FDA Approves Frontline Ramucirumab/Erlotinib for EGFR+ mNSCLC

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

The FDA has approved ramucirumab (Cyramza) in combination with erlotinib (Tarceva) for the first-line treatment of patients with metastatic non–small cell lung cancer (NSCLC) harboring EGFR exon 19 deletions or exon 21 (L858R) mutations, according to a press release from Eli Lilly.1

This marks the only anti–VEGFR/EGFR tyrosine kinase inhibitor combination regimen approved by the FDA for the treatment of patients with EGFR-mutant metastatic NSCLC.

"The approval of this new first-line metastatic EGFR-mutated non–small cell lung cancer regimen, which inhibits the VEGFR and EGFR pathways together, is an important milestone in the treatment of this disease. 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," Edward Garon, MD, David Geffen School of Medicine, University of California, and North America, said in the press release. Garon is the lead investigator of the RELAY trial that supported the approval. "Ramucirumab, in combination with erlotinib, is a welcomed first-line option to offer our patients with metastatic EGFR-mutated non–small cell lung cancer."

In the global, randomized, placebo-controlled phase 3 RELAY trial (NCT02411448), the combination of ramucirumab and erlotinib demonstrated a progression-free survival (PFS) benefit of 7 months compared with erlotinib alone in patients with EGFR-mutant NSCLC (19.4 vs 12.4 months; HR, 0.59; 95% CI, 0.46-0.76; P <.0001).1,2

PFS benefit was maintained in both EGFR mutation subgroups, with a hazard ratio of 0.65 for patients with EGFR exon 19 deletions and a hazard ratio of 0.62 for those with L858R mutations.

"This Cyramza combination regimen represents a new and meaningful treatment option for people with metastatic EGFR-mutated non-small cell lung cancer, and we are proud that it has been approved by the FDA for patients with this disease and the doctors who treat them," said Anne White, president of Lilly Oncology, in a statement. "Today's approval underscores Lilly's continued commitment to people living with lung cancer and to delivering meaningful medicines that are tailored for those with advanced or metastatic cancers. It also further reinforces the value that Cyramza can provide in treating certain advanced or metastatic cancers."

RELAY enrolled 449 patients with stage IV NSCLC who had either EGFR exon 19 deletions or L858R mutations, and ECOG performance status of 0 or 1, and no central nervous system metastases. Patients were randomized 1:1 to receive either the combination of 150 mg/day of oral erlotinib with 10 mg/kg of intravenous ramucirumab or erlotinib with matching placebo once every 2 weeks.

The primary end point of the trial was PFS in the intention-to-treat population by investigator assessment according to RECIST 1.1 criteria. Secondary end points included safety and toxicity, overall survival, overall response rate (ORR), disease control rate (DCR), duration of response (DOR), pharmacokinetics and immunogenicity, and patient-reported outcomes.

Patients had a median age of 65 years between the 2 arms (range, 56-71) and 63% of the participants were female. The participants were predominantly Asian (77%) with never-smoker status (61%) and an ECOG performance status of 0 (53%). The majority of patients had stage IV disease at baseline (86%) and exon 19 deletions (54%).

Follow-up lasted for a median of 20.7 months (range, 15.8-27.2). At 1 year, the PFS rate was 71.9% with the ramucirumab regimen versus 50.7% with erlotinib alone.

The ORR was similar between the 2 arms at 76% with the combination and 75% with erlotinib monotherapy; the DCR was 95% and 96%, respectively. The median DOR was 18.0 months with ramucirumab and erlotinib compared with 11.1 months with erlotinib and placebo (HR, 0.62; 95% CI, 0.48-0.81; P = .0003).

Overall survival data were not yet mature at the time of data cutoff, and the median was not yet reached in either arm.

All patients included in the safety analysis had at least 1 treatment-emergent adverse event (TEAE) and grade ≥3 TEAEs were seen in 72% of patients in the combination arm versus in 54% in the monotherapy arm. The most common grade ≥3 TEAEs in the combination arm were hypertension (24%) and dermatitis acneiform (15%).

Serious treatment-related AEs were observed in 15% of patients treated with ramucirumab and erlotinib versus 12% treated with erlotinib and placebo. The most common serious AEs of any grade in the ramucirumab and erlotinib group were pneumonia (3%), cellulitis (2%), and pneumothorax (2%).

Six deaths due to TEAEs were reported in the combination arm compared with none in the placebo group; one death from hemothorax was considered related to treatment.

The label for ramucirumab includes warnings for hemorrhage and gastrointestinal hemorrhage, gastrointestinal perforations, impaired wound healing, arterial thromboembolic events, infusion-related reactions, proteinuria, worsening of pre-existing hepatic impairment, Posterior Reversible Encephalopathy Syndrome (PRES); thyroid dysfunction, and embryo-fetal toxicity. Permanent discontinuation should be considered for patients who experience severe bleeding, gastrointestinal perforation, an arterial thromboembolic event, infusion-related reaction of grade 3 or 4, PRES, or nephrotic syndrome.

Ramucirumab is also FDA approved for the treatment of patients with select lung, liver, stomach, and colorectal cancers.


  1. Lilly's CYRAMZA® (ramucirumab) Receives FDA Approval as First-Line Treatment for Metastatic EGFR-Mutated Non-Small Cell Lung Cancer. News release. Eli Lilly and Company. May 29, 2020. Accessed May 30, 2020. https://bit.ly/2zKc9oI
  2. 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. 2019;20(12):1655-1669. doi:10.1016/S1470-2045(19)30634-5