PRESCRIBER'S CORNER Section Editors: Christopher J. Campen and Beth Eaby-Sandy Ramucirumab: A New Therapy for Advanced Gastric Cancer ANDREA LANDGRAF OHOLENDT, PharmD, BCOP, and JENNIFER L. ZADLO, PharmD, BCOP From The University of Texas MD Anderson astric cancer is the fourth a third agent, which is typically epi- Cancer Center, Houston, Texas most common cancer in rubicin or docetaxel. Two-drug regi- Authors’ disclosures of potential conflicts of interest are found at the end of this article. men and the fifth most mens are generally preferred, since Correspondence to: Andrea Landgraf Oholendt, common cancer in wom- they are associated with less toxic- PharmD, BCOP, The University of Texas MD Gen worldwide (Jemal et al., 2011). ity (National Comprehensive Cancer Anderson Cancer Center, Division of Pharmacy, The American Cancer Society (ACS) Network [NCCN], 2014). 1515 Holcombe Boulevard, FC6.3002, Unit 90, Houston, TX 77030. has estimated there were 22,220 new Prior to 2014, there were no cate- E-mail: [email protected] cases diagnosed in 2014, with an es- gory 1 recommendations for second- © 2015 Harborside Press® timated 10,990 deaths (Siegel, Ma, line therapy for gastric cancer. The Zou, & Jemal, 2014). Despite some decision to give second-line therapy advances in treatment, gastric can- was generally based on the patient’s cer continues to be associated with performance status and prior ther- poor outcomes. apy exposure. Preferred regimens Approximately two-thirds of pa- included single-agent irinotecan tients diagnosed with gastric cancer or taxane (docetaxel or paclitaxel; have locally advanced or metastatic NCCN, 2014). The development of disease, with a median survival of new therapies offers viable treat- around 10 months (Chau et al., 2004). ment options for patients with ad- Chemotherapy is the primary modal- vanced and metastatic disease. ity for management of advanced and metastatic gastric cancers and has ANGIOGENESIS been shown to improve quality of life Angiogenesis is an important and prolong survival (Wagner et al., process in cancer development and 2006). The standard of care for treat- growth. Angiogenesis is primarily ment of advanced disease is poorly driven by the interactions between defined, with no preferred first- or vascular endothelial growth factor second-line regimens. (VEGF) ligands and VEGF recep- Category 1 recommendations for tors (VEGFRs). The VEGF ligands first-line therapy for locally advanced include VEGF-A, VEGF-B, VEGF- and metastatic disease include a two- C, VEGF-D, VEGF-E, and placental drug regimen of cisplatin combined growth factor (PGF; Claesson-Welsh with a fluoropyrimidine (fluoroura- & Welsh, 2013). Overexpression cil or capecitabine) or cisplatin and of VEGF has been associated with J Adv Pract Oncol 2015;6:71–75 a fluoropyrimidine combined with advanced-stage disease and poor- 71 PRESCRIBER'S CORNER LANDGRAF OHOLENDT and ZADLO er outcomes and prognosis in gastric cancer A total of 238 patients received ramucirum- (Maeda et al., 1996). ab intravenously (IV) at a dose of 8 mg/kg every Bevacizumab (Avastin) was the first antian- 2 weeks, and 117 patients were randomized to giogenic agent approved by the US Food and Drug the placebo arm. The study investigators found a Administration (FDA) and exerts its effect by pre- statistically significant difference in the primary venting the binding of the VEGF-A ligand to its re- endpoint, median overall survival (OS). Patients ceptors. However, a phase III clinical trial did not who received ramucirumab plus BSC had a longer demonstrate a significant improvement in overall median OS, 5.2 months (range, 2.3–9.9 months), survival when adding bevacizumab to chemother- than did patients who received placebo plus BSC, apy for first-line treatment of advanced gastric 3.8 months (1.7–7.1 months); the hazard ratio was cancer (Ohtsu et al., 2011). 0.776 (95% confidence interval [CI], 0.603–0.998), Ramucirumab (Cyramza) is the first FDA- and the p value was .047. Of note, the longer me- approved agent to reduce tumor angiogenesis by dian OS in the ramucirumab arm was preserved targeting the extracellular domain of the VEGFR. when repeated with multivariate analysis (p = It remains unclear why ramucirumab has demon- .037; Fuchs et al., 2014). strated efficacy for advanced gastric cancer while Progression free survival (PFS) was also lon- bevacizumab demonstrated mixed results. One ger with ramucirumab plus BSC (2.1 months; rationale is ramucirumab blocks VEGFR-2, the range, 1.3–4.2 months) than with placebo plus primary receptor for VEGF-A, rather than block- BCS (1.3 months; range, 1.1–2.1 months); the haz- ing the ligand itself (Park, Thomas, Yoon, & Yoon, ard ratio was 0.483 (95% CI, 0.376–0.620), and the 2015; Spratlin, Mulder, & Mackey, 2010). p value was < .0001. Also statistically significant was an increased disease control rate of 49% with MECHANISM OF ACTION ramucirumab plus BSC, compared with 23% with Ramucirumab is a recombinant human immu- placebo