Combination Ramucirumab and Erlotinib for NSCLC with EGFR Exon 19 or Exon 21 Mutations

First-line use of ramucirumab plus erlotinib extends progression-free survival in patients with EGFR-mutated metastatic NSCLC compared with erlotinib alone with no negative effect on quality of life.

The RELAY clinical trial evaluated the efficacy and safety of erlotinib (Tarceva), an EGFR tyrosine kinase inhibitor, together with either ramucirumab (Cyramza), a human immunoglobulin G vascular endothelial growth factor receptor 2 antagonist, or placebo in patients with EGFR-mutated metastatic NSCLC as first-line therapy.¹ Eligible patients had untreated metastatic NSCLC with exon 19 deletion or exon 21 L858R substitution and no evidence of CNS metastasis.¹ Randomized patients received erlotinib (150 mg per day) combined with ramucirumab (10 mg/kg every 2 weeks) or erlotinib plus placebo.¹ The study arms were stratified by gender, geographic region (East Asia vs others), EGFR mutation type (exon 19 deletion vs exon 21 L858R substitution), and EGFR mutation testing method (Therascreen or cobas vs others).¹

The primary end point of the RELAY trial was investigator-assessed PFS. Other end points included ORR, DOR, time from randomization to progression after a subsequent therapy, OS, safety, and rate of plasma T790M mutation using the Guardant next-generation sequencing test.¹

A total of 449 patients were randomized in the RELAY trial.¹ Disease and demographic characteristics were well-balanced between the 2 treatment arms: Asian race (77%), female gender (63%), and exon 19 deletion (54%).¹ The combination of ramucirumab plus erlotinib significantly prolonged PFS, DOR, and time from randomization to progression after a subsequent therapy.¹

Grade 3 and higher treatment-emergent AEs were more common with ramucirumab plus erlotinib (72%) compared with erlotinib plus placebo (54%).¹ This difference was largely driven by hypertension (24% vs 5%, no grade 4).¹ There was 1 treatment-related on-study death due to hemothorax in the ramucirumab plus erlotinib arm versus none in the placebo arm.¹

In RELAY, patient-reported outcomes were evaluated as a part of the secondary outcome measures. Disease-related symptoms and their burden for patients were prospectively assessed by the Lung Cancer Symptom Scale.² Mean Lung Cancer Symptom Scale scores were found to be similar for the 2 treatment arms across all study treatment visits, including the 30-day follow-up visit.²

Researchers concluded that first-line use of ramucirumab plus erlotinib led to superior PFS in patients with EGFR-mutated metastatic NSCLC compared with erlotinib plus placebo.¹ The safety profile of this combination was consistent with known risks of the individual drug therapies.¹ Overall quality of life and symptom burden were no different with the addition of ramucirumab to erlotinib compared with erlotinib plus placebo.²

References
1. 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(15_suppl). Abstract 9000.
2. Yoh K, Atagi S, Reck M, et al; for the RELAY Investigators. Patient-reported outcomes in RELAY, a phase 3 trial of ramucirumab plus erlotinib versus placebo plus erlotinib in untreated EGFR-mutated metastatic non-small-cell lung cancer. Curr Med Res Opin. 2020;36:1667-1675.