Abstract 1298P
Background
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 (C min,1 or C min,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.
Methods
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 (C min,1), and at steady state (C min,ss), which were used to evaluate correlation between RAM exposure and efficacy (primary end point, PFS, analyzed using multivariate Cox regression by C min,1 quartiles, and case-matched controls) and safety (incidence rates for safety parameters by quartiles, with ordered categorical model used for ALT/AST only).
Results
As expected, RAM 10 mg/kg Q2W delivered C min,ss equivalent to the upper C min,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 C min,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).
Conclusions
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.
Clinical trial identification
NCT02411448.
Editorial acknowledgement
Medical writing assistance was provided by John Bilbruck PhD, ProScribe – part of the Envision Pharma Group.
Legal entity responsible for the study
Eli Lilly and Company.
Funding
Eli Lilly and Company.
Disclosure
E.B. Garon: Research grant/Funding (institution), To institution for clinical trial: Eli Lilly and Company; Research grant/Funding (institution), To institution for clinical trial: AstraZeneca; Research grant/Funding (institution), To institution for clinical trial: BMS; Research grant/Funding (institution), To institution for clinical trial: Eli Lilly and Company; Research grant/Funding (institution), To institution for clinical trial: Genentech; Research grant/Funding (institution), To institution for clinical trial: Merck; Research grant/Funding (institution), To institution for clinical trial: Novartis; Research grant/Funding (institution), To institution for clinical trial: Iovance; Research grant/Funding (institution), To institution for clinical trial: Neon; Research grant/Funding (institution), To institution for clinical trial: Dynavax; Research grant/Funding (institution), To institution for clinical trial: Mirati; Advisory/Consultancy, Advisory board: Dracen; Advisory/Consultancy, Steering committee: EMD Serono. L. Gao: Shareholder/Stockholder/Stock options: Eli Lilly and Company. S. Callies: Shareholder/Stockholder/Stock options, Full/Part-time employment: Eli Lilly and Company. A.H. Zimmermann: Shareholder/Stockholder/Stock options, Full/Part-time employment: Eli Lilly and Company. R. Walgren: Shareholder/Stockholder/Stock options, Full/Part-time employment, Patent pending: Eli Lilly and Company. C.M. Visseren-Grul: Shareholder/Stockholder/Stock options, Full/Part-time employment: Eli Lilly and Company. M. Reck: Honoraria (self), Honoraria for lectures and consultancy: AbbVie; Honoraria (self), Honoraria for lectures and consultancy: Amgen; Honoraria (self), Honoraria for lectures and consultancy: AstraZeneca; Honoraria (self), Honoraria for lectures and consultancy: BMS; Honoraria (self), Honoraria for lectures and consultancy: Boehringer Ingelheim; Honoraria (self), Honoraria for lectures and consultancy: Celgene; Honoraria (self), Honoraria for lectures and consultancy: Eli Lilly and Company; Honoraria (self), Honoraria for lectures and consultancy: Merck; Honoraria (self), Honoraria for lectures and consultancy: MSD; Honoraria (self), Honoraria for lectures and consultancy: Novartis; Honoraria (self), Honoraria for lectures and consultancy: Pfizer; Honoraria (self), Honoraria for lectures and consultancy: Roche . All other authors have declared no conflicts of interest.