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  • br Although ipatasertib did not improve PFS in this trial

    2019-11-05


    Although ipatasertib did not improve PFS in this trial, it has demonstrated efficacy in other advanced malignancies. In the phase II LOTUS trial in metastatic triple-negative breast cancer, first-line treatment with ipatasertib com-bined with paclitaxel yielded modest improvement in PFS in the ITT population, with greater improvement observed in patients with PIK3CA/Akt1/PTEN pathwayeactivated tumours [6]. A phase Ib/II study in metastatic castration-resistant prostate cancer previously treated with docetaxel demonstrated improved PFS with ipatasertib plus the anti-androgen abiraterone versus pla-cebo plus abiraterone, particularly in patients with PTEN-loss tumours [21].
    Safety results were generally consistent with known safety profiles of PI3K/Akt pathway inhibitors [1] and results reported in previous ipatasertib studies (mostly gastrointestinal-related AEs and grade 1e2 severity), with no new or unexpected safety concerns [6,10]. More AEs leading to dose withdrawal and/or P 22077 and more deaths occurred with ipatasertib/mFOLFOX6 versus placebo/mFOLFOX6. AEs leading to withdrawal due to any component of the mFOLFOX6 regimen were more common in patients in the ipatasertib versus pla-cebo arms. The dose intensity of mFOLFOX6 did not appear to be affected by ipatasertib. However, the lower dose intensity of ipatasertib/placebo and/or higher rate of withdrawals in the ipatasertib arm due to toxicity may have contributed to lower-than-expected efficacy. In regard to the patient who died from cardiac arrest, no clinically significant cardiovascular safety signals were identified from the ipatasertib non-clinical studies. Furthermore, cardiac toxicity has not been reported as an identified or potential risk with ipatasertib administration in other clinical studies in patients with metastatic triple-negative breast cancer or metastatic prostate cancer. It is noted that this patient discussed in the study did develop severe chest pain during the infusion of fluorouracil.
    5. Conclusions
    In conclusion, although this study did not meet its pri-mary end-point of improved PFS in patients with GC/ GEJC treated with ipatasertib/mFOLFOX6 compared with placebo/mFOLFOX6, ipatasertib is biomass being explored in other studies at lower doses to improve tolerability [6].
    Funding
    This work was supported by F. Hoffmann-La Roche Ltd. and Genentech, Inc., a member of the Roche Group. No grant number is applicable. 
    Data sharing
    Qualified researchers may request access to individual patient-level data through the clinical study data request platform (www.clinicalstudydatarequest.com). Further details on Roche’s criteria for eligible studies are available here (https://clinicalstudydatarequest.com/
    Study-Sponsors/Study-Sponsors-Roche.aspx). For further details on Roche’s Global Policy on the Sharing of Clinical Information and how to request access to related clinical study documents, see here (https://www.roche.com/research_and_development/ who_we_are_how_we_work/clinical_trials/our_ commitment_to_data_sharing.htm).
    Author contributions
    JA provided study concepts and study design; HCC, MN, YKK, YB, JA and IC helped in data acquisition; HCC assisted in quality control of data and algorithms; HCC, MN, NX, YKK, YB, WC, JA and IC contributed toward data analysis and interpretation; NX helped in statistical analysis; and all the authors took part in manuscript preparation, editing and review.
    Conflict of interest
    YJB has been a consultant/advisor for ADC Thera-peutics, 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, Mac-roGenics, Merck Serono, Merck Sharp & Dohme, Novartis, Ono, Otsuka, Pfizer, Taiho and Takeda.