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 Studies2,3
|
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.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