Combination therapy with erlotinib plus ramucirumab (Cyramza; Lilly) yields superior progression-free survival compared with erlotinib plus placebo in patients with untreated epidermal growth factor receptor (EGFR)-mutated metastatic non small-cell lung cancer (NSCLC), according to a new study. 

The treatment regimen, the investigators noted, also demonstrated a safety profile consistent with those of the individual compounds used in the trial.

White pills. Source: Getty

Reporting in a recent issue of Lancet Oncology, an international, multi-center team of researchers explained that both preclinical and clinical data support the notion of dual blockade of the EGFR and vascular endothelial growth factor (VEGF) pathways in EGFR-mutated metastatic NSCLC. Nevertheless, the approach has yet to be widely implemented. 

As such, the current study – dubbed RELAY by the investigators (NCT02411448) -- assessed the safety and efficacy of standard-of-care EGFR tyrosine kinase inhibitor (TKI) erlotinib in combination with the human IgG1 VEGFR2 antagonist ramucirumab in patients with untreated disease. Controls received erlotinib plus placebo.

The double-blind, phase 3 trial was performed at 100 institutions across 13 countries around the world. Study participants comprised adults with stage IV NSCLC, all of whom had an EGFR exon 19 deletion or exon 21 substitution mutation, with an Eastern Cooperative Oncology Group performance status of 0 or 1, and no central nervous system metastases. 

Patients were randomly assigned to receive either 150 mg/day of oral erlotinib, plus either 10 mg/kg intravenous ramucirumab or matching placebo once every two weeks. The trial’s primary endpoint was investigator-assessed progression-free survival in the intention-to-treat population. Safety was assessed in all patients who received at least one dose of treatment. 

The trial enrolled a total of 449 patients between January 2016 and February 2018, 224 in the erlotinib plus ramucirumab group and 225 controls. Their median duration of follow-up was 20.7 months. 

At the time of the primary analysis, progression-free survival was found to be 19.4 months in the erlotinib plus ramucirumab group (95% confidence interval: 15.4-21.6 months), significantly longer than the 12.4 months in the erlotinib plus placebo group (95% CI: 11.0-13.5 months). The stratified hazard ratio was found to be 0.59 (95% CI: 0.46-0.76; p<0.0001). 

With respect to safety, grade 3-4 treatment-emergent adverse events were reported in 159 of the 221 patients in the combination therapy group (72%), compared with 121 of the 225 in the control group (54%). Of these, the most common in the erlotinib plus ramucirumab group were hypertension (24%) and dermatitis acneiform (33%); in the placebo group they were dermatitis acneiform (9%) and increased alanine aminotransferase (8%). 

Serious treatment-emergent adverse events occurred in 29% of the patients in the treatment group and 21% of those in the control group. The most common of these in the treatment group were pneumonia (3%), cellulitis (2%) and pneumothorax (2%). In the control group, on the other hand, these included pyrexia (2%) and pneumothorax (1%). One treatment-related death occurred as a result of an adverse event, in the erlotinib plus ramucirumab group, a hemothorax after a thoracic drainage procedure for a pleural empyema.

In light of these encouraging results, the researchers concluded that combination therapy with erlotinib plus ramucirumab is superior to erlotinib plus placebo in patients with untreated EGFR-mutated metastatic NSCLC. 

“The RELAY regimen,” they concluded, “is a viable new treatment option for the initial treatment of EGFR-mutated metastatic NSCLC.”

The trial is ongoing for long-term survival follow-up.