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 May;19(3):213-220.e4. doi: 10.1016/j.cllc.2017.11.003. Epub 2017 Nov 21.

Abstract

Background: Despite the likelihood of an initial response to an epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI), EGFR-mutant non-small-cell lung cancer (NSCLC) patients develop disease progression. Antiangiogenic agents in combination with an EGFR TKI might provide additional benefit in patients with EGFR-mutant NSCLC. In this article we report safety, exposure, and progression-free survival (PFS) results for part A (phase Ib) of RELAY, a randomized, double-blind, phase Ib/III study investigating safety and efficacy of erlotinib (EGFR TKI) with ramucirumab (anti-vascular endothelial growth factor receptor-2 antibody) or placebo in first-line EGFR-mutant stage IV NSCLC.

Patients and methods: Eligible patients had untreated stage IV NSCLC, Eastern Cooperative Oncology Group performance status of 0 to 1, and activating EGFR mutation (exon 19 deletion or exon 21 L858R substitution). Patients received ramucirumab 10 mg/kg on day 1 of a repeating 14-day cycle and erlotinib 150 mg/d. Treatment continued until disease progression or unacceptable toxicity. The primary objective was to assess safety and tolerability, in terms of dose-limiting toxicities (DLTs), during the first 2 cycles.

Results: Fourteen patients were treated and 12 were evaluable for DLTs. One patient experienced a DLT of Grade 3 elevated alanine aminotransferase during the DLT assessment period. Adverse events were reported in all patients, but were generally mild and manageable. The most common Grade 3 adverse events were hypertension, rash, and diarrhea. No serious or Grade 4 to 5 events occurred. Median PFS was 17.1 months (95% confidence interval, 8.8-not reached). Five patients continue receiving study treatment.

Conclusion: Ramucirumab with erlotinib showed no unexpected toxicities and encouraging clinical activity in part A. Phase III enrollment has been initiated, maintaining ramucirumab 10 mg/kg every 2 weeks with erlotinib 150 mg/d.

Trial registration: ClinicalTrials.gov NCT02411448.

Keywords: Antiangiogenic; Epidermal growth factor receptor; First-line; NCT02411448; Vascular endothelial growth factor receptor.

Publication types

  • Clinical Trial, Phase I
  • Multicenter Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Aged
  • Aged, 80 and over
  • Angiogenesis Inhibitors / administration & dosage*
  • Angiogenesis Inhibitors / adverse effects
  • Antibodies, Monoclonal / administration & dosage*
  • Antibodies, Monoclonal / adverse effects
  • Antibodies, Monoclonal, Humanized
  • Antineoplastic Combined Chemotherapy Protocols / therapeutic use
  • Carcinoma, Non-Small-Cell Lung / drug therapy*
  • Double-Blind Method
  • ErbB Receptors / genetics
  • Erlotinib Hydrochloride / administration & dosage
  • Female
  • Humans
  • Lung Neoplasms / drug therapy*
  • Male
  • Maximum Tolerated Dose
  • Middle Aged
  • Mutation
  • Ramucirumab
  • Vascular Endothelial Growth Factor Receptor-2 / antagonists & inhibitors

Substances

  • Angiogenesis Inhibitors
  • Antibodies, Monoclonal
  • Antibodies, Monoclonal, Humanized
  • Erlotinib Hydrochloride
  • EGFR protein, human
  • ErbB Receptors
  • KDR protein, human
  • Vascular Endothelial Growth Factor Receptor-2

Associated data

  • ClinicalTrials.gov/NCT02411448