On Target? Off Target? Why We Really Do Not Know
Authors: Lawrence Leichman
Journal: Journal of Clinical Oncology (2010)

With the proliferation of cellular targets and targeted agents, it would appear that we can soon expect great strides in improving survival and cure rates for patients with advanced solid tumors. In gastrointestinal oncology, the greatest contributions of targeted agents are found in disseminated colorectal cancer where the targeted agents, cetuximab and bevacizumab, have added survival benefit when combined with an old targeted agent, fluorouracil (FU). In addition, oxaliplatin and irinotecan have secured places in the treatment strategies for incurable colorectal cancers. The result of appropriately adding the new targeted agents to proven cytotoxic therapy has been an association with an extension in median survival that has more than doubled in the past 5 years in comparison to median survival statistics in the late 1980s and early 1990s. However, a careful, perhaps more skeptical, evaluation of our current progress in combining cytotoxic and targeted agents against gastrointestinal malignancies is cautionary. In colorectal cancers, irinotecan and targeted agents have yet to be successfully integrated into the adjuvant or potentially curative setting. Although we have recently learned that patients with K-ras–mutated tumors will not benefit from cetuximab, we do not fully understand why the majority of K-ras wild-type patients do not respond. If FU works best as a single agent when intratumoral thymidylate is low, does the same apply when oxaliplatin, irinotecan, bevacizumab, and/or cetuximab are added? Why have combinations of bevacizumab and cetuximab been unsuccessful? In pancreas cancers, the addition of erlotinib has added a precious 2 weeks to median overall survival, but the targeted agent’s actual target is not known. In gastric and gastroesophageal (GE) junction tumors, therapy with vascular endothelial growth factor receptor (VEGFR) and epithelial growth factor receptor (EGFR) -1 inhibitors have made no impact in response rates or survival. However, in what appears to be the first major breakthrough in the use of a targeted agent against gastric cancer, investigators reporting the ToGA trial noted that the addition of the trastuzumab to chemotherapy for the approximately 20% of patients with disseminated gastric and GE junction tumors overexpressing and/or amplifying EGFR 2 (HER2) led to a statistically significant improvement in progression-free survival (PFS) and overall survival (OS). As in breast cancer, it appears that HER2 overexpression and/or amplification drives a fraction of gastric and GE junction tumors. In this issue of Journal of Clinical Oncology, Sun et al report the results of Eastern Cooperative Oncology Group (ECOG) 5203, a phase II trial of the targeted agent, sorafenib, plus docetaxel and cisplatin for patients with advanced, incurable gastric or GE junction tumors. Sorafenib is an oral small molecule tyrosine kinase inhibitor targeting Raf-1, wild-type and mutant Braf, VEGFR1, VEGFR2, VEGFR3, platelet derived growth factor, and Mcl-1. The trial was designed and conducted by experts in gastric cancer under the auspices of and with the approval of the National Cancer Institute’s (NCI) Cancer Therapy Evaluation Program (CTEP). The trial hit its objective for response (40% or more). Furthermore, the authors note that the 5.8-month progression-free survival and the 11.3-month median survival for disseminated tumors and a 17.6-month median survival for locally advanced tumors “suggest that sorafenib may have a role in this (gastric and GE junction) disease.” The authors’ conclusions may be correct. Indeed, there is great reason to hope they are correct. New, effective agents against gastric cancer are desperately needed. However, the data generated by E5203 and the mechanics of the trial lead to few, if any, conclusions about the role of sorafenib in this disease. With no clear standard chemotherapy for advanced gastric cancer, a number of minimally active cytotoxic agents are generally used in combination. Most frequently, systemic therapy for advanced gastric cancer combines a platinum compound with a fluoropyrimidine or taxane. Some investigators believe that the best results combine all three. Phase II data from a number of these trials indicate that in chemotherapy-naive patients, a PFS of 5.8 months and a median overall survival for those with disseminated cancer of 11.6 months is not particularly striking. Bearing in mind that the E5203 trial included both locally advanced (approximately 20%), one might ask if the investigators aimed too low? In considering ECOG 5203, a more relevant question is why sorafenib was chosen to be administered with docetaxel and cisplatin. As a single agent, sorafenib has demonstrated modest efficacy against hepatocellular and renal cell carcinomas. Such single-agent efficacy has not been demonstrated against gastric cancer. Moreover, the ECOG 5203 manuscript does not indicate any translational effort to determine if responding patients had a molecular profile in their tumors different from those who did not respond. Such information, while preliminary in nature, would have allowed for a future trial aimed at a specific group with selected molecular profile (an enriched population, as in the ToGA trial). The design of ECOG 5203 harkens back to the “bad old days” when investigators piggybacked or grafted compounds onto one another with the hope that two minimally responsive agents would be better than one or that three would be JOURNAL OF CLINICAL ONCOLOGY E D I T O R I A L S VOLUME 28 NUMBER 18 JUNE 2