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Cyramza ® (ramucirumab)
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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. https://doi.org/10.1016/S1470-2045(19)30634-5
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. https://meetinglibrary.asco.org/record/173373/abstract
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. 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. http://dx.doi.org/10.1016/S0140-6736(13)61719-5
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. http://dx.doi.org/10.1016/S1470-2045(14)70420-6
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. http://dx.doi.org/10.1016/S1470-2045(15)70127-0
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. http://dx.doi.org/10.1016/S1470-2045(18)30937-9
Glossary
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