observed in biomarker-selected patients. No new safety signals were observed when ipatasertib was added to mFOLFOX6.