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Cyramza ® (ramucirumab)
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The RELAY trial was designed in three parts.
Part A (phase 1b) was a single-arm trial to assess safety, tolerability, and recommended starting dose of the ramucirumab/erlotinib combination for part B.1-3
Part B (phase 3) initiated enrollment after the completion of the DLT and the phase 3 dose was selected.1-3
Part C (exploratory cohort) is ongoing and being conducted in East-Asian patients evaluating ramucirumab plus gefitinib and then upon progression, ramucirumab plus osimertinib in T790 mutation-positive patients.1,3,4
A diagram of the full RELAY design is summarized in Figure 1. Additional details on the study design of each part of the study are summarized in the sections below.
Figure 1. RELAY Study Design: Parts A, B, and C1,3,4
Abbreviations: ECOG = Eastern Cooperative Oncology Group; EGFR = epidermal growth factor receptor; NSCLC = non-small cell lung cancer; PFS = progression-free survival; PS = performance status; Q2W = every 2 weeks; TKI = tyrosine kinase inhibitor.
Study Design
The RELAY trial (part A) was a phase 1b, open-label, single-arm trial in patients with previously untreated EGFR mutation-positive, metastatic NSCLC. The planned target enrollment of part A was 12 patients (6 patients from Japan and 6 patients from North America and Europe). All patients had an EGFR mutation of exon 19 deletion or exon 21 L858R and an ECOG PS of 0 or 1. Patients received treatment with erlotinib (150 mg/day) plus ramucirumab (10 mg/kg every 2 weeks) until disease progression or unacceptable toxicity. Safety and tolerability were evaluated on the basis of DLT assessment during the first 2 cycles of treatment (approximately 28 days). One of the 12 evaluable patients experienced a grade 3 DLT (elevated ALT). No unexpected toxicities were observed, and the ramucirumab starting dose of 10 mg/kg every 2 weeks was recommended for the phase 3 part of the study. Part A confirmed the safety and tolerability of the ramucirumab dose of 10 mg/kg every 2 weeks when used in combination with erlotinib 150 mg/day.1,3 Dose-limiting toxicity was defined as
grade ≥3
thrombocytopenia
febrile neutropenia
nonhematologic toxicity excluding electrolyte abnormality, or
skin rash
grade 4
anemia
neutropenia lasting more than 7 days
hypertension, or
elevated urine protein of ≥3 g per 24 hours, or
refractory hypertension.1
Outcome Measures
The primary endpoint of part A was safety and tolerability of the recommended part B dose of ramucirumab.1
Study Design
The RELAY trial (part B) 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 status, and EGFR testing method) to receive treatment with erlotinib (150 mg/day) plus ramucirumab (10 mg/kg every 2 weeks; n=224) or placebo (10 mg/kg every 2 weeks; n=225) until disease progression or unacceptable toxicity.2
Patients were excluded from participation if they had
previous treatment for stage IV NSCLC
known T790M EGFR mutation
clinically active ILD
CNS system metastasis
uncontrolled hypertension
gross hemoptysis
significant bleeding disorders
evidence of intratumor cavitation or major blood vessel invasion by cancer
history of ATE within 6 months before enrollment
clinically relevant CHF (New York Heart Association classification of II-IV), or
significant ophthalmic abnormalities of the surface of eye.1,2
Outcome Measures
The primary endpoint of the RELAY study (part B) was
PFS (investigator-assessed).2
Secondary endpoints included
OS
ORR (assessed using RECIST v1.1)
DCR
DOR
safety (assessed using CTCAE v4.0)
PK and immunogenicity of ramucirumab, and
patient reported outcomes (assessed using LCSS and EQ-5D-5L).2
Prespecified exploratory analyses included
PFS2 (investigator-assessed), and
biomarker analyses.2
Study Design
The RELAY trial (part C) is an ongoing, open-label, single arm, 2-period, exploratory portion of the RELAY trial. The planned target enrollment of part C is 80 patients from East-Asian regions. Part C is designed in 2 periods to evaluate the efficacy and safety of ramucirumab in combination with
gefitinib in treatment-naive patients with EGFR mutation-positive metastatic NSCLC (period 1), and
osimertinib in patients with T790M-positive metastatic NSCLC whose disease has progressed on ramucirumab plus gefitinib (period 2).4
In period 1, patients will receive treatment with gefitinib (250 mg/day) plus ramucirumab (10 mg/kg every 2 weeks) until disease progression or unacceptable toxicity. In period 2, T790M-positive patients will receive treatment with osimertinib (80 mg/day) plus ramucirumab (10 mg/kg every 2 weeks) until disease progression or unacceptable toxicity.1,3,4
Outcome Measures
The primary endpoint of part C is
1-year PFS.4
Secondary endpoints include
PFS and
PFS2.4
The exploratory objectives of part C include the evaluation of
the efficacy and safety of ramucirumab when administered in combination with
gefitinib in previously untreated patients with EGFR mutation-positive metastatic NSCLC, or
osimertinib in patients with T790M-positive metastatic NSCLC whose disease has progressed on ramucirumab plus gefitinib in this study
PK and immunogenicity of ramucirumab, and
patient-reported outcomes (assessed using LCSS and EQ-5D-5L).4
1. Garon EB, Reck M, Paz-Ares L, et al. Treatment rationale and study design for the RELAY study: A multicenter, randomized, double-blind study of erlotinib with ramucirumab or placebo in patients With epidermal growth factor receptor mutation-positive metastatic non-small-cell lung cancer. Clin Lung Cancer. 2017;18(1):96-99. https://doi.org/10.1016/j.cllc.2016.05.023
2. 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
3. Reck M, Garon EB, Paz-Ares L, et al. Randomized, double-blind phase Ib/III study of erlotinib with ramucirumab or placebo in previously untreated EGFR-mutant metastatic non-small-cell lung cancer (RELAY): phase Ib results. Clin Lung Cancer. 2018;19(3):213-220. https://doi.org/10.1016/j.cllc.2017.11.003
4. Data on file, Eli Lilly and Company and/or one of its subsidiaries.
Glossary
ALT = alanine aminotransferase
ATE = arterial thromboembolic event
CHF = congestive heart failure
CNS = central nervous system
CTCAE = Common Terminology Criteria for Adverse Events
DCR = disease control rate
DLT = dose-limiting toxicity
DOR = duration of response
ECOG = Eastern Cooperative Oncology Group
EGFR = epidermal growth factor receptor
EQ-5D-5L = EuroQoL five-dimension, five-level health status questionnaire
ILD = interstitial lung disease
LCSS = Lung Cancer Symptom Scale
NSCLC = non-small cell lung cancer
ORR = objective response rate
OS = overall survival
PFS = progression-free survival
PFS2 = progression-free survival from randomization to progression (or death) on second-line systemic therapy
PK = pharmacokinetic(s)
PS = performance status
RECIST = Response Evaluation Criteria in Solid Tumors
Datum fӧr senaste ӧversyn 2019 M07 24