As reviewed in this issue of The ASCO Post (page 155), the RAINBOW trial is an international phase III study demonstrating improved overall survival with ramucirumab (Cyramza) plus paclitaxel as second-line therapy for patients with advanced gastric/gastroesophageal junction adenocarcinoma over paclitaxel alone.1 This is the second study examining ramucirumab—an antibody inhibitor of vascular endothelial growth factor receptor 2 (VEGFR2)—in advanced gastric cancer. The first was the REGARD study, which was also an international phase III study that demonstrated improved overall survival over best supportive care in the second-line treatment of gastric cancer.2
Ramucirumab is a viable biologic treatment for this disease and, moreover, a harbinger of a new era of targeted therapies in advanced gastric/gastroesophageal junction adenocarcinomas.
REGARD and RAINBOW
Both the REGARD and RAINBOW trials were well designed and well performed. REGARD was a double-blind, placebo-controlled trial, employing a 2:1 randomization of 355 patients, with 238 patients assigned to receive ramucirumab and 117 assigned to placebo. Patients were required to have disease progression within 4 months of their last dose of a platinum and/or fluoropyrimidine-containing therapeutic regimen when administered for metastatic or incurable disease or within 6 months of completion of adjuvant therapy. Patients were also required to have an Eastern Cooperative Oncology Group performance status 0 or 1, a highly functioning patient population for second-line treatment in advanced gastric/gastroesophageal carcinoma.
Patients assigned to receive ramucirumab had significantly improved overall survival, with a hazard ratio (HR) of 0.78 (95% confidence interval [CI] = 0.603–0.998, P = .047). Progression-free survival was also improved, with a hazard ratio of 0.48 (95% CI = 0.38–0.62, P < .0001).2
As described in the publication summary, RAINBOW was a larger study, randomly assigning 665 patients in a 1:1 manner to receive paclitaxel with or without ramucirumab. The hazard ratio for overall survival was 0.81, with an associated median survival of 9.6 months with the addition of ramucirumab to paclitaxel and 7.4 months with paclitaxel alone (P = .017). Progression-free survival was also improved, with a highly significant hazard ratio of 0.635 (4.4 months with ramucirumab/paclitaxel vs 2.9 months with paclitaxel alone, P < .0001).1
Related Studies
Another important and related phase III study was reported at the ASCO Annual Meeting (by Professor Shukui Qin) this past June—that is, the double-blind study of apatinib in advanced gastric cancer, which also demonstrated benefit of antiangiogenic therapy in gastric cancer.3 In this trial, 270 patients were randomly assigned 2:1 to apatinib, an oral small-molecule inhibitor of VEGFR2, vs placebo in the third-line setting. The study also demonstrated a similar improvement in overall survival, with a hazard ratio of 0.71 (95% CI = 0.54–0.94, P < .016).3
Also of relevance is the first phase III study to test the paradigm of antiangiogenic treatment in gastric cancer with the antibody VEGF inhibitor bevacizumab (Avastin). The AVAGAST study was a large, international randomized phase III study of first-line chemotherapy with or without bevacizumab in advanced gastric cancer.4 Although a negative study (median overall survival of 12.1 months vs 10.1 months, HR = 0.87, P = .1), it did provide evidence of improved efficacy with the addition of antiangiogenic therapy.
Patients randomly assigned to receive chemotherapy with bevacizumab had significantly improved progression-free survival and response rates. Two candidate biomarkers were identified—plasma VEGF-A and neuropilin 1 (NRP1). Specifically, improved patient survival was suggested in patients with plasma VEGF-A levels above the median (HR = 0.72, 95% CI = 0.57–0.93) or low NRP1 expression (HR = 0.75, 95% CI = 0.59–0.97).5 The biomarker analysis is ongoing and eagerly awaited.
Validated Target
Together, these studies validate VEGFR2 inhibition (and I would submit, antiangiogenic therapy) as a validated target in the treatment of advanced gastric cancer, now the second validated target in this disease (the first being HER2 targeting with trastuzumab [Herceptin]).6 We are certainly in the dawn of a new era in the treatment of upper gastrointestinal malignancies, with several thousand patients enrolling on random assignment studies evaluating novel targeted agents.7
Perhaps most exciting is that genomic or precision medicine may also be a reality, with the recent report of four molecular subtypes of gastric cancer based on comprehensive genomic analyses.8 With guarded optimism, I would suggest that the strategy validated by the RAINBOW and REGARD studies will represent one of several new options in the relatively near future for our patients with upper gastrointestinal malignancies. ■
Disclosure: Dr. Shah has received research funding from Genentech and Sanofi-Aventis.
References
1. Wilke H, Muro K, Van Cutsem E, et al: Ramucirumab plus paclitaxel versus placebo plus paclitaxel in patients with previously treated advanced gastric or gastro-esophageal junction adenocarcinoma (RAINBOW): A double-blind randomised phase 3 trial. Lancet Oncol 15:1224-1235, 2014.
2. Fuchs CS, Tomasek J, Yong CJ, et al: Ramucirumab monotherapy for previously treated advanced gastric or gastro-oesophageal junction adenocarcinoma (REGARD): An international, randomised, multicentre, placebo-controlled, phase 3 trial. Lancet 383:31-39, 2014.
3. Qin S: Phase III study of apatinib in advanced gastric cancer: A randomized, double-blind, placebo-controlled trial. J Clin Oncol 32(5 suppl):Abstract 4003, 2014.
4. Ohtsu A, Shah MA, Van Cutsem E, et al: Bevacizumab in combination with chemotherapy as first-line therapy in advanced gastric cancer: A randomized, double-blind, placebo-controlled phase III study. J Clin Oncol 29:3968-3976, 2011.
5. Van Cutsem E, de Haas S, Kang YK, et al: Bevacizumab in combination with chemotherapy as first-line therapy in advanced gastric cancer: A biomarker evaluation from the AVAGAST randomized phase III trial. J Clin Oncol 30:2119-2127, 2012.
6. Bang YJ, Van Cutsem E, Feyereislova A, et al: Trastuzumab in combination with chemotherapy versus chemotherapy alone for treatment of HER2-positive advanced gastric or gastro-oesophageal junction cancer (ToGA): A phase 3, open-label, randomised controlled trial. Lancet 376:687-697, 2010.
7. Shah MA: Gastrointestinal cancer: Targeted therapies in gastric cancer—the dawn of a new era. Nat Rev Clin Oncol 11:10-11, 2014.
8. Cancer Genome Atlas Research Network: Comprehensive molecular characterization of gastric adenocarcinoma. Nature 513:202-209, 2014.
