AT THE GASTROINTESTINAL CANCERS SYMPOSIUM
Adding the antiangiogenic antibody ramucirumab to second-line therapy for metastatic colorectal cancer improves outcomes with acceptable toxicity, according to results of a randomized, phase III trial that will be reported this week at the annual Gastrointestinal Cancers Symposium sponsored by the American Society of Clinical Oncology.
Researchers led by Dr. Josep Tabernero, director of the Vall d’Hebron Institute of Oncology in Barcelona, enrolled 1,072 patients with metastatic colorectal cancer that had progressed after receipt of first-line therapy containing bevacizumab (Avastin).
They randomized the patients evenly to receive FOLFIRI (folinic acid, 5-fluorouracil, and irinotecan) chemotherapy plus either placebo or ramucirumab (Cyramza), an antibody to vascular endothelial growth factor receptor 2 (VEGFR-2) that is approved by the Food and Drug Administration for treatment of advanced stomach, gastroesophageal junction, and non–small cell lung cancers.
Main results showed that relative to the placebo group, the ramucirumab group had superior overall survival (median 13.3 vs. 11.7 months; hazard ratio, 0.84; P = .022), the primary endpoint, and progression-free survival (median 5.7 vs. 4.5 months; HR, 0.79; P = .0005).
The survival benefit was similar across patients stratified by various clinical and disease factors, including tumor KRAS mutational status and time to progression after first-line therapy, Dr. Tabernero reported.
Patients in the ramucirumab group had higher rates of certain grade 3 and 4 adverse events, most commonly neutropenia, fatigue, diarrhea, and hypertension. But the rate of febrile neutropenia was similar for the ramucirumab and placebo groups (3.6% vs. 2.7%).
The trial, known as RAISE (A Randomized, Double-blind, Multicenter Phase III Study of Irinotecan, Folinic Acid, and 5-Fluorouracil [FOLFIRI] Plus Ramucirumab or Placebo in Patients With Metastatic Colorectal Carcinoma Progressive During or Following First-Line Combination Therapy With Bevacizumab, Oxaliplatin, and a Fluoropyrimidine), was sponsored by Eli Lilly, manufacturer of ramucirumab, with collaboration of ImClone Systems.
“The RAISE study met its primary endpoint,” Dr. Tabernero said in a press briefing held before the symposium. “The combination of ramucirumab and FOLFIRI was well tolerated, and overall, the adverse events that patients presented with were manageable.”
“The RAISE study clearly demonstrates that sustained inhibition of the angiogenesis pathway from first-line to second-line metastatic colorectal cancer improves survival in a clinically representative metastatic colorectal cancer population,” he added. “Therefore, ramucirumab is an effective new treatment option for second-line treatment, including patients with poor prognosis.”
“This is the first randomized study indicating activity for ramucirumab in colorectal cancer,” noted press briefing moderator Dr. Smitha S. Krishnamurthi of Case Western Reserve University, Cleveland. “It’s always exciting to have a new active drug for our patients.”
Ramucirumab now adds to the options of continuing bevacizumab and switching to ziv-aflibercept (Zaltrap) as a component of second-line therapy when patients have a failure of bevacizumab-containing first-line therapy, she said. Oncologists in the United States typically continue bevacizumab, likely because patients are familiar with this agent and presumably tolerating it, but emerging data may establish differing safety and/or efficacy profiles that could shift practice patterns.
“All of these approaches have had a similar increase in survival. It will be interesting to see the effect of ramucirumab in other randomized studies and settings for colorectal cancer,” she added.
Dr. Krishnamurthi acknowledged that the absolute gain in survival with ramucirumab in RAISE was modest. “We’d like the results to be even stronger, but what we find with our patients with colorectal cancer is that as they get exposed to all of our active drugs; it does translate into them living longer,” she said. “So I understand 1.5 months is not a long time, but we want to offer everything that we can to our patients, especially because these agents tend to be well tolerated and can be easily combined with chemotherapy.”
