1298P RELAY, Ramucirumab Plus Erlotinib (RAM+ERL) Versus Placebo Plus Erlotinib (P+ERL) in Untreated EGFR Mutated Metastatic Non-Small Cell Lung Cancer (NSCLC): Exposure-response Relationship

In RELAY, a dose of RAM 10 mg/kg every 2 weeks (Q2W) was selected based on exposure-response analysis, using data from second-line (2L) phase 3 studies investigating RAM 8 mg/kg Q2W in gastric and hepatic cancer and 10 mg/kg Q3W in NSCLC. Data from these studies showed that patients with the higher RAM exposure (Cmin,1 or Cmin,ss) experienced improved efficacy (Tabernero J et al. Mol Cancer Ther. 2017;16:2215-22). Consequently, RELAY used 10 mg/kg Q2W with the goal of optimizing exposure and response. Here we present the exposure–response relationship of RAM from RELAY. Patients received RAM (10 mg/kg, N=216) or P (N=225) Q2W plus ERL (150 mg/day). A population pharmacokinetic model predicted RAM minimum concentration after first dose (Cmin,1), and at steady state (Cmin,ss), which were used to evaluate correlation between RAM exposure and efficacy (primary end point, PFS, analyzed using multivariate Cox regression by Cmin,1 quartiles, and case-matched controls) and safety (incidence rates for safety parameters by quartiles, with ordered categorical model used for ALT/AST only). As expected, RAM 10 mg/kg Q2W delivered Cmin,ss equivalent to the upper Cmin,ss quartile levels achieved in 2L NSCLC (RAM 10 mg/kg Q3W) in ≥70 % of patients. RAM+ERL patients had superior PFS relative to P+ERL patients. No exposure-efficacy relationship was identified in RELAY: PFS HR (mean, 95% CI) for the Cmin,1 quartiles were 0.67 (0.45-0.99), 0.77 (0.53-1.12), 0.57 (0.38-0.84), and 0.50 (0.33-0.76). No apparent exposure-safety relationship was observed for selected safety endpoints, including Grade ≥3 TEAEs (hypertension, diarrhea, dermatitis acneiform) and AESIs (any grade hypertension, any grade and Grade ≥3 proteinuria, and any grade ALT/AST increased within liver failure/liver injury). The recommended 10 mg/kg Q2W RAM dose combined with ERL (150 mg/day) is an efficacious and safe 1L treatment for EGFR-mutated, metastatic NSCLC. RAM exposure was increased compared to that in previous phase 3 trials using 10 mg/kg Q3W. These data suggest that RAM IV 10 mg/kg Q2W with ERL is an optimized dosing regimen for this indication.