plus BSC. noglobulin G1 monoclonal antibody that binds to Best response was modest at best, typically the extracellular binding domain of VEGFR-2 and stable disease (SD), which was seen in 45% of prevents the binding of VEGFR ligands: VEGF-A, patients (n = 108) who received ramucirumab VEGF-C, and VEGF-D (Eli Lilly and Company, plus BSC, and 21% of patients who received pla- 2014; Wadhwa, Taketa, Sudo, Blum-Murphy, & cebo plus BSC (n = 24). Only one patient achieved Ajani, 2013). Through blocking activation of VEG- a complete response, and seven patients (3%) FR-2 by VEGF-A and the other VEGF ligands, achieved a partial response with ramucirum- ramucirumab inhibits the angiogenesis pathways ab plus BSC. Disease progressed in all others involved in the development and progression of (Fuchs et al., 2014). gastric cancer. This study also included a 6-week quality-of- life assessment (QOL), to which data were avail- CLINICAL STUDIES able in 48% and 25% of the patients who received To date, there are two studies evaluating ramucirumab plus BSC and placebo plus BSC, the efficacy of ramucirumab for the treatment respectively. Although not statistically significant of gastric and gastroesophageal (GE) junction (p = .23), there was a trend toward stable or improved adenocarcinoma. The REGARD trial was an in- global QOL reported in patients who received ternational, prospective, double-blind, placebo- ramucirumab plus BSC. There was, however, a sta- controlled, phase III study in adult patients with tistically significant longer time to deterioration advanced or metastatic gastric or GE junction ad- in Eastern Cooperative Oncology Group (ECOG) enocarcinoma. Those patients who failed to re- performance status to a score of ≥ 2 in patients spond to a first-line platinum or fluoropyrimidine- who received ramucirumab plus BSC (5.1 months) containing regimen were randomized in a 2:1 compared with placebo plus BSC (2.4 months; fashion to receive either ramucirumab plus p = .002; Fuchs et al., 2014). best supportive care (BSC) or placebo plus BSC The RAINBOW trial was the second study (Fuchs et al., 2014). to evaluate the efficacy of ramucirumab. The 72 RAMUCIRUMAB PRESCRIBER'S CORNER RAINBOW trial was an international, placebo- As demonstrated in Tables 1 and 2, the adverse controlled, randomized, double-blind, phase drug reaction profile varied when ramucirumab III study of patients with advanced, nonresect- was used as monotherapy vs. in combination with able GE junction or gastric adenocarcinoma that paclitaxel. Because of its antiangiogenic activity, had progressed within 4 months of receiving a concern for serious antiangiogenic adverse drug first-line platinum and fluoropyrimidine-based reactions, including GI perforations, impaired chemotherapy regimen. Patients were ran- wound healing, venous and arterial thrombo- domized to receive ramucirumab at a dose of 8 embolism, and hemorrhage, should be applied. mg/kg IV on days 1 and 15 plus paclitaxel 80 Ramucirumab is currently labeled with a Boxed mg/m2 IV on days 1, 8, and 15 of a 28-day cycle or Warning for hemorrhage and serious bleeding placebo plus paclitaxel 80 mg/m2 IV on days 1, 8, events; however, the incidence of bleeding/hem- and 15 of a 28-day cycle; crossover was prohib- orrhage was similar between ramucirumab and ited. A total of 665 patients were randomized; placebo in the REGARD trial. 330 patients received ramucirumab plus pacli- Although ramucirumab is a recombinant hu- taxel and 335 received placebo plus paclitaxel man monoclonal antibody, infusion-related re- (Wilke et al., 2014). actions have been reported in clinical studies. This study found a statistically significant dif- Therefore, premedication with an IV histamine ference in the primary endpoint of median OS, (H1) antagonist is recommended by the manufac- which was longer in patients who received ramu- turer (Fuchs et al., 2014; Wilke et al., 2014; Eli Lilly cirumab plus paclitaxel (9.6 months) than in those and Company, 2014). who received placebo plus paclitaxel (7.4 months; hazard ratio = 0.807; 95% CI, 0.678–0.962; p = DOSING .017). Improvements in median PFS were also Based on the clinical data presented, ramu- observed with ramucirumab plus paclitaxel (4.4 cirumab is dosed at 8 mg/kg, using actual body months) vs. placebo plus paclitaxel (2.86 months; weight, IV over 60 minutes, every 2 weeks. Cur- p < .0001). A majority of patients achieved SD: 52% rently, ramucirumab is approved by the FDA in in the ramucirumab plus paclitaxel arm vs. 47% in the second-line setting for patients with gastric the paclitaxel plus placebo arm. or GE junction adenocarcinoma, as monotherapy Partial response and complete response were or in combination with paclitaxel, and continued achieved in 27% and < 1%, respectively, of those until disease progression or unacceptable toxicity who received ramucirumab plus paclitaxel com- (Eli Lilly and Company, 2014). pared with 16% and < 1%, respectively, of those who received paclitaxel plus placebo.