The Future of Targeted Therapies in Gastrointestinal Cancers

The Future of Targeted Therapies in Gastrointestinal Cancers

Even in the era of targeted therapies, treatment of gastrointestinal tumors is still challenging. Discussions during Saturday’s Clinical Science Symposium “Looking into the Crystal Ball: Up and Coming Agents for Treating Upper Gastrointestinal Cancers” focused on why this is so, whether some of the targeted agents on the horizon hold promise, and how patients who may benefit from these agents can be identified.

Discussing a presentation by Rachna T. Shroff, MD, of M. D. Anderson Cancer Center, on the value of single nucleotide polymorphisms (SNPs) of the insulin growth factor (IGF) signaling pathway (Abstract 4500), Manuel Hidalgo, MD, PhD, of Johns Hopkins University, indicated that although there are several prognostic factors for pancreatic cancer, there are no known markers that can predict response to IGF1 receptor (IGF1R) treatments. He suggested that SNPs in IGF1R and the insulin receptor substrate 1 (IRS1) that were associated with better survival of patients with locally advanced pancreatic cancer may help identify patients who will likely derive benefit from therapy with agents that target the IGFR pathway. However, he indicated that it was important to determine SNPs in tumor samples, as they are known to affect serum levels of proteins associated with IGF1 signaling.

Lee M. Ellis, MD, of M. D. Anderson Cancer Center, highlighted potential lessons from a study presented by Minaxi P. Jhawer, MD, of Memorial Sloan-Kettering Cancer Center, in which foretinib was ineffective at treating metastatic gastroesophageal cancer (Abstract 4502). According to Dr. Ellis, it was important to match a target with a disease because cancers are dependent on (or “addicted to”) a few genes for both maintenance and survival. “Since foretinib was used as a single agent, this trial was betting on c-Met as being an oncogene-addicted target,” he said. But c-Met is just one of many tyrosine kinase receptors in upper gastrointestinal cancers. In addition, c-Met amplification was seen in three of 59 evaluable patients and was present at a lower-than-expected frequency.

Several challenges must be recognized as oncologists move forward. “Although it is convenient to group [patients with gastroesophageal cancer] for logistic reasons, tumors in these patients are molecularly and clinically distinct,” Dr. Ellis said. “By adding tumor subtypes, one loses the ability to enrich for the tumor target.” In addition, evaluating single-agent targeted therapies in phase II trials in hard-to-treat cancers is not recommended even if one drug hits multiple targets. “Adding the apoptotic hit with chemotherapy is still necessary,” Dr. Ellis concluded.

Metastatic pancreatic cancer also is a disease for which targeted agents have shown little success. A phase Ib study presented by Hedy L. Kindler, MD, of the University of Chicago, using conatumumab (AMG 655) showed better promise for future investigations in treating this disease (Abstract 4501). Conatumumab targets the death receptor 5 (DR5) in cells and induces apoptosis. In this study, conatumumab was used in combination with standard gemcitabine therapy in 13 patients with metastatic pancreatic cancer. Discussant David A. Tuveson, MD, PhD, of Cancer Research UK, contended that, based on an overall survival of 11 months and a progression-free survival of 5.3 months, the combination should be further evaluated in a phase II trial.