Cyramza® (ramucirumab): GI Perforation and Prior Surgery in Gastric Cancer Patients

Study Designs

REGARD Study

The REGARD trial was a phase 3, multicenter, randomized, double-blind, placebo-controlled trial in patients with metastatic or locally advanced gastric or GEJ adenocarcinoma treated previously with fluoropyrimidine- or platinum-based combination therapy with an ECOG PS of 0 or 1. Patients were randomly assigned in a 2:1 ratio (stratified by weight loss, region, and location of the primary tumor) to receive ramucirumab (8 mg/kg every 2 weeks) plus best supportive care (n=238) or placebo (every 2 weeks) plus best supportive care (n=117) until disease progression, unacceptable toxicity, withdrawal, or death.¹

RAINBOW Study

The RAINBOW trial was a phase 3, multicenter, randomized, double-blind, placebo-controlled trial in patients with metastatic or locally advanced nonresectable gastric or GEJ adenocarcinoma following disease progression during or within 4 months after last dose of first-line platinum plus fluoropyrimidine combination chemotherapy with or without an anthracycline and an ECOG PS of 0 or 1. Patients were randomly assigned in a 1:1 ratio (stratified by region, measurable vs non-measurable disease, and time to progression on first–line therapy) to receive ramucirumab (8 mg/kg days 1 and 15) plus paclitaxel (80 mg/m² days 1, 8, and 15) (n=330) or placebo (days 1 and 15) plus paclitaxel (80 mg/m² days 1, 8, and 15) (n=335) of a 28-day cycle until disease progression, unacceptable toxicity, withdrawal, or death.²

Gastrointestinal Perforations

The incidence of grade ≥3 GI perforations among patients in the REGARD and RAINBOW studies is summarized in Table 1. Incidence of GI Perforation Among Patients in the REGARD and RAINBOW Studies.

Table 1. Incidence of GI Perforation Among Patients in the REGARD and RAINBOW Studies^2,3

Abbreviation: GI = gastrointestinal. 

The specific risk of hemorrhagic perforation in the population of patients who had prior surgery is not known because this was not a stratification factor in either trial; however, additional details regarding location of GI perforation and prior surgery are summarized below.^1-3

REGARD Study

In the REGARD study, 2 GI perforation events were observed in patients who received ramucirumab: 1 colon perforation and 1 intestinal perforation. One patient in the placebo arm experienced a colon perforation. All 3 of these events were fatal and investigators assessed the events as probably or definitely related to study treatment.³ 

Of these 3 patients, only 1 patient received prior tumor-related surgery. The patient who received ramucirumab and placebo and experienced an intestinal perforation had received a prior gastrectomy.³ 

RAINBOW Study

In the RAINBOW study, 4 GI perforation events were observed in patients who received ramucirumab plus paclitaxel

• GI perforation (grade 3)

• GI perforation (grade 5)

• diverticular perforation (grade 4), and

• intestinal perforation (grade 4).³

Of these 4 patients, only 1 received prior tumor-related surgery. The patient who received ramucirumab and paclitaxel and experienced a grade 3 GI perforation had received prior gastrojejunostomy.³

References

1. Fuchs CS, Tomasek J, Yong CJ, et al. Ramucirumab monotherapy for previously treated advanced gastric or gastro-oesophageal junction adenocarcinoma (REGARD): an international, randomised, multicentre, placebo-controlled, phase 3 trial. Lancet. 2014;383(9911):31-39. http://dx.doi.org/10.1016/S0140-6736(13)61719-5.

2. Wilke H, Muro K, Van Cutsem E, et al. Ramucirumab plus paclitaxel versus placebo plus paclitaxel in patients with previously treated advanced gastric or gastro-oesophageal junction adenocarcinoma (RAINBOW): a double-blind, randomised phase 3 trial. Lancet Oncol. 2014a;15(11):1224-1235. http://dx.doi.org/10.1016/S1470-2045(14)70420-6

3. Data on file, Eli Lilly and Company and/or one of its subsidiaries.

Glossary

ECOG = Eastern Cooperative Oncology Group

GEJ = gastroesophageal junction

GI = gastrointestinal

PS = performance status