Eric Van Cutsem, MD, PhD
Invited discussant Eric Van Cutsem, MD, PhD, of the University Hospitals Leuven in Belgium, put the JACOB trial findings in context of what is known for HER2-positive metastatic gastric/gastroesophageal junction cancer, where two targeted agents are approved: trastuzumab (Herceptin) in the first line and ramucirumab (Cyramza) in the second line. A third HER2-targeted agent, ado-trastuzumab emtansine (formerly known as T-DM1; Kadcyla), did not improve outcomes over taxanes alone as second-line therapy in the GATSBY study.1
“The JACOB study is the third large phase III trial in metastatic gastric cancer. It was well designed, with adequate endpoints, in a population that was strongly HER2-positive (ie, 3+ by immunohistochemistry [IHC] or IHC 2+ and positive by fluorescent in situ hybridization),” he noted.
Why Was Primary Endpoint Not Met?
“We saw a separation of the curves—you can see clearly there is some activity for pertuzumab (Perjeta)—but the study did not meet the primary endpoint. The hazard ratio of 0.84 was just above the critical cutoff,” he continued. “There was also a numerical benefit in progression-free survival, but because of the hierarchical testing, it was not statistically significant.”
It is difficult to explain why the primary endpoint was not met, according to Dr. Van Custem. The study was well designed, had appropriate statistical considerations, was balanced between the arms in terms of patient characteristics, and enrolled patients with strong HER2 expression. The study was also similar to the positive ToGA trial in terms of the control arm treatment and its outcomes,2 he pointed out.
The answer may have something to do with gastric cancer’s strong heterogeneity and weak membrane staining, as compared with breast cancer (where dual blockade is superior to single). It is also possible that the cutoffs for HER2 amplification or gene copy number influenced outcomes or that patients received too little chemotherapy in the combination arm, because greater toxicity led to lower dose intensity, he suggested.
Dr. Van Cutsem concluded that it is unlikely these potential factors fully explain the results. “There was activity of the combination, but it was just not enough to meet the primary endpoint.” ■
DISCLOSURE: Dr. Van Cutsem reported no conflict of interest.
1. Thuss-Patience PC, Shah MA, Ohtsu A, et al: Trastuzumab emtansine versus taxane use for previously treated HER2-positive locally advanced or metastatic gastric or gastro-oesophageal junction adenocarcinoma (GATSBY): An international randomised, open-label, adaptive, phase 2/3 study. Lancet Oncol 18:640-653, 2017.
2. Bang YJ, Van Cutsem E, Feyereislova A, et al: Trastuzumab in combination with chemotherapy versus chemotherapy alone for treatment of HER2-positive advanced gastric or gastro-oesophageal junction cancer (ToGA): A phase 3, open-label, randomised controlled trial. Lancet 376:687-697, 2010.