Ramucirumab (ImCLone Systems), a monoclonal antibody vascular endothelial growth factor receptor-2 (VEGFR-2) antagonist, showed improved overall survival (OS) and progression-free survival (PFS) in patients who had undergone first-line chemotherapy for advanced gastric cancer.
Median survival for patients completing cytotoxic chemotherapy is eight to 10 months. The international investigators in this Phase III, randomized double-blind, placebo-controlled trial (dubbed the REGARD trial) sought to find an alternative for second-round treatments that would extend OS and improve quality of life (QoL).
The study, whose principal author was Charles S. Fuchs from the Dana-Farber Cancer Institute, Boston, randomized 355 patients with metastatic or unresectable locally recurrent gastric or gastroesophageal junction adenocarcinoma into treatment arms of ramucirumab (n=238) or placebo (n=117). All had experienced disease progression after recent chemotherapy and had Eastern Cooperative Oncology Group performance status scores of 0 or 1. Participants received ramucirumab, 8 mg/kg, or IV placebo once every two weeks. Findings were reported in the Lancet (2014;383:31-39, PMID: 24094768).
At the time of data cutoff, 278 patients had died, 179 (75%) of whom were from the ramucirumab arm and 99 (85%) the placebo arm. Median OS was 5.2 months in the ramucirumab arm and 3.8 months in the placebo arm. Median PFS was 2.1 months in the ramucirumab group and 1.3 months in the placebo group.
Reported adverse events (AEs) in both groups were high (94% for ramucirumab and 88% for placebo). Grade 1 to 3 hypertension was greater in the ramucirumab group; no instances of grade 4 hypertension were reported. There were no increased rates noted of fatigue, decreased appetite, vomiting or anemia in the ramucirumab arm. According to patient-completed QoL surveys, the ramucirumab group experienced a longer time until deterioration in their performance status, and consequently reported a higher QoL for a longer period.
These results indicate ramucirumab may be an effective single-agent treatment option for patients with advanced gastric cancer.
Joseph Chao, MD|
Clinical Assistant Professor
Department of Medical Oncology and Developmental Therapeutics
City of Hope
The REGARD study is remarkable in demonstrating that a monoclonal antibody alone, ramucirumab, added to best supportive care can yield a survival benefit in a treatment-refractory gastric cancer patient population.1 Ramucirumab also has been investigated in combination with paclitaxel in the second-line, Phase III RAINBOW trial, in which an initial press release has indicated this strategy is superior to paclitaxel alone, and these study results will likely have been presented in a major scientific meeting at the time of this commentary’s publication.
Ramucirumab may finally be the second targeted agent approved for gastroesophageal cancer since the initial approval of trastuzumab in 2010. This, however, was not the first prospective, large randomized trial to investigate an antiangiogenesis approach in gastric cancer. Although the AVAGAST (Avastin in Gastric Cancer) trial was considered to be negative on intent-to-treat analysis for OS, there was still a significant improvement in the secondary end points of PFS and disease response rates, providing initial credence to this strategy for this disease.2
Ramucirumab also was well tolerated, with an acceptable safety profile. Both the placebo and ramucirumab arms had a high proportion (>70%) of patients with their primary tumor in place, and also a sizable group (>25%) with peritoneal metastases that may have predisposed patients to bowel obstruction. Despite this, rates of grade 3 or higher hemorrhage (3%), gastrointestinal perforation (<1%) and fistula formation (<1%) were comparable between the two arms.
The REGARD trial also generates some thought-provoking inquiries in meeting its primary end point where AVAGAST did not. Are patients who progress on first-line therapy and eligible for second-line treatment more dependent on VEGF pathway signaling? The biomarker analyses remain to be presented in a separate report, although those that are of great interest to be explored include circulating VEGF-A and tumor neuropilin-1 (NRP-1) expression. In AVAGAST, high baseline circulating VEGF-A levels in non-Asian patients predicted a benefit from bevacizumab,2 and non-Asian patients encompassed the majority (>80%) of the patient population enrolled in the REGARD trial. Whether the greater proportion of Asian patients enrolled in AVAGAST diluted the efficacy signal for bevacizumab would be an interesting conjecture, although subject to the caveats of cross-trial comparisons. Patients with low tumor NRP-1 expression at baseline also appeared to experience a greater beneficial treatment effect from bevacizumab with regard to OS, PFS and objective response rate in the AVAGAST study. NRP-1 has thus far been found to be a co-receptor with VEGFR-1 and VEGFR-2, although the exact molecular mechanisms in which it mediates VEGF signaling and angiogenesis still remain under investigation.3
If circulating VEGF-A and tumor NRP-1 are predictive of ramucirumab benefit we would then have two prospective Phase III trials, including AVAGAST, which support that these biomarkers may predict for benefit from angiogenesis inhibitors in gastric cancer. Furthermore, VEGFR-2 now appears to be a viable target for the further development of novel agents. The next generation of prospective clinical trials that emphasize integral biomarker incorporation4 will hopefully better guide the maximizing of antiangiogenesis strategies for our patients.
- Fuchs CS, Tomasek J, Cho JY, et al. REGARD: a phase III, randomized, double-blinded trial of ramucirumab and best supportive care (BSC) versus placebo and BSC in the treatment of metastatic gastric or gastroesophageal junction (GEJ) adenocarcinoma following disease progression on first-line platinum- and/or fluoropyrimidine-containing combination therapy. ASCO Meeting Abstracts 2013;31:LBA5.
- Van Cutsem E, de Haas S, Kang Y-K, 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. 2012;30:2119-2127, PMID: 22565005.
- Koch S. Neuropilin signalling in angiogenesis. Biochem Soc Trans. 2012;40:20-25, PMID: 22260660.
- Schilsky RL, Doroshow JH, LeBlanc M, Conley BA. Development and use of integral assays in clinical trials. Clin Cancer Res. 2012;18:1540-1546, PMID: 22422406.
Dr. Chao reported no relevant financial disclosures.