Cyramza® (ramucirumab): Design av RELAY-Studien

Study Design

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 C^1,3,4

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.

Part A

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 

Part B

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

Part C

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

References

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