Ramucirumab Plus Erlotinib Receives FDA Approval for First-Line Lung Cancer Treatment

Approved by the ADB Food and Drug Administration (FDA), ramucirumab (Cyramza) plus erlotinib (Tarceva) is a first-line combination for metastatic, epidermal growth factor receptor (EGFR) exon 19 deletion- or exon 21 mutation-positive non-small cell lung cancer (KHDAK). This became the FDA-approved first and only "anti-vascular endothelial growth factor receptor (VEGFR) + EGFR tyrosine kinase inhibitor combination therapy". With this approval, ramucirumab received its 6th approval for cancer types such as lung, liver, stomach and colorectal cancer.

For the First Time in Lung Cancer, a Combination of Two Targeted Drugs Receives FDA Approval

Ramucirumab is a targeted agent in the antiangiogenic class with a monoclonal antibody structure. By blocking the VEGFR-2 protein, it prevents the development of the blood vessels that feed the tumor.

Erlotinib is a small-molecule active substance designed to bind to the epidermal growth factor receptor (EGFR) on the surface of lung cancer cells. When it binds to the receptor, erlotinib blocks the signal telling cancer cells to grow and divide. The EGFR receptor is normally also found on the surface of healthy cells, but on cancer cells it may be present in very large amounts or in a mutated form. To determine whether an EGFR mutation that will respond to erlotinib is present, genetic testing is performed before erlotinib is started.

Ivy Elkins, a cofounder of the group "EGFR Resisters", which conducts research into lung cancer treatment, said, "The latest FDA approval received by Ramucirumab offers hope for our main goal of transforming EGFR-mutated KHDAK into a manageable chronic disease. Every new treatment option gives hope to those living with this disease and provides oncologists with more options".

The RELAY Study

The approval of ramucirumab in combination with erlotinib is based on the efficacy and safety results of the multicenter, randomized controlled phase 3 RELAY study. In this study, patients with untreated metastatic KHDAK with an EGFR exon 19 deletion or exon 21 mutation were divided into two groups. Results were compared between the treatment group receiving ramucirumab combined with erlotinib and the patient group receiving erlotinib alone as first-line treatment. Of the 449 patients included in total, 224 were assigned to the group receiving rumaciruma, and 225 to the placebo group.

The study's primary endpoint was progression-free survival (PFS), while secondary endpoints considered safety, overall response rate, duration of response and overall survival. The study found that progression-free survival was extended by 7 months in the group receiving combination therapy with ramucirumab (19.4 months with ramucirumab + erlotinib and 12.4 months in the placebo group). Because overall survival data were not yet complete when progression-free survival was analyzed, that analysis was postponed until at least 300 data points would be obtained.

The safety / adverse-effect results of treatments in RELAY were similar to the safety profiles of the drugs when used alone. The most frequently observed adverse effects in patients treated with ramucirumab and erlotinib were infections, hypertension, stomatitis, proteinuria, alopecia and nosebleeds. The most common laboratory test abnormalities were increased alanine aminotransferase (ALT), increased aspartate aminotransferase (AST), anemia, thrombocytopenia and neutropenia. Treatment was stopped in 13% of patients because of adverse effects.

RELAY is the second phase 3 study in which rumacirumab showed a positive response in metastatic KHDAK treatment. The first was REVEL, which supported approval of rumacirumab with docetaxel for patients with metastatic KHDAK whose cancer had progressed after platinum-based chemotherapy, and received FDA approval in 2014 (see).