FDA Approves Ramucirumab Plus Erlotinib for Frontline EGFR+ NSCLC

The FDA has approved the combination of ramucirumab (Cyramza) and erlotinib (Tarceva) as a frontline treatment for patients with metastatic non—small cell lung cancer (NSCLC) whose tumors harbor EGFR exon 19 deletions (Ex19del) or exon 21 (L858R) substitution mutations.

At a median follow-up of 20.7 months, the investigator-assessed median progression-free survival (PFS) with the ramucirumab regimen versus erlotinib alone was 19.4 months (95% CI, 15.4-21.6) versus 12.4 months (95% CI, 11.0-13.5), respectively (HR, 0.59; 95% CI, 0.46-0.76; P <.0001).

"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, North America lead investigator of the RELAY trial and associate professor of medicine, David Geffen School of Medicine, University of California, Los Angeles, stated in a press release. "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 multicenter, double-blind, phase 3 RELAY trial, investigators enrolled 449 patients with stage IV NSCLC who harbored either an EGFR Ex19del or exon 21 L858R mutation and had an ECOG performance status of 0 to 1. Those with a known EGFR T790M mutation, received prior treatment with an EGFR TKI or chemotherapy, or had brain metastases were ineligible for enrollment.

Patients were randomized to receive erlotinib at 150 mg daily in combination with either ramucirumab (n = 224) at 10 mg/kg every 2 weeks or placebo (n = 225). Patients received treatment until their disease progressed or they experienced unacceptable toxicity. The primary end point was PFS; secondary end points included safety, OS) overall response rate (ORR), and duration of response (DOR).

The PFS benefit was observed across several patient subgroups, including those with EGFR mutations. Those who harbored Ex19del experienced a median PFS of 19.6 months with the ramucirumab combination compared with 12.5 months with erlotinib (HR, 0.651; 95% CI, 0.469-0.903). Furthermore, those with Ex 21 L858R had a PFS of 19.4 months versus 11.2 months with the combination versus erlotinib alone, respectively.

At an earlier data cutoff of January 23, 2019, 37 OS events were reported in the ramucirumab combination arm compared with 42 events in the erlotinib-alone arm (HR, 0.832; 95% CI, 0.532-1.303). PFS2 data were also immature; however, 61 PFS2 events versus 79 PFS2 events were reported with ramucirumab versus erlotinib alone, respectively.

At the FDA’s request, Eli Lilly and Company, the developer of ramucirumab, provided the agency with an updated OS analysis. With longer follow-up at a data cutoff date of December 31, 2019, the updated hazard ratio for OS was 0.92 (95% CI, 0.65-1.32).

The ORR was 76% in the combination arm compared with 75% in the erlotinib/placebo arm. Moreover, the disease control rate with the ramucirumab combination was 95% versus 96% in those who did not receive the VEGFR-2 inhibitor. The median DOR in the ramucirumab arm versus the control arm was 18 months versus 11.1 months.

In the combination arm in RELAY, the rate of grade ≥3 adverse events (AEs) was 72% compared with 54% for erlotinib alone; the rate of serious AEs was 29% and 21%, respectively. AEs of special interest included bleeding/hemorrhage, hypertension, and proteinuria, and higher incidence of severe infections occurred more frequently in the combination arm.

Investigators also reported that 13% of patients on the ramucirumab/erlotinib arm versus 11% of those on the control arm discontinued treatment due to TEAEs; 85% versus 71% of patients required dose reductions due to these events and 1% versus 0% died due to these events, respectively.

Moreover, more AE-related deaths due to adverse events on study or within 30 days of treatment discontinuation were reported in the ramucirumab plus erlotinib arm (n = 6) compared with 0 in the erlotinib/placebo arm. Of the 6 deaths on the combination arm, the FDA considered 1 death, which was attributed to hemothorax, to be treatment-related. A second death, which occurred from encephalitis influenza, was potentially related to treatment.

Ramucirumab was previously approved for use in combination with docetaxel for the treatment of patients with metastatic NSCLC who progressed while on or following treatment with platinum-based chemotherapy. Patients with EGFR or ALK genomic tumor aberrations should have disease progression on an EGFR or ALK inhibitor.

Ramucirumab also has approved indications in colorectal cancer, hepatocellular carcinoma, and gastric or gastro-esophageal junction adenocarcinoma.

Lilly's CYRAMZA® (ramucirumab) Receives FDA Approval as First-Line Treatment for Metastatic EGFR-Mutated Non-Small Cell Lung Cancer. Published May 29, 2020. https://bit.ly/36V9G7f. Accessed May 30, 2020.

The approval follows a narrow 6 to 5 recommendation vote from the FDA's Oncologic Drugs Advisory Committee and is based on findings from the phase 3 RELAY trial. In the study, results showed that the addition of ramucirumab to erlotinib led to a 41% reduction in the risk of disease progression or death compared with erlotinib alone in the first-line treatment of patients with EGFR-mutated NSCLC.