Cyramza ® (ramucirumab)

This information is intended for UK registered healthcare professionals only as a scientific exchange in response to your search for information. Please refer to the link for full prescribing information: Cyramza Summary of Product Characteristics (SmPC)

Cyramza® (ramucirumab): Gastrointestinal Perforations

Permanently discontinue Cyramza (ramucirumab) in patients who experience a GI perforation.

Incidence of GI Perforation

Clinical Studies

Table 1 describes the overall and grade ≥3 incidence of GI perforation in phase 3 clinical trials.

Table 1. Incidence of Any Grade and Grade ≥3 GI Perforation in the Phase 3 Clinical Studies1-6


Any Grade (%)

Grade ≥3 (%)

GI Perforation

REGARD (second-line gastric cancer)

Ramucirumab (n=236)

0.8

0.8

Placebo (n=115)

0.9

0.9

RAINBOW (second-line gastric cancer)

Ramucirumab + Paclitaxel (n=327)

1.2

1.2

Paclitaxel + Placebo (n=329)

0.3

0

REVEL (second-line NSCLC)

Ramucirumab + Docetaxel (n=627)

1.0

0.8

Docetaxel + Placebo (n=618)

0.3

0.3

RELAY (first-line EGFR mutation+ NSCLC)

Ramucirumab + Erlotinib (n=221)

0.5

0

Erlotinib + Placebo (n=225)

0

0

RAISE (second-line CRC)

Ramucirumab + FOLFIRI (n=529)

1.7

1.7

FOLFIRI + Placebo (n=528)

0.6

0.6

REACH-2 (second-line HCC)

Ramucirumab (n=197)

1.0

1.0

Placebo (n=95)

2.1

2.1

Abbreviations: 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.

Systematic Review and Meta-Analysis

Three meta-analyses of eligible randomized phase 2 and 3 studies were conducted to assess the risk of GI perforation associated with the use of ramucirumab for the treatment of patients with solid tumors. These analyses included between 6 and 11 studies that evaluated the use of ramucirumab in 2538 to 3103 patients. Of the studies that reported rates of GI perforation, the overall incidence ranged from 1% to 1.5%. The RR (ramucirumab vs control) of all grade GI perforation ranged between 2.56 to 3.29. Two meta-analyses reported RR of high-grade GI perforation with values of 3.37 (95% CI: 1.51-7.54; p=.03) and 3.2 (95% CI: 1.4-7.3).7-9

Management of GI Perforations

Permanently discontinue ramucirumab in patients who experience a GI perforation.10

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

3. 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

4. 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

5. Tabernero J, Yoshino T, Cohn AL, et al. Ramucirumab versus placebo in combination with second-line FOLFIRI in patients with metastatic colorectal carcinoma that progressed during or after first-line therapy with bevacizumab, oxaliplatin, and a fluoropyrimidine (RAISE): a randomised, double-blind, multicentre, phase 3 study. Lancet Oncol. 2015;16(5):499-508. http://dx.doi.org/10.1016/S1470-2045(15)70127-0

6. 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

7. Abdel-Rahman O, ElHalawani H. Risk of oral and gastrointestinal mucosal injury in patients with solid tumors treated with ramucirumab: a systematic review and meta-analysis. Expert Opin Drug Saf. 2015;14(10):1495-1506. http://dx.doi.org/10.1517/14740338.2015.1074677.

8. Wang Z, Zhang J, Zhang L, et al. Risk of gastrointestinal perforation in cancer patients receiving ramucirumab: a meta-analysis of randomized controlled trials. J Chemother. 2016;28(4):328-34. https://doi.org/10.1179/1973947815Y.0000000053

9. Arnold D, Fuchs CS, Tabernero J, et al. Meta-analysis of individual patient safety data from six randomized, placebo-controlled trials with the antiangiogenic VEGFR2-binding monoclonal antibody ramucirumab. Ann Oncol. 2017;28(12):2932-2942. https://doi.org/10.1093/annonc/mdx514

10. Cyramza [summary of product characteristics]. Eli Lilly Nederland B.V., The Netherlands.

Glossary

FOLFIRI = irinotecan, folinic acid, and 5-fluorouracil

GI = gastrointestinal

HCC = hepatocellular carcinoma

NSCLC = non-small cell lung cancer

PBO = placebo

Date of Last Review: November 06, 2019

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