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).
Bibliographical noteFunding Information:
This work was supported by F. Hoffmann-La Roche Ltd . and Genentech, Inc., a member of the Roche Group. No grant number is applicable.
YJB has been a consultant/advisor for ADC Therapeutics, AstraZeneca, Bayer, Bristol-Myers Squibb, Eli Lilly, FivePrime, Genentech/Roche, Green Cross, Merck Serono, Merck Sharp & Dohme, Novartis, Ono, Pfizer, Samyang Biopharm, Taiho and Takeda and has received research grants from Astellas , AstraZeneca , Bayer , BeiGene , Boehringer Ingelheim , Boston Biomedical , Bristol-Meyers Squibb , CKD Pharma , Curis , Daiichi Sankyo , Eli Lilly , FivePrime , Genentech / Roche , GlaxoSmithKline , Green Cross , Hanmi , MacroGenics , Merck Serono , Merck Sharp & Dohme , Novartis , Ono , Otsuka , Pfizer , Taiho and Takeda .
HCC has received research grants from Eli Lilly , GlaxoSmithKline , Merck Serono , Merck Sharp & Dohme , Ono and Taiho , served on speakers bureaus for Eli Lilly, Foundation Medicine and Merck Serono and has been a consultant for Bristol-Meyers Squibb, Celltrion, Eli Lilly, Merck Serono, Merck Sharp & Dohme, Quintiles and Taiho.
We thank the patients and their families who participated in the study and all the investigators and their staff. Medical writing assistance was provided by Health Interactions, Inc. and funded by F. Hoffmann-La Roche Ltd .
© 2018 Elsevier Ltd
All Science Journal Classification (ASJC) codes
- Cancer Research