Label
Information
Ramucirumab
is an antiangiogenic therapy and may increase the risk of severe
bleeding. Severe GI hemorrhage was reported in patients with gastric
cancer treated with ramucirumab in combination with paclitaxel, and
in patients with CRC treated with ramucirumab in combination with
FOLFIRI. Permanently discontinue ramucirumab in patients who
experience grade 3 or 4 bleeding.1
Incidence
of Bleeding
Clinical
Studies
The
incidence of any grade and grade ≥3 bleeding/hemorrhage in the
phase 3 registration studies is summarized in Table
1.
Table
1. Incidence of Any Grade and Grade ≥3 Bleeding/Hemorrhagea
in Phase 3 Studies2-6
|
|
Any
Grade (%)
|
Grade ≥3
(%)
|
|
REGARD
(second-line gastric cancer)
|
|
Ramucirumab
(n=236)
|
13
|
3
|
|
Placebo
(n=115)
|
11
|
3
|
|
RAINBOW
(second-line gastric cancer)
|
|
Ramucirumab
+ Paclitaxel (n=327)
|
41.9
|
4.3
|
|
Paclitaxel
+ Placebo (n=329)
|
17.9
|
2.4
|
|
REVEL
(second-line NSCLC)
|
|
Ramucirumab
+ Docetaxel (n=627)
|
29
|
2
|
|
Docetaxel
+ Placebo (n=618)
|
15
|
2
|
|
RAISE
(second-line CRC)
|
|
Ramucirumab
+ FOLFIRI (n=529)
|
43.9b
|
2.5
|
|
FOLFIRI
+ Placebo (n=528)
|
22.7
|
1.7
|
|
REACH-2
(second-line HCC)
|
|
Ramucirumab
(n=197)
|
24
|
5
|
|
Placebo
(n=95)
|
13
|
3
|
|
RELAY
(first-line EGFR mutation+ NSCLC)
|
|
Ramucirumab
+ Erlotinib (n=221)c
|
54.8
|
1.8
|
|
Placebo
+ Erlotinib (n=225)
|
26.2
|
1.8
|
Abbreviations:
CRC = colorectal cancer; EGFR = epidermal growth factor receptor;
FOLFIRI = irinotecan, folinic acid, and 5-fluorouracil; HCC =
hepatocellular carcinoma; NSCLC = non-small cell lung cancer.
a
Bleeding/hemorrhage is a consolidated, Medical Dictionary for
Regulatory Activities-preferred term.
b
p<.05.
c
One death occurred on study and was because of a pulmonary
hemorrhage event of hemothorax.
Systematic
Review and Meta-Analysis
A
systematic review and meta-analysis of eligible phase 2 and 3 studies
was conducted to assess the risk of bleeding associated with the use
of ramucirumab for the treatment of patients with solid tumors
(n=5694). Of the 11 studies that were included in the analysis, a
total of 3103 patients received ramucirumab and were included in the
incidence analysis. Nine studies reported bleeding (all grades) and
the incidence ranged from 13% to 44% (relative risk [ramucirumab vs
control]: 1.98 [95% CI: 1.77-2.21; p<.0001]). The relative risk of
high-grade bleeding was 1.08 (95% CI: 0.78-1.5).7
Management
of Bleeding
Permanently
discontinue ramucirumab in patients who experience grade 3 or 4
bleeding.1
References
1.
Cyramza [summary of product characteristics]. Eli Lilly Nederland
B.V., The Netherlands.
2.
Garon EB, Ciuleanu TE, Arrieta O, et al. Ramucirumab plus docetaxel
versus placebo plus docetaxel for second-line treatment of stage IV
non-small-cell lung cancer after disease progression on
platinum-based therapy (REVEL): a multicentre, double-blind,
randomised phase 3 trial. Lancet. 2014;384(9944):665-673.
http://dx.doi.org/10.1016/S0140-6736(14)60845-X
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
4.
Data on file, Eli Lilly and Company and/or one of its subsidiaries.
5.
Zhu AX, Kang YK, Yen CJ, et al. Ramucirumab after sorafenib in
patients with advanced hepatocellular carcinoma and increased
α-fetoprotein concentrations (REACH-2): a randomised,
double-blind, placebo-controlled, phase 3 trial. Lancet Oncol.
2019;20(2):282-296. http://dx.doi.org/10.1016/S1470-2045(18)30937-9
6.
Nakagawa K, Garon EB, Seto T, et al. Ramucirumab plus erlotinib in
patients with untreated, EGFR-mutated, advanced non-small-cell lung
cancer (RELAY): a randomised, double-blind, placebo-controlled, phase
3 trial. Lancet Oncol. 2019;20(12):1655-1669.
https://doi.org/10.1016/S1470-2045(19)30634-5
7.
Abdel-Rahman O, ElHalawani H. Risk of cardiovascular adverse events
in patients with solid tumors treated with ramucirumab: a meta
analysis and summary of other VEGF targeted agents. Crit Rev Oncol
Hematol. 2016;102:89-100.
http://dx.doi.org/10.1016/j.critrevonc.2016.04.003.
Glossary
CRC
= colorectal cancer
EGFR
= epidermal growth factor receptor
FOLFIRI
= irinotecan, folinic acid, and 5-fluorouracil
GI =
gastrointestinal
HCC
= hepatocellular carcinoma
NSCLC
= non-small cell lung cancer