New findings from the international RAISE phase III study of 1,072 patients with metastatic colorectal cancer (mCRC) whose disease progressed on or after first-line therapy with bevacizumab, oxaliplatin, and a fluoropyrimidine, indicate that a combination of ramucirumab and FOLFIRI provides an overall survival (OS) advantage over standard second-line treatment with FOLFIRI alone. On average, patients treated with the ramucirumab combination lived six weeks longer than those treated with FOLFIRI plus placebo. The study was presented at 2015 Gastrointestinal Cancers Symposium (15-17 January 2015, San Francisco, USA).
The findings provide proof-of-concept for the development of new second-line treatment strategies for advanced colorectal cancer, especially using a combination of an anti-angiogenic drug with standard chemotherapy in those whose disease progresses after first-line chemotherapy with bevacizumab.
Angiogenesis is an important therapeutic target in colorectal cancer; VEGF plays a key role in angiogenesis. Ramucirumab is a human IgG1 monoclonal antibody that targets the extracellular domain of VEGFR-2. The agent is currently approved by FDA for the treatment of gastric and non-small cell lung cancers. The European Medicines Agency until now recommended its approval for gastric cancer only, but it is being studied in a range of other cancers, as well.
Patients with mCRC whose disease progressed on or after first-line treatment with bevacizumab and chemotherapy consisting of oxaliplatin plus a fluoropyrimidine were randomly assigned to treatment with FOLFIRI/ramucirumab or FOLFIRI/placebo (536 patients in each group). Other eligibility criteria were an ECOG performance status 0 or 1 and adequate organ function. The patients were randomised 1:1 (stratified by region, KRAS mutation status, and time to disease progression after beginning first-line treatment) to receive second line-therapy until disease progression, unacceptable toxicity, or death.
The OS was the main objective of the study. Secondary endpoints included progression-free survival (PFS), objective response rate (ORR), and safety.
The median OS was 13.3 months in the ramucirumab group compared with 11.7 months in the placebo group (hazard ratio, HR 0.84, p=0.0219). The PFS HR was 0.79 (p = 0.0005). Median PFS with ramucirumab was 5.7 months and 4.5 months for placebo. The ORR was 13.4% in the ramucirumab arm and 12.5% in the placebo arm (p = 0.6336). Subgroup results were consistent with the OS and PFS results.
Grade ≥3 adverse events occurring in >5% of patients were neutropenia (38.4% in the ramucirumab arm vs. 23.3% in the placebo arm), hypertension (11.2% vs. 2.8%), diarrhoea (10.8% vs. 9.7%), and fatigue (11.5% vs. 7.8%).
The authors concluded that the RAISE study met its primary endpoint, demonstrating a statistically significant improvement in OS for ramucirumab and FOLFIRI in second-line mCRC patients. Benefits were similar across important clinical subgroups and no unexpected adverse events were identified.
According to lead author of the study Dr. Josep Tabernero, director of the Vall d’Hebron Institute of Oncology in Barcelona, Spain, “It is very encouraging that we now have another safe option that adds benefit to standard chemotherapy in this second-line setting.” Dr. Tabernero stated that while this study clearly shows that ramucirumab adds benefit to FOLFIRI chemotherapy, the findings should not be extrapolated to other chemotherapy regimens without formal investigation in clinical trials. Further research is also needed to explore potential benefits of ramucirumab after first-line treatment with the EGFR inhibitor cetuximab.
Other angiogenesis inhibitors that have shown benefit in the second-line treatment of advanced colorectal cancer include bevacizumab and aflibercept, while regorafenib has shown benefit in the refractory setting. Bevacizumab and aflibercept are used in combination with chemotherapy, whereas regorafenib is approved as a single therapy for patients with previously treated mCRC.
The study was funded by Eli Lilly and Company.