Josep Tabernero, MD
Second-line treatment with the VEGFR2 inhibitor ramucirumab (Cyramza) combined with standard FOLFIRI extended survival by 1.6 months versus FOLFIRI alone in patients with metastatic colorectal cancer (mCRC), according to results from the phase III RAISE trial. The data were presented at a presscast held ahead of the 2015 Gastrointestinal Cancers Symposium.
“Ramucirumab is an effective new treatment option for second-line treatment [of mCRC], including patients with poor prognosis,” said lead study author Josep Tabernero, MD, director of the Vall d’Hebron Institute of Oncology in Barcelona, Spain.
The double-blind, phase III RAISE trial randomized 1072 patients with mCRC (ECOG PS, 0 or 1) in a 1:1 ratio to FOLFIRI plus the antiangiogenic agent ramucirumab (8 mg/kg IV) or placebo every 2 weeks until disease progression, unacceptable toxicity, or death. The FOLFIRI regimen included 180 mg/m2
of irinotecan; 400 mg/m2
of folinic acid; and 400 mg/m2
bolus of 5-FU, followed by 2400 mg/m2
IV administered continuously over 46 to 48 hours.
Accrued patients had progressed during or after receiving first-line combination therapy with bevacizumab (Avastin), oxaliplatin, and a fluoropyrimidine. Patients were stratified by region, KRAS
mutation status, and time to progressive disease after starting first-line therapy.
OS was the primary endpoint, with secondary endpoints including progression-free survival (PFS), objective response rate (ORR), and toxicity.
The median OS was 13.3 months with ramucirumab plus chemotherapy versus 11.7 months with chemotherapy alone (HR = 0.84; 95% CI, 0.73-0.98; P
= .0219). Median PFS was 5.7 and 4.5 months, respectively (HR = 0.79; 95% CI, 0.70-0.90; P
The OS and PFS results were comparable across patient subgroups.
“The RAISE trial clearly demonstrates that sustained inhibition of the angiogenesis from first-line to second-line mCRC therapy improves survival in a clinically representative mCRC population,” said Tabernero.
Tumor shrinkage rates were similar between the two arms. There was not a statistically significant difference in ORR at 13.4% with the ramucirumab combination and 12.5% in the placebo arm (P
The most common grade ≥3 adverse events in the ramucirumab arm included neutropenia (38.4% vs 23.3% with placebo), hypertension (11.2% vs 2.8%), diarrhea (10.8% vs 9.7%), and fatigue (11.5% vs 7.8%).
The rate of febrile neutropenia was comparable between the two arms at 3.6% and 2.7% in the ramucirumab and placebo arms, respectively.
“We know that when patients with advanced colorectal cancer have progression of their disease on first-line chemotherapy plus bevacizumab, we can either continue the bevacizumab with second-line chemotherapy or use a different angiogenesis inhibitor, ziv-aflibercept (Zaltrap), with chemotherapy. And now we know that ramucirumab can be given with chemotherapy in this setting, as well,” said Smitha S. Krishnamurthi, MD, ASCO expert and moderator of the presscast.
“All of these approaches have had a similar increase in survival,” added Krishnamurthi. “It will now be interesting to see the effect of ramucirumab in other randomized studies and settings for colorectal cancer.”
Ramucirumab, which is marketed by Eli Lilly and Company, has approved indications as a single-agent and in combination with paclitaxel to treat patients with advanced gastric or gastroesophageal junction adenocarcinoma. It is also approved in combination with docetaxel for the treatment of patients with metastatic non–small cell lung cancer.
The agent has also been examined in HER2-negative metastatic breast cancer, but it failed to delay disease progression in a phase III trial.
Tabernero J, Cohn AL, Obermannova R, et al. RAISE: A randomized, double-blind, multicenter phase III study of irinotecan, folinic acid, and 5-fluorouracil (FOLFIRI) plus ramucirumab (RAM) or placebo (PBO) in patients (pts) with metastatic colorectal carcinoma (CRC) progressive during or following first-line combination therapy with bevacizumab (bev), oxaliplatin (ox), and a fluoropyrimidine (fp). 2015 Gastrointestinal Cancers Symposium; January 15-17, 2015; San Francisco, CA. Abstract 512.
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