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For patients with adenocarcinomas of the esophagus and stomach, conventional 5-fluorouracil (5-FU) plus platinum-based chemotherapy achieves an overall survival of only 9 to 11 months. The only targeted therapy approved for this disease is trastuzumab, which improves response and survival when combined with chemotherapy in human epidermal growth factor receptor 2 (HER2)-positive metastatic disease (JW Oncol Hematol Sep 14 2010).
Investigators from the U.K. now report the results of an industry-funded, open-label, multicenter, randomized, phase III trial of the epidermal growth factor receptor (EGFR)-targeted agent panitumumab plus chemotherapy for untreated metastatic esophagogastric cancer. Patients received either EOC: epirubicin (50 mg/m2), oxaliplatin (130 mg/m2), and capecitabine (1250 mg/m2/day for 21 days) cycled every 3 weeks; or modified EOC plus panitumumab: epirubicin (50 mg/m2), oxaliplatin (100 mg/m2), and capecitabine (1000 mg/m2/day for 21 days) plus panitumumab (9 mg/kg) cycled every 3 weeks.
Of 1000 planned patients, only 553 were treated due to early trial closure after an interim analysis showed inferior overall survival with modified EOC plus panitumumab. Most patients treated were male (82%–83%), were age 60 or older (60%–62%), and had performance status 1 (52%) and cancers of the esophagus (38%–40%) or gastroesophageal junction (27%–34%).
Although rates of response were equivalent in the two treatment arms (42%–46%), modified EOC plus panitumumab resulted in inferior overall survival (the primary endpoint; 8.8 vs. 11.3 months; HR 1.37; P=0.013) and a trend toward inferior progression-free survival (6.0 vs. 7.4 months; HR 1.22; P=0.068). Modified EOC plus panitumumab resulted in more grade 3 or 4 diarrhea, mucositis, and skin rash, but less grade 3 or 4 neuropathy and hematologic toxicity, likely due to a shorter duration of therapy.
Waddell T et al. Epirubicin, oxaliplatin, and capecitabine with or without panitumumab for patients with previously untreated advanced oesophagogastric cancer (REAL3): A randomized, open-label phase 3 trial. Lancet Oncol 2013 May; 14:481.
Comment
This large, randomized trial in unselected patients with advanced esophagogastric cancer indicates that the addition of panitumumab to chemotherapy has a deleterious effect on patient outcomes. These findings are consistent with those simultaneously reported for cetuximab. Given these strikingly negative results, interest in further study of potential EGFR-targeted therapies for esophagogastric cancer will likely diminish, and the possibility of discovering a biomarker to identify patients who might benefit from such treatments is unlikely.