Cyramza® (ramucirumab): Hjärnmetastaser

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

References

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