Drug Development in Advanced Esophagogastric Cancer: The Art of Extrapolation
Authors: Cornelis J.A. Punt
Journal: Journal of Clinical Oncology (2010)

Combination chemotherapy is currently considered to be the standard treatment for patients with advanced esophagogastric cancer, and fluoropyrimidines, anthracyclines, and platinum compounds are the most active and most widely used drugs. However, the median survival benefit of combination therapy versus monotherapy is modest and is estimated at approximately 1 month. In recent years, the results of several randomized phase III trials have been published, and although a small benefit has been demonstrated in some trials, it is disappointing that the median overall survival time remains less than 1 year. The obvious next step was to incorporate targeted drugs into established chemotherapy schedules. Positive results have been presented for trastuzumab in the small subset of patients with human epidermal growth factor receptor 2–positive advanced gastric cancer. More recently, the addition of bevacizumab to chemotherapy in patients with advanced gastric cancer did not significantly improve the median overall survival, but the results appeared to be different among subgroups according to geographic region. A potential disadvantage of bevacizumab compared with trastuzumab is the lack of a specific target for bevacizumab that would allow for optimal selection of patients for treatment. Signal transduction through the epidermal growth factor receptor (EGFR) pathway plays a relevant role in several tumor types, and inhibition of this signal has shown clinical efficacy in some of these. In metastatic colorectal cancer, a mutation in the KRAS oncogene is a negative predictor for outcome of anti-EGFR treatment, and the use of anti-EGFR antibodies is therefore restricted to patients with colorectal cancer with KRAS wild-type tumors. The rationale of testing anti-EGFR therapy in esophagogastric cancer is founded on the fact that these tumors frequently exhibit EGFR overexpression, which is associated with poor outcome. Favorable response rates of cetuximab, a chimeric immunoglobulin G1 (IgG1) anti-EGFR antibody, combined with chemotherapy have been reported in phase II trials in advanced gastric cancer. Cetuximab is currently being tested in a randomized phase III trial. Panitumumab, a human IgG2 anti-EGFR antibody, has shown comparable efficacy to cetuximab in metastatic colorectal cancer. In this issue, Okines et al present safety data regarding an ongoing phase III trial (Randomized ECF for Advanced and Locally Advanced Esophegogastric Cancer [REAL-3]) that investigates the efficacy of panitumumab at 9 mg/kg every 3 weeks when added to a schedule of epirubicin, oxaliplatin, and capecitabine (EOC) given at standard doses every 3 weeks. The trial was amended due to an unexpectedly high rate of severe toxic events (primarily diarrhea) in four of the first five patients treated with panitumumab and EOC. The dose of capecitabine was reduced, but given that grade 3 diarrhea and grade 5 infection occurred in one of the next two patients, a formal dosefinding study was conducted to assess the optimal doses of this fourdrug schedule. The combination of panitumumab and EOC proved safe and feasible when the doses of both capecitabine and oxaliplatin were reduced, and these results are presented. The first question that comes into mind is whether this severe toxicity could have been avoided by having a dose-finding study performed before the initiation of the phase III study, given that no data were available regarding the safety of the combination of an antiEGFR antibody with the EOC regimen. The argument against this, which is also used by the REAL-3 investigators, is that the standard dose of single-agent cetuximab has been safely administered in combination with several chemotherapy schedules at standard doses in phase II studies in patients with esophagogastric cancer; this finding is confirmed by the experience with cetuximab or panitumumab plus chemotherapy in much larger series of patients with colorectal cancer. Now that we know the outcome of the REAL-3 trial, the arguments that would have supported an initial dose-finding study are the lack of experience with panitumumab in esophagogastric cancer, the greater concern of diarrhea in schedules that include capecitabine instead of fluorouracil (FU), the lack of experience with anti-EGFR therapy in combination with anthracycline-based chemotherapy, and the lack of experience with a 3-weekly schedule of panitumumab with chemotherapy. These arguments will be discussed separately. The first implies a clinically relevant difference between panitumumab and cetuximab. Except for a difference in allergic reactions, as a result of the different origin of the two antibodies, and in IgG subtype, which may be relevant for the induction of antibodydependent cellular cytotoxicity, current data do not suggest an outright difference in efficacy or in toxicity between panitumumab and cetuximab, although a formal comparison has not been performed (and most likely never will be). Especially concerning the incidence of severe diarrhea, which was the most notable adverse effect in REAL-3, trials of panitumumab and cetuximab in monotherapy or in combination with chemotherapy have not shown a marked difference between the antibodies. Cross-study comparisons suggest that panitumumab may be even better tolerated in combination with oxaliplatin-based chemotherapy compared with cetuximab, but this remains speculative. JOURNAL OF CLINICAL ONCOLOGY E D I T O R I A L S