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

Gastrointestinal Perforations

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

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

	Grade 3 n (%)	Grade 4 n (%)	Grade 5 n (%)
REGARD
Ramucirumab (n=236)	0	0	2 (<1)
Placebo (n=115)	0	0	1 (<1)
RAINBOW
Ramucirumab + Paclitaxel (n=327)	1 (<1)	2 (<1)	1 (<1)
Placebo + Paclitaxel (n=329)	0	0	0

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.¹ 

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.¹ 

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).¹

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.¹

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 BSC (n=238) or placebo (every 2 weeks) plus BSC (n=117) until disease progression, unacceptable toxicity, withdrawal, or death.³

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 nonmeasurable disease, and TTP 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

References

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

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. 2014;15(11):1224-1235. http://dx.doi.org/10.1016/S1470-2045(14)70420-6

3. 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

Glossary

BSC = best supportive care

ECOG = Eastern Cooperative Oncology Group

GEJ = gastroesophageal junction

GI = gastrointestinal

PS = performance status