Ramucirumab (RAM) is approved for the treatment of advanced gastric cancer or gastroesophageal junction adenocarcinoma with disease progression after prior platinum and/or fluoropyrimidine chemotherapy at 8 mg/kg every 2 weeks (Q2W) based on results of 2 phase 3 trials. Exposure-response analyses from these trials indicated efficacy of RAM correlated with exposure. JVDB is an open-label RAM monotherapy study that examined pharmacokinetics (PK) and safety of the standard and 3 higher exposure regimens.
Patients (n = 164) were randomized 1:1:1:1 to 4 treatment arms: 8 mg/kg Q2W (Arm 1), 12 mg/kg Q2W (Arm 2), 6 mg/kg every week (Arm 3), and 8 mg/kg Days 1 and 8 (D1D8) every 3 weeks (Q3W) (Arm 4). PK was collected from all groups. Treatment-emergent adverse events (TEAEs) were graded by NCI CTCAE v4.0. Tumor response was assessed by RECIST 1.1.
Mean RAM trough and peak concentrations are shown (Table). Median (months) progression-free survival (PFS) was similar across all arms (Arm 1=1.45; Arm 3=1.54; Arm 4=1.51), with the exception of Arm 2=2.50. PFS hazard ratio (HR) for Arm 2 vs 1=0.82; Arm 3 vs 1=0.88; Arm 4 vs 1=0.77. Overall survival (OS) HR for Arm 2 vs 1=0.70; Arm 3 vs 1=0.95; Arm 4 vs 1=0.90. The most common TEAEs were fatigue (22.4%), decreased appetite (21.1%), abdominal pain (18%), and vomiting (18%), consistent with the REGARD trial.Table:
|Trough (μg/ml)||Peak (μg/ml)|
|Arm||Regimen||Week 6||Week 12||Week 6||Week 12|
|1||8 mg/kg Q2W (standard)||47.6||64.3||189||195|
|2||12 mg/kg Q2W||71.0||79.4||303||309|
|3||6 mg/kg QW||83.0||125||187||226|
|4||8 mg/kg D1D8 Q3W||57.4||81.6||180||210|
Trough concentrations of the 3 experimental regimens were greater than the standard regimen. Arm 2 displayed the highest peak RAM concentration. Though efficacy findings were not significant, some trends toward improved PFS and OS versus the standard regimen were observed. Despite higher RAM exposures observed with the alternative regimens, safety profiles were comparable to the standard regimen.
Clinical trial identification
Legal entity responsible for the study
Eli Lilly and Company
Eli Lilly and Company
J.A. Ajani: Honoraria: Lilly, Bayer, Novartis, Five Prime Therapeutics, Taiho, Genentech, Celgene Funding: Novartis, BMS, Taiho, Genentech, MedImmune, Amgen, Lilly, Merck, Delta-Fly, Gilead Sciences, Takeda, Celgene. M. Shenker: Corporate-sponsored research, meaning international clinical trials (like JVDB trial), for which I have financial contract as PI: Eli Lilly, Pfizer, Roche, Novartis, BMS, MSD, Merck Serono, Boehringer Ingelheim, Amgen, Astellas, Mylan. C. Tournigand: Honoraria from Eli Lilly. D. Ferry, Y. Zhang, A. Long, W-L. Kuo, L. Gao, J. Kauh: Employee of Eli Lilly. All other authors have declared no conflicts of interest.