Ramucirumab Plus Erlotinib Improves Progression-Free Survival in Previously Untreated EGFR-Mutated Advanced NSCLC

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As reported in The Lancet Oncology by Kazuhiko Nakagawa, MD, of the Department of Medical Oncology, Kindai University Faculty of Medicine, Osaka, and colleagues, the phase III RELAY trial has shown that the addition of the VEGFR2 inhibitor ramucirumab to the EGFR inhibitor erlotinib improved progression-free survival in the first-line treatment of advanced -EGFR-mutated non–small cell lung cancer (NSCLC).1

Study Details

In the double-blind trial, 449 patients from 100 sites in 13 countries were randomly assigned between January 2016 and February 2018 to receive ramucirumab plus erlotinib (n = 224) or placebo plus erlotinib (n = 225). To qualify for enrollment, patients could have no central nervous system (CNS) metastases.

Treatment consisted of erlotinib at 150 mg/d plus either intravenous ramucirumab at 10 mg/kg or matching placebo once every 2 weeks. Randomization was stratified by sex, region (east Asia vs other), EGFR mutation type (Ex19del vs Leu858Arg), and local EGFR testing method (therascreen or cobas vs other polymerase chain reaction [PCR] and sequencing-based methods).

Ramucirumab plus erlotinib demonstrated superior progression-free survival compared with placebo plus erlotinib in patients with untreated EGFR-mutated metastatic NSCLC.
— Kazuhiko Nakagawa, MD

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Treatment continued until investigator-assessed radiographic disease progression, unacceptable toxicity, or withdrawal of consent. The primary endpoint was investigator-assessed progression-free survival in the intention-to-treat population.

For the ramucirumab/erlotinib vs erlotinib/placebo groups, the median age was65 vs 64 years (54% vs 49% ≥ 65 years), 63% were female in both groups, and 77% were Asian in both groups. With regard to smoking status, 29% vs 32% were ever-smokers and 60% vs 62% were never-smokers, with smoking status unknown in the remainder. Geographic region was East Asia in 74% vs 76%, and Eastern Cooperative Oncology Group (ECOG) performance status was 0 in 52% vs 53% and 1 in 48% vs 47%.

As to diagnosis, 96% vs 97% had adenocarcinoma, with the remainder having NSCLC–not otherwise specified; 87% vs 84% had stage IV disease; EGFR mutation type was Ex19del in 55% vs 53% and Leu858Arg in 44% vs 47%; and the EGFR testing method was therascreen or cobas in 43% vs 45% and other PCR and sequencing-based methods in 57% vs 55%.

Progression-Free Survival

The median follow-up was 20.7 months. Median progression-free survival was 19.4 months in the ramucirumab-plus-erlotinib group vs 12.4 months in the erlotinib group (stratified hazard ratio [HR] = 0.59, P < .0001). Progression-free survival at 1 year was 71.9% vs 50.7%. Analysis according to independent radiologic review in 440 patients showed a median progression-free survival of 16.5 months vs 11.1 months (HR = 0.67, 95% confidence interval [CI] = 0.52–0.87).

In subgroup analysis by stratification factors, unstratified hazard ratios were 0.51 (95% CI = 0.34–0.75) among men and 0.73 (95% CI = 0.54–0.99) among women, 0.64 (95% CI = 0.49–0.83) in East Asia sites and 0.61 (95% CI = 0.36–1.01) in other sites, 0.65 (95% CI = 0.47–0.90) among patients with Ex19del mutation and 0.62 (95% CI = 0.44–0.87) among those with Leu858Arg mutation, and 0.40 (95% CI = 0.27–0.58) among patients tested with therascreen or cobas and 0.87 (95% CI = 0.64–1.19) among those tested with other methods.

In other subgroup analyses, unstratified hazard ratios were 0.58 (95% CI = 0.37–0.90) among ever-smokers and 0.69 (95% CI = 0.51–0.95) among never-smokers; 0.53 (95% CI = 0.38–0.75) among patients aged < 65 years and 0.77 (95% CI = 0.55–1.09) among those aged ≥ 65 years; 0.58 (95% CI = 0.41–0.83) in those with ECOG performance status of 0 and 0.67 (95% CI = 0.49–0.93) in those with performance status of 1; and 0.62 (95% CI = 0.48–0.80) in those with stage IV disease and 0.74 (95% CI = 0.35–1.54) in those with other-stage disease.

Time to diagnosis of CNS metastases was a prespecified study endpoint. No statistical analysis was performed due to the small number of events; CNS metastases were diagnosed in two patients in the ramucirumab/erlotinib group and in eight patients in the erlotinib/placebo group.

Overall survival data were not mature at interim analysis. Overall survival was 93% vs 94% at 1 year and 83% vs 79% at 2 years. Overall response rates were 76% (complete response in 1%) vs 75% (complete response in 1%), with a median duration of response of 18.0 vs 11.1 months.

Adverse Events

Grade 3 or 4 adverse events were reported in 72% of patients in the ramucirumab-plus-erlotinib group vs 54% of the erlotinib-placebo group. The most common events in the ramucirumab-plus-erlotinib group were hypertension (24%, all grade 3) and dermatitis acneiform (15%); the most common events in the erlotinib-placebo group were dermatitis acneiform (9%) and increased alanine aminotransferase levels (8%).

Serious adverse events were reported in 29% vs 21% of patients. The most common events in the ramucirumab-plus-erlotinib group were pneumonia (3%), cellulitis (2%), and pneumothorax (2%); the most common events in the erlotinib-placebo group were pyrexia (2%) and pneumothorax (1%).


  • In patients with previously untreated EGFR-mutated advanced NSCLC, dual VEGF and EGFR inhibition with ramucirumab and erlotinib improved progression-free survival vs erlotinib alone.
  • Median progression-free survival was 19.4 months vs 12.4 months.

Adverse events led to ramucirumab dose reductions in 10% of patients, with the most common cause being proteinuria (8%). Adverse events led to discontinuation of all study treatment in 13% of the ramucirumab/erlotinib group vs 11% of the erlotinib-placebo group, with the most common causes in the ramucirumab/erlotinib group being increased alanine aminotransferase levels and paronychia (each in three patients). One patient in the ramucirumab/erlotinib group died of an adverse event considered related to study treatment (hemothorax after thoracic drainage procedure for pleural empyema).

The investigators concluded: “Ramucirumab plus erlotinib demonstrated superior progression-free survival compared with placebo plus erlotinib in patients with untreated EGFR-mutated metastatic NSCLC. Safety was consistent with the safety profiles of the individual compounds in advanced lung cancer. The RELAY regimen is a viable new treatment option for the initial treatment of EGFR-mutated metastatic NSCLC.” 

DISCLOSURE: The study was funded by Eli Lilly. For full disclosures of the study authors, visit


1. 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. October 4, 2019 (early release online).

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