BACKGROUND: Angiogenesis is an important therapeutic target in colorectal carcinoma. Ramucirumab is a human IgG-1 monoclonal antibody that targets the extracellular domain of VEGF receptor 2. We assessed the efficacy and safety of ramucirumab versus placebo in combination with second-line FOLFIRI (leucovorin, fluorouracil, and irinotecan) for metastatic colorectal cancer in patients with disease progression during or after first-line therapy with bevacizumab, oxaliplatin, and a fluoropyrimidine. METHODS: Between Dec 14, 2010, and Aug 23, 2013, we enrolled patients into the multicentre, randomised, double-blind, phase 3 RAISE trial. Eligible patients had disease progression during or within 6 months of the last dose of first-line therapy. Patients were randomised (1:1) via a centralised, interactive voice-response system to receive 8 mg/kg intravenous ramucirumab plus FOLFIRI or matching placebo plus FOLFIRI every 2 weeks until disease progression, unacceptable toxic effects, or death. Randomisation was stratified by region, KRAS mutation status, and time to disease progression after starting first-line treatment. The primary endpoint was overall survival in the intention-to-treat population. This study is registered with ClinicalTrials.gov, number NCT01183780.ld FINDINGS: We enrolled 1072 patients (536 in each group). Median overall survival was 13·3 months (95% CI 12·4-14·5) for patients in the ramucirumab group versus 11·7 months (10·8-12·7) for the placebo group (hazard ratio 0·844 95% CI 0·730-0·976; log-rank p=0·0219). Survival benefit was consistent across subgroups of patients who received ramucirumab plus FOLFIRI. Grade 3 or worse adverse events seen in more than 5% of patients were neutropenia (203 [38%] of 529 patients in the ramucirumab group vs 123 [23%] of 528 in the placebo group, with febrile neutropenia incidence of 18 [3%] vs 13 [2%]), hypertension (59 [11%] vs 15 [3%]), diarrhoea (57 [11%] vs 51 [10%]), and fatigue (61 [12%] vs 41 [8%]). INTERPRETATION: Ramucirumab plus FOLFIRI significantly improved overall survival compared with placebo plus FOLFIRI as second-line treatment for patients with metastatic colorectal carcinoma. No unexpected adverse events were identified and toxic effects were manageable. FUNDING: Eli Lilly.
- MeSH
- dospělí MeSH
- fluorouracil aplikace a dávkování MeSH
- humanizované monoklonální protilátky aplikace a dávkování MeSH
- kamptothecin aplikace a dávkování analogy a deriváty MeSH
- kolorektální nádory farmakoterapie patologie MeSH
- leukovorin aplikace a dávkování MeSH
- lidé středního věku MeSH
- lidé MeSH
- metastázy nádorů MeSH
- monoklonální protilátky aplikace a dávkování MeSH
- organoplatinové sloučeniny aplikace a dávkování MeSH
- přežití po terapii bez příznaků nemoci MeSH
- protokoly antitumorózní kombinované chemoterapie aplikace a dávkování MeSH
- senioři nad 80 let MeSH
- senioři MeSH
- staging nádorů MeSH
- Check Tag
- dospělí MeSH
- lidé středního věku MeSH
- lidé MeSH
- mužské pohlaví MeSH
- senioři nad 80 let MeSH
- senioři MeSH
- ženské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
- klinické zkoušky, fáze III MeSH
- multicentrická studie MeSH
- práce podpořená grantem MeSH
- randomizované kontrolované studie MeSH
BACKGROUND: The Panitumumab Randomized trial In combination with chemotherapy for Metastatic colorectal cancer to determine Efficacy (PRIME) demonstrated that panitumumab-FOLFOX4 significantly improved progression-free survival (PFS) versus FOLFOX4 as first-line treatment of wild-type (WT) KRAS metastatic colorectal cancer (mCRC), the primary end point of the study. PATIENTS AND METHODS: Patients were randomized 1:1 to panitumumab 6.0 mg/kg every 2 weeks + FOLFOX4 (arm 1) or FOLFOX4 (arm 2). This prespecified final descriptive analysis of efficacy and safety was planned for 30 months after the last patient was enrolled. RESULTS: A total of 1183 patients were randomized. Median PFS for WT KRAS mCRC was 10.0 months [95% confidence interval (CI) 9.3-11.4 months] for arm 1 and 8.6 months (95% CI 7.5-9.5 months) for arm 2; hazard ratio (HR) = 0.80; 95% CI 0.67-0.95; P = 0.01. Median overall survival (OS) for WT KRAS mCRC was 23.9 months (95% CI 20.3-27.7 months) for arm 1 and 19.7 months (95% CI 17.6-22.7 months) for arm 2; HR = 0.88; 95% CI 0.73-1.06; P = 0.17 (68% OS events). An exploratory analysis of updated survival (>80% OS events) was carried out which demonstrated improvement in OS; HR = 0.83; 95% CI 0.70-0.98; P = 0.03 for WT KRAS mCRC. The adverse event profile was consistent with the primary analysis. CONCLUSIONS: In WT KRAS mCRC, PFS was improved, objective response was higher, and there was a trend toward improved OS with panitumumab-FOLFOX4, with significant improvement in OS observed in an updated analysis of survival in patients with WT KRAS mCRC treated with panitumumab + FOLFOX4 versus FOLFOX4 alone (P = 0.03). These data support a positive benefit-risk profile for panitumumab-FOLFOX4 for patients with previously untreated WT KRAS mCRC. KRAS testing is critical to select appropriate patients for treatment with panitumumab.
- MeSH
- dospělí MeSH
- fluorouracil aplikace a dávkování škodlivé účinky MeSH
- geny ras MeSH
- kolorektální nádory farmakoterapie genetika patologie MeSH
- kvalita života MeSH
- leukovorin aplikace a dávkování škodlivé účinky MeSH
- lidé středního věku MeSH
- lidé MeSH
- metastázy nádorů MeSH
- monoklonální protilátky aplikace a dávkování škodlivé účinky MeSH
- organoplatinové sloučeniny aplikace a dávkování škodlivé účinky MeSH
- protokoly antitumorózní kombinované chemoterapie aplikace a dávkování škodlivé účinky MeSH
- senioři nad 80 let MeSH
- senioři MeSH
- Check Tag
- dospělí MeSH
- lidé středního věku MeSH
- lidé MeSH
- mužské pohlaví MeSH
- senioři nad 80 let MeSH
- senioři MeSH
- ženské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
- klinické zkoušky, fáze III MeSH
- práce podpořená grantem MeSH
- randomizované kontrolované studie MeSH