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Adding the VEGF inhibitor ramucirumab (Cyramza) to first-line treatment in EGFR-mutant non-small cell lung cancer (NSCLC) significantly slowed disease progression, the international phase III RELAY trial indicated.

In stage IV patients with exon 19 deletions/L858R mutations treated with erlotinib (Tarceva), median progression-free survival (PFS) reached 19.4 months with the addition of ramucirumab compared with 12.4 months with placebo (HR 0.59, 95% CI 0.46-0.76, P<0.0001), Kazuhiko Nakagawa, MD, PhD, of Kindai University in Osaka, Japan, and colleagues reported.

"Ramucirumab plus erlotinib provided superior progression-free survival versus placebo plus erlotinib in first-line metastatic EGFR-mutated NSCLC. Safety was consistent with the established safety profiles of the individual compounds and a metastatic NSCLC population," Nakagawa's group wrote in the . "The RELAY regimen is therefore a viable new treatment option for the initial treatment of patients with metastatic EGFR-mutated NSCLC."

While overall response rates were similar, at 76% in the combination group versus 75% in the monotherapy group, median duration of response was superior with erlotinib-ramucirumab (18.0 vs 11.1 months).

Overall survival (OS) data were immature, however. At 12 months, 94% in the monotherapy group were alive compared with 93% in the combination group. At 24 months, these rates were 79% and 83%, respectively. But the authors said an assessment of time to second progression, which can serve as a potential surrogate for OS, "suggest that the ramucirumab plus erlotinib treatment effect was preserved after discontinuation of study treatment and that patients maintained a benefit from the treatment combination through their second progression."

Findings from RELAY mirror a similar trial () in this setting, where adding the anti-VEGFA antibody bevacizumab (Avastin) to erlotinib improved PFS compared with erlotinib alone (16.9 vs 13.3 months).

"Ramucirumab, a human monoclonal IgG1 antibody, selectively targets VEGFR2, thereby blocking signalling mediated by VEGFA, VEGFC, and VEGFD in NSCLC," Nakagawa's group explained. "Therefore, ramucirumab has the potential for broader anti-tumor activity than inhibitors of VEGFA."

In an , Rafael Rosell, MD, PhD, and Carlos Pedraz-Valdunciel, both of the Autonomous University of Barcelona in Spain, pointed to the low complete response rates with the addition of VEGFR2 blockade (1% in RELAY and 7% in NEJ026) and questioned the rationale of the current approach.

"Although the combination of erlotinib with bevacizumab or ramucirumab has shown a longer progression-free survival than erlotinib alone, it might activate Met, as has been seen in cancer cell lines, the consequences of which are invasion and metastases," they wrote. "Unfortunately, this hypothesis is not easily proven."

Rosell and Pedraz-Valdunciel suggested that other combinatorial approaches with currently available agents might confer greater benefit at preventing treatment resistance in EGFR-mutant disease.

Since RELAY was started, however, first-line treatment of EGFR-mutated NSCLC has evolved. In the U.S., patients are treated with osimertinib (Tagrisso) alone based on findings from the FLAURA trial, which most recently reported a nearly 7-month OS advantage against physician's choice of erlotinib or gefitinib (Iressa).

From 2016 to 2018, RELAY randomized 225 stage IV NSCLC patients without brain involvement to oral erlotinib (150 mg daily) plus placebo and 224 patients to erlotinib plus intravenous ramucirumab (10 mg/kg) every 2 weeks at 100 centers across 13 countries. Median patient age was about 65, and roughly three-quarters of the cohort were Asian and 22% were white.

Stratification factors included sex, geography, and EGFR mutation type. The PFS benefit with ramucirumab versus placebo was similar regardless of mutation type:

• Exon 19 deletions: 19.6 vs 12.5 months
• L858R mutations: 19.4 vs 11.2 months

Common grade 3/4 treatment-emergent adverse events (AEs) included hypertension (24%) and dermatitis acneiform (15%) in the combination arm; and dermatitis acneiform (9%) and increased liver enzymes (8%) in the erlotinib group. Serious AEs were reported in 29% of patients in the ramucirumab arm versus 21% in the placebo group.