Cyramza ® (ramucirumab)

För fullständig produktresumé för Cyramza® se FASS.

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Cyramza® (ramucirumab): Hjärnmetastaser

RELAY uteslöt patienter med CNS-metastaser. Två patienter som fick ram+erlotinib utvecklade CNS-metastaser vid progression. I REVEL deltog 37 patienter som fick ram+docetaxel med CNS-metastaser.

Brain Metastases in Non-Small Cell Lung Cancer: RELAY

Study Design

The RELAY trial was a phase 3, global, multicenter, randomized, double-blind, placebo-controlled trial in patients (N=449) with previously untreated EGFR mutation-positive, metastatic NSCLC. All patients had an EGFR mutation of exon 19 deletion or exon 21 L858R and an ECOG PS of 0 or 1. Patients were randomly assigned in a 1:1 ratio (stratified by sex, region, EGFR mutation type, and EGFR testing method) to receive treatment with erlotinib (150 mg/day) plus ramucirumab (10 mg/kg every 2 weeks; n=224) or placebo (every 2 weeks; n=225) until disease progression or unacceptable toxicity.1

Exclusion Criteria Related to Brain Metastasis

All patients were required to have brain imaging prior to enrollment and patients with known CNS metastases were excluded from participation in RELAY.2 

CNS Metastasis as Disease Progression

In the RELAY study, 10 patients developed CNS metastasis as first site of progression including

  • 2 patients (0.9%) in the ramucirumab plus erlotinib arm, and 

  • 8 patients (3.6%) in the placebo plus erlotinib arm.2

Considering the small subset of patients who developed brain metastases, no conclusions with regard to efficacy or safety can be drawn at this time. 

Brain Metastases in Non-Small Cell Lung Cancer: REVEL

Study Design

The REVEL trial was a phase 3, multicenter, randomized, double-blind, placebo-controlled trial in patients with pathologically confirmed, squamous or nonsquamous, stage IV NSCLC with disease progression during or after 1 prior platinum-based chemotherapy. Prior treatment with bevacizumab and prior maintenance therapy were allowed and all patients had an ECOG PS of 0 or 1. Patients were randomly assigned in a 1:1 ratio (stratified by sex, region, PS, and previous maintenance therapy) to receive treatment with ramucirumab (10 mg/kg every 3 weeks) plus docetaxel (75 mg/m2 every 3 weeks) (n=628) or placebo plus docetaxel (75 mg/m2 every 3 weeks) (n=625) until disease progression, unacceptable toxicity, withdrawal, or death.3

Inclusion/Exclusion Criteria

In the REVEL trial, patients were excluded if they had untreated CNS metastases.3

Patients with treated brain metastases were eligible if they

  • were clinically stable with regard to neurologic function

  • were off steroids after cranial irradiation (WBRT, focal radiation therapy, and stereotactic radiosurgery) ending at least 2 weeks prior to randomization, or after surgical resection was performed at least 28 days prior to randomization, and

  • had no evidence of grade ≥1 CNS hemorrhage based on retreatment MRI or IV contrast CT scan (performed within 21 days before randomization).3

Patients with CNS Metastases

A total of 4.9% of patients in REVEL had CNS metastatic sites including

  • 37 patients (5.9%) who received ramucirumab plus docetaxel, and

  • 24 patients (3.8%) who received placebo plus docetaxel.4

According to a preplanned subgroup analysis, patients in both treatment groups with CNS metastases had similar OS (HR=1.09; 95% CI: 0.62-1.93) and PFS (HR=1.16; 95% CI: 0.69-1.95). The small population of patients in this subgroup precludes a meaningful assessment of treatment effect in this group of patients.4

Gastric, Colorectal and Hepatocellular Cancer: Exclusion of Patients with CNS Metastases

Patients with documented brain metastases were excluded from the other phase 3 registration trials of ramucirumab.5-8


1. 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.

2. Nakagawa K, Garon E, Seto T, et al. RELAY: A multicenter, double-blind, randomized, phase 3 study of erlotinib (ERL) in combination with ramucirumab (RAM) or placebo (PL) in previously untreated patients with epidermal growth factor receptor (EGFR) mutation-positive metastatic non-small cell lung cancer (NSCLC). Talk presented at: 55th Annual Meeting of the American Society of Clinical Oncology (ASCO); May 31-June 4, 2019; Chicago, IL.

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.

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

5. Fuchs CS, Tomasek J, Yong CJ, et al; for the REGARD Trial Investigators. 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.

6. 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.

7. 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.

8. 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.


CNS = central nervous system

CT = computed tomography

ECOG = Eastern Cooperative Oncology Group

EGFR = epidermal growth factor receptor

HR = hazard ratio

IV = intravenous

MRI = magnetic resonance imaging 

NSCLC = non-small cell lung cancer

OS = overall survival

PFS = progression-free survival

PS = performance status

WBRT = whole brain radiotherapy

Datum fӧr senaste ӧversyn 2019 M11 14

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