Y-J Bang1, Y-K Kang2, M Ng3, H C Chung4, Z A Wainberg5, S Gendreau6, W Y Chan7, N Xu8, D Maslyar9, R Meng10, I Chau11, J A Ajani12. 1. Department of Internal Medicine, Seoul National University College of Medicine, 101 Daehak-ro, Jongno-gu Seoul 03080, South Korea. Electronic address: bangyj@snu.ac.kr. 2. Asan Medical Center, University of Ulsan College of Medicine, 88, Olympic-ro 43-gil, Songpa-gu, Seoul 05505, South Korea. Electronic address: ykkang@amc.seoul.kr. 3. National Cancer Centre Singapore, Singapore. Electronic address: matthew.ng.c.h@singhealth.com.sg. 4. 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. Electronic address: unchung8@yuhs.ac. 5. David Geffen School of Medicine at UCLA, Los Angeles, CA 90095, USA. Electronic address: ZWainberg@mednet.ucla.edu. 6. Genentech, Inc., South San Francisco, CA 94080, USA. Electronic address: gendreau.steven@gene.com. 7. Genentech, Inc., South San Francisco, CA 94080, USA. Electronic address: wychan4@gmail.com. 8. Genentech, Inc., South San Francisco, CA 94080, USA. Electronic address: xu.na@gene.com. 9. Genentech, Inc., South San Francisco, CA 94080, USA. Electronic address: dmaslyar@gmail.com. 10. Genentech, Inc., South San Francisco, CA 94080, USA. Electronic address: meng.raymond@gene.com. 11. The Royal Marsden NHS Foundation Trust, Sutton, Surrey, United Kingdom SM2 5PT UK. Electronic address: ian.chau@rmh.nhs.Uk. 12. Department of Gastrointestinal Medical Oncology, Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA. Electronic address: jajani@mdanderson.org.
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).
RCT Entities:
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).
Authors: Mahamat Babagana; Lorin R Brown; Hannah Z Slabodkin; Julia V Kichina; Eugene S Kandel Journal: Int J Mol Sci Date: 2021-10-21 Impact factor: 5.923