Table 1 Inclusion criteria for the INTEGA study

 • All subjects must have inoperable, advanced or metastatic esophagogastric adenocarcinoma.

 • Subjects must have HER2-positive disease defined as either IHC 3+ or IHC 2+, the latter in combination with ISH+, as assessed locally on a primary or metastatic tumor (Note: Availability of formalin-fixed paraffin-embedded (FFPE) representative tumor tissue for central confirmation of HER2 is mandatory (Preferably fresh biopsy))

 • Subject must be previously untreated with systemic treatment (including HER 2 inhibitors) given as primary therapy for advanced or metastatic disease.

 • Prior adjuvant or neoadjuvant chemotherapy, radiotherapy and/or chemoradiotherapy are permitted as long as the last administration of the last regimen (whichever was given last) occurred at least 3 months prior to randomization.

 • Subjects must have measurable or evaluable non-measurable disease as assessed by the investigator, according to RECIST v1.1.

 • ECOG performance status score of 0 or 1.

 • Screening laboratory values must meet the following criteria (using NCI CTCAE v.4.03):

  o WBC ≥ 2000/uL

  o Neutrophils ≥1500/μL

  o Platelets ≥100 × 10³/μL

  o Hemoglobin ≥9.0 g/dL

  o eGFR ≥30 ml/min

  o AST ≤ 3.0 x ULN (or ≤ 5.0X ULN if liver metastases are present)

  o ALT ≤3.0 x ULN (or ≤ 5.0X ULN if liver metastases are present)

  o Total Bilirubin ≤1.5 x ULN (except subjects with Gilbert Syndrome who must have a total bilirubin level of < 3.0 x ULN)

 • Males and Females, ≥ 18 years of age

 • Subjects must have signed and dated an IRB/IEC approved written informed consent form in accordance with regulatory and institutional guidelines. This must be obtained before the performance of any protocol-related procedures that are not part of normal subject care.

 • Subjects must be willing and able to comply with scheduled visits, treatment schedule, laboratory tests and other requirements of the study.

 • Women of childbearing potential (WOCBP) must have a negative serum or urine pregnancy test (minimum sensitivity 25 IU/L or equivalent units of HCG) within 24 h prior to the start of study drug. Women must not be breastfeeding.

 • WOCBP must use a highly effective method(s) of contraception for a period of 30 days (duration of ovulatory cycle) plus the time required for the investigational drug to undergo 5 half-lives. The terminal half-lives of nivolumab and ipilimumab are approximately 25 days and 15 days, respectively. WOCBP should use an adequate method to avoid pregnancy for approximately 5 months (30 days plus the time required for nivolumab to undergo 5 half-lives) after the last dose of investigational drug.

 • Males who are sexually active with WOCBP must agree to follow instructions for method(s) of contraception for a period of 90 days (duration of sperm turnover) plus the time required for the investigational drug to undergo 5 half-lives. The terminal half-lives of nivolumab and ipilimumab are approximately 25 days and 15 days, respectively. Males who are sexually active with WOCBP must continue contraception for approximately 7 months (90 days plus the time required for nivolumab to undergo 5 half-lives) after the last dose of investigational drug. In addition, male subjects must be willing to refrain from sperm donation during this time.