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

Y. J. Bang; Y. K. Kang; M. Ng; H. C. Chung; Z. A. Wainberg; S. Gendreau; W. Y. Chan; N. Xu; D. Maslyar; R. Meng; I. Chau; J. A. Ajani

doi:10.1016/j.ejca.2018.11.017

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

Y. J. Bang, Y. K. Kang, M. Ng, H. C. Chung, Z. A. Wainberg, S. Gendreau, W. Y. Chan, N. Xu, D. Maslyar, R. Meng, I. Chau, J. A. Ajani

Department of Internal Medicine

Research output: Contribution to journal › Article › peer-review

22 Citations (Scopus)

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).

Original language	English
Pages (from-to)	17-24
Number of pages	8
Journal	European Journal of Cancer
Volume	108
DOIs	https://doi.org/10.1016/j.ejca.2018.11.017
Publication status	Published - 2019 Feb

Bibliographical note

Funding Information:
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.

Funding 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.IC has served as an advisor for AstraZeneca, Bayer, Bristol-Meyers Squibb, Eli Lilly, FivePrime, Merck Serono, Merck Sharp & Dohme and Roche, received research funding from Eli Lilly, Janssen-Cilag, Merck Serono and Sanofi Oncology and honoraria from Eli Lilly.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.

Funding 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.

Publisher Copyright:
© 2018 Elsevier Ltd

All Science Journal Classification (ASJC) codes

Oncology
Cancer Research

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1016/j.ejca.2018.11.017

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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. (2019). 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. European Journal of Cancer, 108, 17-24. https://doi.org/10.1016/j.ejca.2018.11.017

@article{ff8f4b0863794bda813e72cba2893420,

title = "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",

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).",

author = "Bang, {Y. J.} and Kang, {Y. K.} and M. Ng and Chung, {H. C.} and Wainberg, {Z. A.} and S. Gendreau and Chan, {W. Y.} and N. Xu and D. Maslyar and R. Meng and I. Chau and Ajani, {J. A.}",

note = "Funding Information: 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. Funding 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.IC has served as an advisor for AstraZeneca, Bayer, Bristol-Meyers Squibb, Eli Lilly, FivePrime, Merck Serono, Merck Sharp & Dohme and Roche, received research funding from Eli Lilly, Janssen-Cilag, Merck Serono and Sanofi Oncology and honoraria from Eli Lilly.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. Funding 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. Publisher Copyright: {\textcopyright} 2018 Elsevier Ltd",

year = "2019",

month = feb,

doi = "10.1016/j.ejca.2018.11.017",

language = "English",

volume = "108",

pages = "17--24",

journal = "European Journal of Cancer",

issn = "0959-8049",

publisher = "Elsevier Limited",

}

Bang, YJ, Kang, YK, Ng, M, Chung, HC, Wainberg, ZA, Gendreau, S, Chan, WY, Xu, N, Maslyar, D, Meng, R, Chau, I & Ajani, JA 2019, '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', European Journal of Cancer, vol. 108, pp. 17-24. https://doi.org/10.1016/j.ejca.2018.11.017

TY - JOUR

T1 - 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

AU - Bang, Y. J.

AU - Kang, Y. K.

AU - Ng, M.

AU - Chung, H. C.

AU - Wainberg, Z. A.

AU - Gendreau, S.

AU - Chan, W. Y.

AU - Xu, N.

AU - Maslyar, D.

AU - Meng, R.

AU - Chau, I.

AU - Ajani, J. A.

N1 - Funding Information: 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. Funding 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.IC has served as an advisor for AstraZeneca, Bayer, Bristol-Meyers Squibb, Eli Lilly, FivePrime, Merck Serono, Merck Sharp & Dohme and Roche, received research funding from Eli Lilly, Janssen-Cilag, Merck Serono and Sanofi Oncology and honoraria from Eli Lilly.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. Funding 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. Publisher Copyright: © 2018 Elsevier Ltd

PY - 2019/2

Y1 - 2019/2

N2 - 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).

AB - 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).

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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

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Bibliographical note

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UN SDGs

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