Cyramza ® (ramucirumab)

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Fick patienter med hjärnmetastaser delta i Cyramza® (ramucirumab) kliniska prövningar?

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.

Inclusion and exclusion criteria relating to brain metastases in our studies

We provide a summary of RELAY and REVEL in the section Study designs.

Table 1. Inclusion and exclusion criteria relating to brain metastases in our studies.1-6

Study

Indication

Exclusion Criteria Related to Brain Metastasis

Inclusion Criteria Related to Brain Metastasis

CNS Metastasis as Disease Progression

RELAY

Non-Small Cell Lung Cancer (NSCLC)

All patients were required to have brain imaging prior to enrollment and patients with known CNS metastases were excluded from participation in RELAY.1 

 

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.1


REVEL

Non-Small Cell Lung Cancer

Patients were excluded if they had untreated CNS metastases.2

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).2

 

RAINBOW

Gastric or gastroesophageal (GEJ) adenocarcinoma

Patients with documented brain metastases were excluded from the trial.3

 

 

REGARD

Gastric or GEJ adenocarcinoma

Patients with documented brain metastases were excluded from the trial.4

 

 

RAISE

Colorectal Cancer

Patients with documented brain metastases were excluded from the trial.5



REACH-2

Hepatocellular Carcinoma 

Patients with documented brain metastases were excluded from the study.6



 CNS = central nervous system: CT = computed tomography; WBRT = whole brain radiotherapy; MRI = magnetic resonance imaging; IV = intravenous

Outcome among patients with CNS metastases

Patients with CNS metastases in RELAY

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.1

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

Patients with CNS metastases in REVEL        

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.7

According to a pre-planned subgroup analysis, patients in both treatment groups with CNS metastases had similar overall survival (OS) (hazard ratio [HR]=1.09; 95% CI: 0.62-1.93) and progression-free survival (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.7

Study designs

The RELAY study

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 epidermal growth factor receptor (EGFR) mutation of exon 19 deletion or exon 21 L858R and an Eastern Cooperative Oncology Group (ECOG) performance status (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.

The REVEL study

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.2

References

1. 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

2. 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

3. 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

4. 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

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

Datum fӧr senaste ӧversyn 2019 M11 14


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