Study design and patients

JACOB ({"type":"clinical-trial","attrs":{"text":"NCT01774786","term_id":"NCT01774786"}}NCT01774786) was a double-blind, placebo-controlled, randomized, multicenter, phase III trial. Details have been published previously [8].

Eligible patients with previously untreated HER2-positive (centrally assessed immunohistochemistry [IHC] 3  + or IHC 2  +  /in situ hybridization [ISH]-positive) GC/GEJC (n = 780) were randomized 1:1 to intravenous pertuzumab (840 mg) / placebo plus trastuzumab (8 mg/kg loading, 6 mg/kg maintenance doses) and chemotherapy (intravenous cisplatin 80 mg/m² plus capecitabine 1000 mg/m² orally twice daily, or intravenous 5-flurouracil 800 mg/m² every 24 h continuously for 120 h) every 3 weeks. Chemotherapy discontinuation during/before cycle 6 was allowed for progressive disease/unacceptable toxicity. Chemotherapy continuation post-cycle 6 was at the discretion of the patient and treating physician. Pertuzumab/placebo and trastuzumab were continued following chemotherapy completion until disease progression, unacceptable toxicity, or withdrawal from the study.

The primary endpoint was OS. Secondary endpoints included progression-free survival (PFS), objective response rate (ORR), duration of response (DoR), and safety. Exploratory endpoints included association of biomarkers with efficacy outcomes.

To assess HER2 heterogeneity further, subgroups were defined by percentages of stained cancer cells, per the following categories: focal staining: 0–29% of cells staining positive for HER2; heterogenous staining: 30–79% of cells staining positive for HER2; and homogenous staining: 80–100% of cells staining positive for HER2. Subgroups were also defined by the gene copy number; this term refers to the number of copies of the HER2 gene that were determined by an in situ hybridization test. An average of 6 copies of the HER2 gene per cell/nucleus was used as a cutoff for this analysis to signify gene amplification. Per the American Society of Clinical Oncology (ASCO) guidelines, a gene copy number of > 6 signifies true amplification, whereas 4–6 copies is considered an equivocal result [9].