Ramucirumab/Erlotinib Significantly Improves PFS in Frontline EGFR+ NSCLC

Adding ramucirumab (Cyramza) to erlotinib (Tarceva) reduced the risk of disease progression or death by over 40% versus erlotinib alone as a frontline treatment for patients with EGFR-positive NSCLC, according to findings from the phase III RELAY trial presented at the 2019 ASCO Annual Meeting.

At a median follow-up of 20.7 months, the median progression-free survival (PFS) by investigator assessment was 19.4 months (95% CI, 15.4-21.6) with the ramucirumab combination compared with 12.4 months (95% CI, 11.0-13.5) with erlotinib alone (HR, 0.591; 95% CI, 0.461-0.760; P <.0001).

When presenting the data at the ASCO meeting, lead study author Kazuhiko Nakagawa, MD, PhD, said the median PFS for the ramucirumab combination was comparable to the median PFS with osimertinib (Tagrisso) in the pivotal phase III FLAURA trial that led to the FDA approval of the third-generation TKI for frontline EGFR-positive NSCLC.

The PFS benefit with the ramucirumab combination in the RELAY trial was observed across several key subgroups, including EGFR mutation type. Among patients with Ex19del, the median PFS was 19.6 months with the combination versus 12.5 months with erlotinib alone (HR, 0.651; 95% CI, 0.469-0.903). Among patients with Ex 21 L858R, the median PFS was 19.4 months versus 11.2 months, respectively (HR, 0.618, 95% CI, 0.437-0.874).

“The RELAY regimen is a new treatment option for initial treatment of EGFR-mutated metastatic NSCLC,” said Nakagawa, of the Department of Medical Oncology, Kindai University Faculty of Medicine, Osaka-Sayama, Osaka, Japan.

Nakagawa explained that there is an “unmet need for treatment options that extend EGFR TKI efficacy,” adding that prior research supports dual blockade of VEGF/EGFR signaling pathways in EGFR-positive NSCLC. This led Nakagawa et al to explore the combination of the EGFR TKI erlotinib with the VEGFR2 antagonist ramucirumab in this setting.

The multicenter, double-blind phase III RELAY trial accrued 449 patients with stage IV NSCLC harboring an EGFR Ex19del or Ex 21 L858R mutation, who had an ECOG performance status of 0 to 1. Patients were excluded if they had a known EGFR T790M mutation, prior EGFR TKI or chemotherapy treatment, or brain metastases.

Patient characteristics were well balanced between the study arms. The median patient age was 65 years and 63% of patients were female. Three-fourths of patients were Asian and a quarter of patients were white. About 60% of patients in each arm were never-smokers and half the patients in each arm had an ECOG performance status of 0.

Patients were randomized to erlotinib at 150 mg/day plus either placebo (n = 225) or ramucirumab (n = 224) at 10 mg/kg every 2 weeks. Treatment was administered until disease progression or unacceptable toxicity. The primary endpoint was PFS. Key secondary endpoints included safety, overall survival (OS), overall response rate (ORR), and duration of response.

Overall survival data are not yet mature. At the data cutoff, there were 37 OS events in the combination arm and 42 in the control arm, with an HR of 0.832 (95% CI, 0.532-1.303) favoring the ramucirumab group.

Likewise, the data remain immature for PFS2—the time from randomization to progression on an additional systemic anticancer treatment. There were 61 and 79 PFS2 events in the combination and control arms, respectively, with an HR of 0.690 (95% CI, 0.490-0.972) favoring the ramucirumab arm.

The ORRs were 76% with the combination and 75% in the control arm. The disease control rate was 95% versus 96%, respectively. The median duration of response favored the ramucirumab arm at 18 months compared with 11.1 months for the erlotinib-alone group.

Seventy percent of patients in the ramucirumab arm and 81% of patients in the erlotinib-alone arm had discontinued treatment at the data cutoff date of January 23, 2019. Progressive disease was the primary reason for discontinuation in both arms.

The rate of grade ≥3 treatment-emergent adverse events (TEAEs) was 72% with the ramucirumab combination compared with 54% with erlotinib alone. The rates of serious TEAEs were 29% versus 21%, respectively. The rates of TEAE-related treatment discontinuation, dose adjustment, and death in the combination versus control arms were 13% versus 11%, 85% versus 71%, and 1% versus 0%, respectively.

Two patients in the ramucirumab arm and 3 patients in the control arm had grade 4 increased ALT level. One patient receiving erlotinib alone had grade 4 increase AST level. The most common grade 3 TEAEs in the ramucirumab arm were hypertension (24% vs 5% in the erlotinib-alone arm), acneiform dermatitis (15% vs 9%, respectively), increased ALT (8% vs 6%), diarrhea (7% vs 1%), and increased AST (5% vs 4%).

Nakagawa K, Garon EB, Seto T, et al. RELAY: A multinational, double-blind, randomized Phase 3 study of erlotinib (ERL) in combination with ramucirumab (RAM) or placebo (PL) in previously untreated patients with epidermal growth factor receptor mutation-positive (EGFRm) metastatic non-small cell lung cancer (NSCLC). J Clin Oncol. 2019;37 (suppl; abstr 9000).

<<< 2019 ASCO Annual Meeting