• What is the approach to second-line therapy for metastatic gastric cancer?
Improvements in our understanding of the molecular pathways that lead to tumorigenesis have contributed to the development of several targeted agents whose efficacy in gastric cancer is being investigated. The NCCN guidelines recommend that for all patients who progress on frontline therapy, second-line therapy consists of a combination of ramucirumab and paclitaxel. Other options include single-agent docetaxel, paclitaxel, irinotecan, or ramucirumab. Combination therapy using irinotecan with either docetaxel, fluorouracil, or cisplatin may also be used.
Ramucirumab, a human IgG1 monoclonal antibody that targets the vascular endothelial growth factor receptor 2 (VEGFR2), was initially approved in 2014 as monotherapy for patients who had previously progressed on first-line chemotherapy. Its approval was based on the results of the phase 3 randomized, double-blind placebo-controlled REGARD study.26 The trial randomly assigned 355 patients with advanced gastric or GEJ adenocarcinoma and disease progression after first-line platinum-containing or fluoropyrimidine-containing chemotherapy to receive best supportive care plus either ramucirumab (n = 238) or placebo (n = 117). Monotherapy with ramucirumab significantly improved median OS compared with placebo (5.2 months versus. 3.8 months; HR 0.776 [95% CI 0.6 to 0.99], P = 0.047). There was also an improvement in PFS of 2.1 months in the ramucirumab cohort, as compared to 1.3 months in the placebo cohort (P < 0.0001). Patients in the ramucirumab arm experienced a higher incidence of hypertension (16% versus 8%), but all other adverse events occurred at comparable rates. Five deaths in the ramucirumab group were thought to be secondary to the study drug, as compared to 2 deaths in the placebo group.
In the subsequent phase 3 RAINBOW trial, the addition of ramucirumab to paclitaxel was investigated, with 330 patients assigned to the combination group and 335 to the paclitaxel-only group.27 The trial again showed that combination therapy afforded patients a significant survival advantage compared to paclitaxel alone, with a median OS of 9.6 months versus 7.4 months for the monotherapy group (HR 0.807 [95% CI 0.678 to 0.962], P = 0.017). A PFS benefit of 4.4 months was observed in the combination therapy groups, as compared with 2.9 months in the monotherapy group (HR 0.635, P < 0.0001). The ramucirumab/paclitaxel group also had a higher overall response rate of 28% versus 16%. The combination cohort had an increased incidence of grade 3 or higher adverse hypertensive events (14% versus 2%) and neutropenia (41% versus 19%), while the incidence of grade 3 febrile neutropenic events was similar between the groups (3% versus 2%).
The addition of bevacizumab, another monoclonal antibody against VEGF, to standard chemotherapy regimens has been explored, but studies have failed to show a survival benefit with this agent in the first-line treatment of advanced gastric cancer. The phase 3 Avastin in Gastric Cancer (AVAGAST) trial was a multinational, randomized study where patients received either bevacizumab (n = 387) or placebo (n = 387) in addition to cisplatin and capecitabine.28 The substitution of fluorouracil for capecitabine was permitted for patients who were unable to tolerate oral medications. Cisplatin was administered for a maximum of 6 cycles, while capecitabine and bevacizumab were administered until disease progression. The study failed to show an improvement in OS, with a median OS of 12.1 months noted in the bevacizumab cohort, as compared to 10.1 months in the placebo arm (HR 0.87 [95% CI 0.73 to 1.03], P = 0.1002). However, there was a modest improvement in median PFS (6.7 months versus 5.3 months; HR 0.80 [95% CI 0.68 to 0.93], P = 0.0037) and overall response rate (46% versus 37.4%, P = 0.0315). The most commonly reported grade 3 to 5 adverse events included neutropenia (35%), anemia (10%), and loss of appetite (8%). Interestingly, in a follow-up report, higher serum levels of VEGF-A were thought to correlate with an enhanced response to bevacizumab.29 However, the routine use of biomarker analysis in selecting patients for treatment with bevacizumab in metastatic gastric cancer remains to be further clarified.