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)

Definition, Management and Incidence of Hypertension with Cyramza® (ramucirumab)

Ramucirumab was allowed in patients with controlled hypertension and permanently discontinued if it could not be controlled.

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Management of Hypertension

Label Information

The blood pressure of patients should be monitored before each ramucirumab administration and treated as clinically indicated,

  • Control pre-existing hypertension before starting ramucirumab
  • If the patient experiences severe hypertension, discontinue ramucirumab temporarily until controlled with medical management
  • If the patient experiences significant hypertension that cannot be controlled safely with antihypertensive therapy, discontinue ramucirumab therapy permanently.1

Definition and Management of Hypertension in Clinical Trials

Protocol-Specified Management of Hypertension summarizes the treatment guidelines used to manage hypertension and is specified in the ramucirumab expanded access program protocol. 

According to the protocol, patients who developed hypertension during the study were treated with antihypertensives according to standard medical practice.2

Protocol-Specified Management of Hypertension2

If the hypertension was…

Which was defined as…

And…

Then…

Controlled

<160/100 mg Hg

not associated with symptoms

ramucirumab was continued and antihypertensive therapy was initiated.

symptomatic

ramucirumab was held until symptoms resolved and antihypertensive therapy was initiated.

Grade 3

systolic BP ≥160 mm Hg, diastolic BP ≥100 mm Hg, medical intervention indicated, or more than 1 drug or more intensive therapy than used previously is indicated

not associated with symptoms

ramucirumab was continued with more intensive antihypertensive therapy.

symptomatic

ramucirumab was held until symptoms resolved and antihypertensive therapy was initiated.

occurred more than 2 weeks after initiation of additional antihypertensive therapy

ramucirumab was held while appropriate antihypertensive was continued.

Grade 4

life-threatening consequences (ie, malignant hypertension, transient or permanent neurologic deficit, hypertensive crisis) or urgent intervention indicated

occurred in the presence of appropriate oral medicationa

patients were discontinued from study therapy. 

Refractory

poorly controlled with systolic BP >160 mm Hg or diastolic BP >100 mm Hg for more than 4 weeks

occurred in the presence of appropriate oral medicationa

Abbreviation: BP = blood pressure.  

aMore than 2 oral agents at maximum tolerated doses.

If ramucirumab therapy was held more than once for hypertension, the dose of ramucirumab was reduced upon retreatment to 6 mg/kg every other week.

A second dose reduction to 5 mg/kg every other week was undertaken if an additional postponement of therapy was required.2

Interventions for Hypertension Associated With Ramucirumab Therapy During Clinical Trials

In two phase 3 trials for previously treated gastric or GEJ adenocarcinoma, the median first occurrence of hypertension was 21 days for patients treated with ramucirumab alone and 37 days for patients treated with ramucirumab plus paclitaxel.

1.7% of patients that received ramucirumab monotherapy and 1.5% of patients that received ramucirumab plus paclitaxel required dose delays and dose modifications.

No therapy discontinuations were required, and the severity of hypertension lessened or resolved in most patients. During these trials, 21.2% of patients treated with ramucirumab alone and 37.9% of patients treated with ramucirumab plus paclitaxel initiated new antihypertensive agents.3

Incidence of Hypertension

Clinical Studies

An increased incidence of severe hypertension was reported in patients receiving ramucirumab as compared to placebo, and presented in Incidence of Any Grade and Grade ≥3 Hypertension in the Phase 3 Clinical Studies. In most cases, hypertension was controlled using standard antihypertensive treatment.2

Incidence of Any Grade and Grade ≥3 Hypertension in the Phase 3 Clinical Studies2,4-9

 

Any Grade (%)

Grade ≥3 (%)

Hypertension

REGARD (second-line gastric cancer)

Ramucirumab (n=236)

16.1

7.6

Placebo (n=115)

7.8

2.6

RAINBOW (second-line gastric cancer)a

Ramucirumab + Paclitaxel (n=327)

25.1

14.7

Paclitaxel + Placebo (n=329)

5.8

2.7

REVEL (second-line NSCLC)

Ramucirumab + Docetaxel (n=627)

10.8

5.6

Docetaxel + Placebo (n=618)

4.9

2.1

RELAY (first-line EGFR mutation+ NSCLC)

Ramucirumab + Erlotinib (n=221)

45.2

23.5

Erlotinib + Placebo (n=225)

12.0

5.3

RAISE (second-line CRC)

Ramucirumab + FOLFIRI (n=529)

26.1

11.2

FOLFIRI + Placebo (n=528)

8.5

2.8

REACH-2 (second-line HCC)

Ramucirumab (n=197)

24.9

12.7

Placebo (n=95)

12.6

5.3

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.

aIncludes hypertensive cardiomyopathy.

Systematic Review and Meta-Analysis

A meta-analysis of all completed phase 3 studies and 5 meta-analyses combining eligible phase 2 and 3 studies evaluated the risk of hypertension associated with the use of ramucirumab for the treatment of patients with solid tumors.10-15

These analyses included 1495 to 3103 patients in 6 -11 studies. The incidence of all grade hypertension ranged from 10.8% to 40.5% of patients.

Five analyses found that the risk of developing hypertension was greater in ramucirumab-treated patients with relative risk (RR) between 2.28 and 2.83 for all grade hypertension and RR between 3.58 and 3.73 for high-grade hypertension.10-13,15

One analysis also suggested that hypertension was frequently associated with ramucirumab therapy, with an odds ratio (OR) of 3.60 for any grade of hypertension and 4.16 for grade 3-4 hypertension.14

References

1Cyramza [summary of product characteristics]. Eli Lilly Nederland B.V., The Netherlands.

2Data on file, Eli Lilly and Company and/or one of its subsidiaries.

3Opincar L, Zalcberg J, Fausel C, et al. Hypertension and proteinuria risks during ramucirumab therapy for metastatic gastric cancer [abstract]. Support Care Cancer. 2016;24(suppl 1):S191. https://doi.org/10.1007/s00520-016-3209-z

4Fuchs 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.

5Wilke 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

6Garon 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

7Nakagawa 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

8Tabernero 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

9Zhu 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

10Wang J, Wang Z, Zhao Y. Incidence and risk of hypertension with ramucirumab in cancer patients: a meta-analysis of published studies. Clin Drug Investig. 2015;35(4):221-228. http://dx.doi.org/10.1007/s40261-015-0272-z.

11Abdel-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.

12Qi WX, Fu S, Zhang Q, Guo XM. Incidence and risk of hypertension associated with ramucirumab in cancer patients: a systematic review and meta-analysis. J Cancer Res Ther. 2016;12(2):775-781. http://dx.doi.org/10.4103/0973-1482.148700

13Wang K, Qu X, Wang Y, et al. The impact of ramucirumab on survival in patients with advanced solid tumors: a systematic review and meta-analysis of randomized II/III controlled trials. Clin Drug Investig. 2016;36(1):27-39. https://doi.org/10.1007/s40261-015-0355-x

14Roviello G, Pacifico C, Corona P, Generali D. Risk of hypertension with ramucirumab-based therapy in solid tumors: data from a literature based meta-analysis. Invest New Drugs. 2017;35(4):518-523. https://doi.org/10.1007/s10637-017-0452-1

15Arnold 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

Date of Last Review: July 11, 2019


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