Second-Line Option for Colorectal Cancer

A combination of the angiogenesis inhibitor ramucirumab (Cyramza; Eli Lilly) and FOLFIRI (folinic acid, fluoruracil, and irinotecan) chemotherapy significantly improves overall survival compared with FOLFIRI alone in patients with previously treated advanced colorectal cancer, which is particularly difficult to treat after first-line therapy fails, according to results of a trial presented at the American Society of Clinical Oncology's 2015 Gastrointestinal Cancers Symposium in San Francisco, CA, January 15–17.

The RAISE study randomly assigned 1,072 patients with metastatic colorectal cancer whose disease had progressed after first-line treatment with bevacizumab and chemotherapy (Avastin; Genentech) to receive FOLFIRI with either ramucirumab or placebo every 2 weeks until disease progression, unacceptable toxicity, or death. Tumor shrinkage rates were similar in both groups, but the ramucirumab group had a longer median overall survival (13.3 vs. 11.7 months) and progression-free survival (5.7 vs. 4.5 months) than the control group.

“The RAISE trial clearly demonstrates that sustained inhibition of angiogenesis during first-line and second-line metastatic colorectal cancer therapy improves survival in a clinically representative metastatic colorectal cancer population,” said lead author Josep Tabernero, MD, director of Vall d'Hebron Institute of Oncology in Barcelona, Spain, who presented the findings. “Ramucirumab is an effective new option for second-line treatment, including for patients with poor prognosis.”

The survival benefit was consistent across subgroups, including KRAS mutant and wild-type tumors, noted Tabernero. Patients in the ramucirumab group had a higher incidence of grade 3 and 4 adverse events, such as neutropenia, but most adverse events were manageable and did not cause discontinuation of treatment.

Although the overall survival benefit was small, it adds another active drug to the arsenal of therapies available to patients with colorectal cancer, said Smitha Krishnamurthi, MD, medical oncologist and associate professor of medicine at University Hospitals Case Medical Center and Case Western Reserve University in Cleveland, OH.

“We would certainly like to see stronger results,” she said. “But although 1.5 months is not a long time, we want to offer everything we can, especially since these agents tend to be well tolerated and can be easily combined with chemotherapy.”

The trial should spur development of other second-line treatment strategies that combine angiogenesis inhibitors with chemotherapy, said Tabernero. In addition, more randomized trials are needed to determine whether ramucirumab is effective with chemotherapy regimens other than FOLFIRI. Future investigations should also explore the efficacy of ramucirumab after first-line therapy with the EGFR inhibitor cetuximab (Erbitux; Eli Lilly).

Ramucirumab plus FOLFIRI is not the only treatment option for patients with advanced colorectal cancer. Currently, two other angiogenesis inhibitors—bevacizumab and ziv-aflibercept (Zaltrap; Sanofi)—are approved for use with chemotherapy as second-line treatment. In addition, regorafenib (Stivarga; Bayer), which inhibits multiple kinases, is approved as monotherapy in the refractory setting.

“We already knew that when patients with metastatic colorectal cancer have progression of their disease on first-line chemotherapy plus bevacizumab, we can either continue with bevacizumab and second-line FOLFIRI or use a different angiogenesis inhibitor, such as ziv-aflibercept, with chemotherapy,” said Krishnamurthi. “We now know that ramucirumab can also be given with chemotherapy in this setting.”