Cyramza® (Ramucirumab)

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Ramucirumab: RELAY Study Rationale

Preclinical and clinical data provided justification for the exploration of ramucirumab in combination with erlotinib in patients with metastatic NSCLC with activating EGFR mutations.


Study Design

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 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 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.1

Study Rationale

Preclinical Evidence

At the time of the RELAY study design, several preclinical studies had shown that the VEGFR and EGFR pathways were interrelated. These studies suggested that dual blockade of the VEGF and EGFR pathways would be more effective than either approach alone and could also have activity in tumors with acquired resistance to EGFR inhibitors.2-4

In a mouse xenograft model of NSCLC harboring either EGFR exon 19 deletion or the exon 21 (L858R) substitution, the ramucirumab surrogate antimouse VEGFR-2 antibody DC101 in combination with erlotinib demonstrated stronger antitumor effect as compared with either treatment as a monotherapy.4,5 Similar results have also been observed using the combination of DC101 and osimertinib.6

In an experiment done in multiple different NSCLC cell lines, it was shown that dual inhibition of the VEGFR and EGFR pathways reduced the number of proliferating endothelial cells and also abrogated primary and secondary tumor resistance to EGFR TKIs.4,7

Dual Inhibition Mechanisms of EGFR and VEGFR Pathways

Please click on this video link for a visual representation of the dual inhibition mechanisms of the EGFR and VEGFR pathways. 

Dual Inhibition Mechanisms of EGFR and VEGFR Pathways

Clinical Evidence

Clinical data have shown improved efficacy with a clinically acceptable toxicity profile when VEGF and EGFR treatments for NSCLC were combined. Studies have reported that bevacizumab, a VEGF inhibitor, in combination with an EGFR TKI could provide additional clinical benefit in patients with NSCLC with EGFR activating mutations.4,8-10

These studies did have limitations (sample sizes, open-label, and Japan-only); therefore, the question remained as to whether dual inhibition of EGFR and VEGFR pathways was a viable treatment strategy in a global EGFR mutation-positive NSCLC population.8-10


1Nakagawa 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.

2Viloria-Petit A, Crombet T, Jothy S, et al. Acquired resistance to the antitumor effect of epidermal growth factor receptor-blocking antibodies in vivo: a role for altered tumor angiogenesis. Cancer Res. 2001;61(13):5090-5101.

3Byers LA, Heymach JV. Dual targeting of the vascular endothelial growth factor and epidermal growth factor receptor pathways: rationale and clinical applications for non-small-cell lung cancer. Clin Lung Cancer. 2007;8(2 suppl):S79-S85.

4Data on file, Eli Lilly and Company and/or one of its subsidiaries.

5Kayatani H, Ohashi K, Imao T, et al. Combination effect of anti-VEGFR-2 antibody with erlotinib on EGFR mutant non-small cell lung cancer [abstract]. Cancer Res. 2016;76(14 suppl):5198.

6Chintharlapalli S, Fischl A, Yu CP, Iversen PW. Enhanced antitumor effect of dual EGFR and VEGFR2 inhibition in EGFR-mutated non-small cell lung cancer (NSCLC) patient-derived tumor xenograft (PDX) models. Poster presented at: 111th Annual Meeting of the American Association for Cancer Research (AACR Virtual); June 22-24, 2020. Accessed January 5, 2021.!/9045/presentations/ramucirumab/1

7Naumov GN, Nilsson MB, Cascone T, et al. Combined vascular endothelial growth factor receptor and epidermal growth factor receptor (EGFR) blockade inhibits tumor growth in xenograft models of EGFR inhibitor resistance. Clin Cancer Res. 2009;15(10):3484-3494.

8Herbst RS, Ansari R, Bustin F, et al. Efficacy of bevacizumab plus erlotinib versus erlotinib alone in advanced non-small-cell lung cancer after failure of standard first-line chemotherapy (BeTa): a double-blind, placebo-controlled, phase 3 trial. Lancet. 2011;377(9780):1846-1854.

9Johnson BE, Kabbinavar F, Fehrenbacher L, et al. ATLAS: randomized, double-blind, placebo-controlled, phase IIIB trial comparing bevacizumab therapy with or without erlotinib, after completion of chemotherapy, with bevacizumab for first-line treatment of advanced non-small-cell lung cancer. J Clin Oncol. 2013;31(31):3926-3934.

10Seto T, Kato T, Nishio M, et al. Erlotinib alone or with bevacizumab as first-line therapy in patients with advanced non-squamous non-small-cell lung cancer harbouring EGFR mutations (JO25567): an open-label, randomised, multicentre, phase 2 study. Lancet Oncol. 2014;15(11):1236-1244.


ECOG = Eastern Cooperative Oncology Group

EGFR = epidermal growth factor receptor

NSCLC = non-small cell lung cancer

PS = performance status

TKI = tyrosine kinase inhibitor

VEGF = vascular endothelial growth factor

VEGFR = vascular endothelial growth factor receptor

VEGFR-2 = vascular endothelial growth factor receptor 2

Fecha de la última revisión: 2021 M01 05

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