FDA Approves Ramucirumab Injection in Combination with Erlotinib for NSCLC

The FDA approved ramucirumab injection in combination with erlotinib for the first-line treatment of patients with metastatic non-small cell lung cancer with EGFR exon 19 deletions or exon 21 mutations.

The FDA has approved a 10 mg/mL solution of ramucirumab injection (Cyramza) in combination with erlotinib (Tarceva) for the first-line treatment of patients with metastatic non-small cell lung cancer (NSCLC) with epidermal growth factor receptor (EGFR) exon 19 deletions or exon 21 (L858R) mutations, according to Eli Lilly and Company, the developer of the injection.

This combination is now the first and only FDA-approved anti-VEGFR/EGFR TKI combination therapy for this patient population. With this approval, ramucirumab has now received 6 FDA approvals to treat certain types of lung, liver, stomach, and colorectal cancers. 

“We’re encouraged by (ramucirumab’s) latest approval, which represents one step towards our goal of making EGFR-mutated non-small cell lung cancer in a manageable chronic disease,” Ivy Elkins, cofounder of EGFR Resisters, said in a press release. “Each new treatment options gives hope to those living with this disease and provides oncologists with more options that may help slow the spread of this deadly cancer, which is an important goal for many patients.”

The approval of ramucirumab in combination with erlotinib was based on efficacy and safety results from the global, randomized, placebo-controlled phase III RELAY trial. The study is designed to assess ramucirumab in combination with erlotinib compared to placebo in combination with erlotinib as a first-line treatment in previously untreated patients with metastatic NSCLC whose tumors have EGFR exon 19 deletions or exon 21 substitution mutations. 

In total, the study randomized 449 patients receive either the rumacirumab-containing regimen (n = 224) or the placebo-containing regimen (n = 225). The primary endpoint of the trial was progression-free survival (PFS). Key secondary endpoints included safety, overall response rate (ORR), duration of response (DOR), and overall survival (OS).

In the study, the combination with ramucirumab demonstrated a statistically significant and clinically meaningful improvement in median PFS by 7 months compared to the placebo-containing arm (19.4 months vs 12.4 months; HR, 0.59; 95% CI, 0.46-0.76; P < 0.0001). Notably, the PFS treatment effect was consistent across exon 19 and exon 21 subgroups.

At the time of the final analysis of PFS, OS data were not mature as only 26% of planned analysis had occurred (HR, 0.83; 95% CI, 0.53-1.30). A final OS analysis is planned when at least 300 events have occurred. 

The overall safety profiles observed in the RELAY study was similar to that of its individual components. The most common adverse events (AEs) of all grades observed in patients treated with ramucirumab and erlotinib were infections, hypertension, stomatitis, proteinuria, alopecia, and epistaxis. The most common laboratory abnormalities were increased alanine aminotransferase, increased aspartate aminotransferase, anemia, thrombocytopenia, and neutropenia. 

Treatment discontinuation of all study drugs due to AEs occurred in 13% of rumacirumab with erlotinib-treated patients, with increased alanine aminotransferase (1.4%) and paronychia (1.4%) being the most common. Even further, the most common AEs leading to treatment discontinuation of rumacirumab were proteinuria (8.6%) and hyperbilirubinemia (6%).

“The approval of this new first-line metastatic EGFR-mutated non-small cell lung cancer regiment, which inhibits the VEGFR and EGFR pathways together, is an important milestone in the treatment of this disease,” Edward Garon, MD, of the Davide Geffen School of Medicine and North America lead investigator of the RELAY trial, said in the release. “It is wonderful that patients now have multiple options for initial therapy capable of delaying disease progression for considerably longer than erlotinib, which has been our traditional standard approach.”

RELAY is the second positive phase III trial of rumacirumab in metastatic NSCLC. The first was REVEL, which supported the approval of rumacirumab plus docetaxel (Taxotere) as a treatment for patients with metastatic NSCLC whose cancer has progressed after prior platinum-based chemotherapy.


Lilly's CYRAMZA® (ramucirumab) Receives FDA Approval as First-Line Treatment for Metastatic EGFR-Mutated Non-Small Cell Lung Cancer [news release]. Indianapolis. Published May 29, 2020. investor.lilly.com/news-releases/news-release-details/lillys-cyramzar-ramucirumab-receives-fda-approval-first-line. Accessed May 30, 2020.