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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
a Department of Internal Medicine, Seoul National University College of Medicine, 101 Daehak-ro, Jongno-gu Seoul 03080, South Korea b Asan Medical Center, University of Ulsan College of Medicine, 88, Olympic-ro 43-gil, Songpa-gu, Seoul 05505, South Korea
c National Cancer Centre Singapore, Singapore
d Department of Medical Oncology, Yonsei Cancer Center, Yonsei University College of Medicine, Yonsei University Health System, Yonsei-ro 50-1 Seodaemun-gyu Shinchon-dong 134 Seoul 03722, South Korea e David Geffen School of Medicine at UCLA, Los Angeles, CA 90095, USA
g The Royal Marsden NHS Foundation Trust, Sutton, Surrey, United Kingdom SM2 5PT UK
h Department of Gastrointestinal Medical Oncology, Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
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
* Corresponding author: Department of Gastrointestinal Medical Oncology, Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd, Houston, TX 77030 USA.
Uk (I. Chau), [email protected] (J.A. Ajani). 1 Associated at time of study.
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)elow patients. Secondary end-points included PFS in patients with PI3K/Akt pathwayeactivated 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 in-terval [CI], 5.7e7.5) with ipatasertib/mFOLFOX6 versus 7.5 months (90% CI, 6.2e8.1) with placebo/mFOLFOX6 (hazard ratio, 1.12; 90% CI, 0.81e1.55; P Z 0.56). No statistically sig-nificant PFS benefit was observed in biomarker-selected patient subgroups (PTEN-low and PI3K/Akt pathwayeactivated tumours) with ipatasertib/mFOLFOX6 versus placebo/mFOL-FOX6. 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 treat-ment 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.