title: A Randomized Phase II Study of FOLFOX With or Without the MET Inhibitor Onartuzumab in Advanced Adenocarcinoma of the Stomach and Gastroesophageal Junction.
abstract: The phase II YO28252 study (NCT01590719) examined first-line onartuzumab plus mFOLFOX6 in patients with metastatic, human epidermal growth factor receptor 2-negative adenocarcinoma of the stomach or gastroesophageal junction. MET immunohistochemistry expression as a biomarker of onartuzumab activity was also examined.
  
  
  
  Patients were randomized 1:1 to receive standard mFOLFOX6 plus onartuzumab (10 mg/kg) or placebo in 2-week cycles for 12 cycles, followed by onartuzumab or placebo until disease progression. Coprimary endpoints were progression-free survival (PFS) in intent-to-treat (ITT) and MET-positive populations. The target hazard ratio (HR) was 0.70 for patients in the ITT group and 0.60 in the MET-positive population. Secondary endpoints were overall survival (OS), overall response rate (ORR), and safety.
  
  
  
  Overall, 123 patients were enrolled (n = 62 onartuzumab, n = 61 placebo). Median PFS was 6.77 versus 6.97 months for onartuzumab versus placebo, respectively (HR, 1.08; 95% confidence interval [CI], 0.71-1.63; p = .71). In the MET-positive population, median PFS was 5.95 versus 6.80 months, onartuzumab versus placebo (HR, 1.38; 95% CI, 0.60-3.20; p = .45). Median OS was 10.61 months for onartuzumab versus 11.27 months for placebo) (HR, 1.06, 0.64-1.75; p = .83). In the MET-positive population, median OS was 8.51 versus 8.48 months for onartuzumab versus placebo, respectively (HR, 1.12, 95% CI, 0.45-2.78; p = .80). ORR was 60.5% for the onartuzumab group and 57.1% for placebo. Grade 3-5 adverse events (AEs) were seen in 88.3% of patients receiving onartuzumab and in 78.3% of patients receiving placebo, with serious AEs in 55% and 40%, respectively.
  
  
  
  The addition of onartuzumab to mFOLFOX6 in gastric cancer did not improve efficacy in an unselected population or in a MET immunohistochemistry-positive population.
  
  
  
  The YO28252 study demonstrated that the addition of the anti-MET agent onartuzumab to mFOLFOX6 for treatment of gastric cancer did not improve efficacy in an overall study population or those selected for positive MET status by immunohistochemistry. This highlights the importance of correctly selecting biomarkers for targeted therapies. A multivariate analysis suggested that MET positivity may still be prognostic for worse median overall survival in gastric cancer; therefore, it is important to continue investigation into the optimal approach to inhibit MET signaling in gastric cancer.
authors.affiliation: Weill Cornell Medicine Center for Advanced Digestive Care, New York-Presbyterian Hospital, New York, New York, USA.
authors.forename: Manish A
authors.initials: MA
authors.lastname: Shah
authors.affiliation: Severance Hospital (Gangnam), Seoul, Republic of Korea.
authors.forename: Jae-Yong
authors.initials: JY
authors.lastname: Cho
authors.affiliation: National Cancer Centre, Singapore.
authors.forename: Iain B
authors.initials: IB
authors.lastname: Tan
authors.affiliation: Austin Health, Heidelberg, Australia.
authors.forename: Niall C
authors.initials: NC
authors.lastname: Tebbutt
authors.affiliation: National Cheng Kung University Hospital, Tainan City, Taiwan, Republic of China.
authors.forename: Chia-Jui
authors.initials: CJ
authors.lastname: Yen
authors.affiliation: Roche Product Development in Asia Pacific, Shanghai, People's Republic of China.
authors.forename: Alice
authors.initials: A
authors.lastname: Kang
authors.affiliation: Oncology Biomarker Development, Genentech Inc., South San Francisco, California, USA.
authors.forename: David S
authors.initials: DS
authors.lastname: Shames
authors.affiliation: Roche Product Development in Asia Pacific, Shanghai, People's Republic of China.
authors.forename: Lilian
authors.initials: L
authors.lastname: Bu
authors.affiliation: Asan Medical Center, University of Ulsan, Seoul, Republic of Korea ykkang@amc.seoul.kr.
authors.forename: Yoon-Koo
authors.initials: YK
authors.lastname: Kang
mesh_terms: D000230:Adenocarcinoma / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000911:Antibodies, Monoclonal / Q000008:administration & dosage* / Q000009:adverse effects; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage* / Q000009:adverse effects; D018572:Disease-Free Survival; D004938:Esophageal Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D004943:Esophagogastric Junction / Q000187:drug effects / Q000473:pathology; D005260:Female; D005472:Fluorouracil / Q000008:administration & dosage; D006801:Humans; D002955:Leucovorin / Q000008:administration & dosage; D008297:Male; D008875:Middle Aged; D058990:Molecular Targeted Therapy; D009944:Organoplatinum Compounds / Q000008:administration & dosage; D019859:Proto-Oncogene Proteins c-met / Q000037:antagonists & inhibitors* / Q000235:genetics; D013274:Stomach Neoplasms / Q000188:drug therapy* / Q000473:pathology
chemical_list: D000911:Antibodies, Monoclonal; D009944:Organoplatinum Compounds; C491743:MET protein, human; D019859:Proto-Oncogene Proteins c-met; C584058:onartuzumab; D002955:Leucovorin; D005472:Fluorouracil
keywords: Chemotherapy; First line; Gastric cancer; HER2-negative; MET; Onartuzumab