Final results from a randomized phase 3 study of FOLFIRI {+/-} panitumumab for second-line treatment of metastatic colorectal cancer.

BACKGROUND The study 20050181 demonstrated significant improvements in progression-free survival (PFS), objective response, and a nonsignificant trend toward increased overall survival (OS) with panitumumab-FOLFIRI versus FOLFIRI alone for second-line wild-type (WT) KRAS metastatic colorectal cancer (mCRC). Updated long-term data from a prespecified descriptive analysis are reported. PATIENTS AND METHODS Patients receiving one prior mCRC treatment were randomly assigned (1:1) to panitumumab (6.0 mg/kg)-FOLFIRI versus FOLFIRI every 2 weeks. Co-primary end points (PFS and OS) were prospectively analyzed by tumor KRAS status. RESULTS One thousand one hundred and eighty-six patients were randomly assigned. In patients with WT KRAS tumors, panitumumab-FOLFIRI significantly improved PFS versus FOLFIRI [median 6.7 versus 4.9 months; hazard ratio (HR) 0.82 [95% confidence interval (CI) 0.69, 0.97]; P = 0.023]. A trend toward longer OS was observed (median 14.5 versus 12.5 months; HR 0.92 [95% CI 0.78, 1.10]; P = 0.37). Response rates improved from 10% to 36% (P < 0.0001). From post hoc analyses in patients receiving prior oxaliplatin-bevacizumab, panitumumab-FOLFIRI improved PFS (median 6.4 versus 3.7 months; HR 0.58 [95% CI 0.37, 0.90]; P = 0.014). PFS and OS appeared longer for worst-grade skin toxicity of 2-4, versus 0-1 or FOLFIRI. Safety results were as previously reported and consistent with the known toxicities with anti-epidermal growth factor receptor therapy. CONCLUSIONS These data confirm the primary efficacy and safety findings of this trial and support panitumumab-FOLFIRI as a second-line treatment of WT KRAS mCRC.

[1]  E. Van Cutsem,et al.  Intrapatient cetuximab dose escalation in metastatic colorectal cancer according to the grade of early skin reactions: the randomized EVEREST study. , 2012, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[2]  E. Vasile,et al.  Cetuximab plus irinotecan after irinotecan failure in elderly metastatic colorectal cancer patients: clinical outcome according to KRAS and BRAF mutational status. , 2011, Critical reviews in oncology/hematology.

[3]  Josep Tabernero,et al.  Randomized, phase III trial of panitumumab with infusional fluorouracil, leucovorin, and oxaliplatin (FOLFOX4) versus FOLFOX4 alone as first-line treatment in patients with previously untreated metastatic colorectal cancer: the PRIME study. , 2010, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[4]  E. Van Cutsem,et al.  Randomized phase III study of panitumumab with fluorouracil, leucovorin, and irinotecan (FOLFIRI) compared with FOLFIRI alone as second-line treatment in patients with metastatic colorectal cancer. , 2010, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[5]  M. Stockler,et al.  Capecitabine, bevacizumab, and mitomycin in first-line treatment of metastatic colorectal cancer: results of the Australasian Gastrointestinal Trials Group Randomized Phase III MAX Study. , 2010, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[6]  E. Van Cutsem,et al.  Advanced colorectal cancer: ESMO Clinical Practice Guidelines for treatment. , 2010, Annals of oncology : official journal of the European Society for Medical Oncology.

[7]  S. Dakhil,et al.  A phase II trial of FOLFOX6 and cetuximab in the first-line treatment of patients with metastatic colorectal cancer. , 2010, Clinical colorectal cancer.

[8]  E. Van Cutsem,et al.  Cetuximab and chemotherapy as initial treatment for metastatic colorectal cancer. , 2009, The New England journal of medicine.

[9]  J. Kim,et al.  The Role of KRAS Mutations in Predicting the Efficacy of Cetuximab-Plus-Irinotecan Therapy in Irinotecan-Refractory Korean Metastatic Colorectal Cancer Patients , 2009, Oncology.

[10]  E. Van Cutsem,et al.  Association of progression‐free survival, overall survival, and patient‐reported outcomes by skin toxicity and KRAS status in patients receiving panitumumab monotherapy , 2009, Cancer.

[11]  W. Scheithauer,et al.  EPIC: phase III trial of cetuximab plus irinotecan after fluoropyrimidine and oxaliplatin failure in patients with metastatic colorectal cancer. , 2008, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[12]  W. Scheithauer,et al.  Bevacizumab in combination with oxaliplatin-based chemotherapy as first-line therapy in metastatic colorectal cancer: a randomized phase III study. , 2008, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[13]  Daniel J. Freeman,et al.  Wild-type KRAS is required for panitumumab efficacy in patients with metastatic colorectal cancer. , 2008, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[14]  E. Van Cutsem,et al.  KRAS wild-type state predicts survival and is associated to early radiological response in metastatic colorectal cancer treated with cetuximab. , 2008, Annals of oncology : official journal of the European Society for Medical Oncology.

[15]  Dongsheng Tu,et al.  Cetuximab for the treatment of colorectal cancer. , 2007, The New England journal of medicine.

[16]  Sung Sook Lee,et al.  A Phase II Study of Cetuximab (Erbitux®) plus FOLFIRI for Irinotecan and Oxaliplatin-refractory Metastatic Colorectal Cancer , 2007, Journal of Korean medical science.

[17]  Manuel Hidalgo,et al.  Expression of epiregulin and amphiregulin and K-ras mutation status predict disease control in metastatic colorectal cancer patients treated with cetuximab. , 2007, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[18]  Marc Peeters,et al.  Open-label phase III trial of panitumumab plus best supportive care compared with best supportive care alone in patients with chemotherapy-refractory metastatic colorectal cancer. , 2007, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[19]  P. Catalano,et al.  Bevacizumab in combination with oxaliplatin, fluorouracil, and leucovorin (FOLFOX4) for previously treated metastatic colorectal cancer: results from the Eastern Cooperative Oncology Group Study E3200. , 2007, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[20]  T. Frebourg,et al.  Clinical relevance of KRAS mutation detection in metastatic colorectal cancer treated by Cetuximab plus chemotherapy , 2007, British Journal of Cancer.

[21]  A. Lièvre,et al.  KRAS mutation status is predictive of response to cetuximab therapy in colorectal cancer. , 2006, Cancer research.

[22]  E. Van Cutsem,et al.  Clinical signs, pathophysiology and management of skin toxicity during therapy with epidermal growth factor receptor inhibitors. , 2005, Annals of oncology : official journal of the European Society for Medical Oncology.

[23]  E. Van Cutsem,et al.  Cetuximab monotherapy and cetuximab plus irinotecan in irinotecan-refractory metastatic colorectal cancer. , 2004, The New England journal of medicine.

[24]  J. Berlin,et al.  Bevacizumab plus irinotecan, fluorouracil, and leucovorin for metastatic colorectal cancer. , 2004, The New England journal of medicine.

[25]  M. van Glabbeke,et al.  New guidelines to evaluate the response to treatment in solid tumors , 2000, Journal of the National Cancer Institute.

[26]  R. Greil,et al.  First-line panitumumab plus irinotecan/5-fluorouracil/leucovorin treatment in patients with metastatic colorectal cancer , 2011, Journal of Cancer Research and Clinical Oncology.

[27]  A. Jemal,et al.  Global cancer statistics , 2011, CA: a cancer journal for clinicians.