Cyramza® (Ramucirumab)

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Ramucirumab: RELAY Study Design

The RELAY study was a global, multicenter, randomized, placebo-controlled, double-blind, phase 1b/3 study.

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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 RELAY Study Design: Parts A, B, and C. Additional details on the study design of each part of the study are summarized in the sections below.

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.

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

1Garon 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

2Nakagawa 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

3Reck 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

4Data 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

Fecha de la última revisión: 2019 M07 24


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