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  • br Conclusions Ipatasertib mFOLFOX compared with

    2019-11-05


    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).
    ª 2018 Elsevier Ltd. All rights reserved.
    1. Introduction
    Activating alterations in the phosphoinositide 3-kinase (PI3K)/Akt pathway are common in human cancers, including gastric/gastroesophageal junction cancer (GC/ GEJC) [1] and can lead to chemoresistance [2]. Aberrant PI3K/Akt pathway activation can occur through mul-tiple mechanisms and is associated with poor prognosis [3]. Up to 36% of GC/GEJC tumours have loss of phosphatase and tensin homolog (PTEN), a negative regulator of PI3K/Akt signalling [3]. PIK3CA mutations are commonly found in GC/GEJC [4]. Increased PI3K protein MPP+ Iodide was observed in 62.9% of patients with GC in a Korean retrospective study and signifi-cantly correlated with tumour invasiveness, phenotype and poor survival [5]. Clinical trials have demonstrated the clinical activity of Akt inhibitors in multiple tumour types, either as monotherapy or in combination with other agents [1,6].
    Ipatasertib (GDC-0068) is a potent, novel, selective, adenosine triphosphate-competitive, small-molecule in-hibitor of all three Akt isoforms. In preclinical cancer xenograft models, ipatasertib demonstrated anti-tumour activity in tumours with high levels of phosphorylated Akt, PTEN loss and PIK3CA mutations [6e10]. Ipata-sertib inhibits PI3K/Akt signalling at clinically achiev-able doses [8]. In a phase I study in patients with diverse solid tumours, ipatasertib was well tolerated, and 34% of patients experienced stable disease [10]. Many of these patients had PI3K/Akt pathwayeactivated tumours, providing the rationale for further clinical studies of 
    ipatasertib in tumours known to harbour activating al-terations in this pathway, including GC/GEJC.
    Akt inhibitors enhance the anti-tumour activity of chemotherapy in GC models [11]. Given that Akt acti-vation is common in GC/GEJC tumours and associated with chemotherapy resistance, treatment with ipata-sertib may potentiate the efficacy of chemotherapy in GC/GEJC. Fluoropyrimidine-based regimens are effec-tive as first-line therapy for advanced GC/GEJC [12]. A randomised, double-blind, placebo-controlled, multi-centre, phase II trial (NCT01896531) compared the ef-ficacy and safety of ipatasertib plus mFOLFOX6 (modified regimen of leucovorin, bolus and infusional 5-fluorouracil [5-FU] and oxaliplatin) versus placebo plus mFOLFOX6 in patients with locally advanced or met-astatic GC/GEJC not amenable to curative therapy.
    2. Methods
    The study was done in accordance with Good Clinical Practice guidelines and the Declaration of Helsinki. Written informed consent was obtained from patients before enrolment, in agreement with approved protocols from ethics committees at each site.
    Eligible patients had histologically confirmed, inoper-able, locally advanced; metastatic; or recurrent GC/ GEJC not amenable to curative therapy. Other eligi-bility criteria included measurable disease per Response
    Evaluation Criteria in Solid Tumors (RECIST) v1.1, Eastern Cooperative Oncology Group performance status (ECOG PS) 0 or 1, life expectancy 12 weeks, and adequate haematologic and organ function. Key exclusion criteria included prior chemotherapy for inoperable locally advanced, metastatic or, recurrent GC/GEJC (neoadjuvant or adjuvant chemotherapy and/ or radiation therapy was allowed if completed 6 months before randomisation); known human epidermal growth factor receptor 2 (HER2)epositive disease; radiation treatment within 28 days of random-isation (palliative radiation treatment to peripheral sites such as bone metastases was permitted if the patient had recovered from all acute, reversible effects and the medical monitor was notified); and previous therapy for GC/GEJC with an Akt, PI3K and/or a mammalian target of rapamycin (mTOR) kinase inhibitor.