Evaluating Alternative Ramucirumab Doses as a Single Agent or with Paclitaxel in Second-Line Treatment of Locally Advanced or Metastatic Gastric/Gastroesophageal Junction Adenocarcinoma: Results from Two Randomized, Open-Label, Phase II Studies

SIMPLE SUMMARY: Ramucirumab is indicated at a dosage of 8 mg/kg every 2 weeks as monotherapy or in combination with paclitaxel for second-line advanced/metastatic gastric/gastroesophageal junction (GEJ) adenocarcinoma. A post hoc analysis of the phase III trials REGARD and RAINBOW suggested a positive correlation between ramucirumab exposure and efficacy. Studies JVDB and JVCZ explored different ramucirumab dosing regimens as monotherapy and in combination with paclitaxel, respectively. Here we report results from these studies, in which JVDB evaluated the pharmacokinetics and safety of the currently registered dosing regimen for ramucirumab monotherapy and three exploratory dosing regimens, and JVCZ evaluated the efficacy and safety of a higher dosing regimen of ramucirumab in combination with paclitaxel in second-line gastric/GEJ adenocarcinoma. Overall, the safety profiles were similar between the registered dose and the exploratory dosing regimens. However, a lack of a dose/exposure-response relationship supports the standard dose of ramucirumab as second-line treatment for patients with advanced/metastatic gastric/GEJ adenocarcinoma. ABSTRACT: Studies JVDB and JVCZ examined alternative ramucirumab dosing regimens as monotherapy or combined with paclitaxel, respectively, in patients with advanced/metastatic gastric/gastroesophageal junction (GEJ) adenocarcinoma. For JVDB, randomized patients (N = 164) received ramucirumab monotherapy at four doses: 8 mg/kg every 2 weeks (Q2W) (registered dose), 12 mg/kg Q2W, 6 mg/kg weekly (QW), or 8 mg/kg on days 1 and 8 (D1D8) every 3 weeks (Q3W). The primary objectives were the safety and pharmacokinetics of ramucirumab monotherapy. For JVCZ, randomized patients (N = 245) received paclitaxel (80 mg/m(2)-D1D8D15) plus ramucirumab (8 mg/kg- or 12 mg/kg-Q2W). The primary objective was progression-free survival (PFS) of 12 mg/kg-Q2W arm versus placebo from RAINBOW using meta-analysis. Relative to the registered dose, exploratory dosing regimens (EDRs) led to higher ramucirumab serum concentrations in both studies. EDR safety profiles were consistent with previous studies. In JVDB, serious adverse events occurred more frequently in the 8 mg/kg-D1D8-Q3W arm versus the registered dose; 6 mg/kg-QW EDR had a higher incidence of bleeding/hemorrhage. In JVCZ, PFS was improved with the 12 mg/kg plus paclitaxel combination versus placebo in RAINBOW; however, no significant PFS improvement was observed between the 12 mg/kg and 8 mg/kg arms. The lack of a dose/exposure-response relationship in these studies supports the standard dose of ramucirumab 8 mg/kg-Q2W as monotherapy or in combination with paclitaxel as second-line treatment for advanced/metastatic gastric/GEJ adenocarcinoma.