No Survival Benefit With First-Line Ramucirumab Addition In Advanced Gastric Cancer

Patients with metastatic or inoperable adenocarcinoma of the oesophagus, gastro-oesophageal junction or stomach do not benefit from combining ramucirumab with FOLFOX in the first-line setting

medwireNews: Adding ramucirumab to a first-line modified FOLFOX6 regimen does not improve survival in patients with advanced oesophageal, gastro-oesophageal junction or gastric adenocarcinoma, shows a phase II trial.

These findings are in contrast to two phase III trials in which combining ramucirumab with paclitaxel or best supportive care prolonged survival, say the investigators. But they point out that the previous studies were conducted in the second-line setting, and disease biology could differ between the patient populations.

In the current trial, the primary endpoint of progression-free survival (PFS) was a median of 6.4 months for the 84 patients with metastatic or unresectable disease randomly assigned to receive ramucirumab 8 mg/kg every 2 weeks alongside modified FOLFOX6. This did not differ significantly from the 6.7 months observed for their 84 counterparts given placebo plus modified FOLFOX6.

The secondary endpoints of overall survival and objective response rate were also comparable between arms, report Harry Yoon, from Mayo Clinic in Rochester, Minnesota, USA, and team in the Annals of Oncology.

They note that most adverse events of grade 3 or worse did not differ significantly between groups. Nonetheless, premature discontinuation for reasons other than progressive disease (ie, patient or physician decision or toxicity-related) occurred more frequently in the ramucirumab than the placebo arm, at 48% and 16%, respectively.

Certain side effects – such as grade 3 or higher nausea, dehydration and decreased appetite – were more common in ramucirumab- than placebo-treated participants, but the team says that no specific toxicity was implicated for study discontinuation.

Harry Yoon et al wonder whether the increased rate of premature discontinuation could be another reason for the discrepancy between their and previous results.

And indeed, in an exploratory analysis that censored patients who discontinued prematurely for reasons other than progression or death, PFS was more favourable in the ramucirumab than the placebo arm, with a hazard ratio of 0.76.

Ramucirumab was also favoured over placebo in the gastric or gastro-oesophageal junction adenocarcinoma subgroup, for whom median PFS was 9.3 months with the vascular endothelial growth factor receptor-2 inhibitor versus 7.6 months with placebo, but this was not the case for the oesophageal cancer subgroup.

The authors say that their results “have relevance for further development of this agent.” They await results of the phase III RAINFALL trial evaluating first-line ramucirumab “in gastric/[gastro-oesophageal junction] adenocarcinoma combined with different chemotherapy (cisplatin/[fluoropyrimidine]), using more frequent dosing of ramucirumab and excluding tumors arising from the esophagus.”


Yoon HH, Bendell JC, Braiteh FS, et al. Ramucirumab combined with FOLFOX as front-line therapy for advanced esophageal, gastroesophageal junction, or gastric adenocarcinoma: a randomized, double-blind, multicenter Phase II trial. Ann Oncol; Advance online publication 20 October 2016. doi: 10.1093/annonc/mdw423

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