Treatments have same target, different responses for lung cancer patients with genetic mutation

The gene mutation that identifies the lung cancer patients most likely to respond to the drug gefitinib (Iressa) is not associated with a response to the drug cetuximab (Erbitux), according to a new study published in the August 17 issue of the Journal of the National Cancer Institute. Both drugs target the same gene but through different mechanisms.

Some patients with non–small-cell lung cancer (NSCLC) have mutant versions of the epidermal growth factor receptor (EGFR). This protein activates signaling pathways involved with cell growth and survival. Previous studies have shown that small-molecule EGFR inhibitors such as gefitinib and erlotinib (Tarceva) work by blocking signals in the intracellular domain of EGFR–between the EGFR and the cell nucleus. Additionally, many NSCLC patients with mutations in this intracellular domain of EGFR appear to benefit from these drugs.

Toru Mukohara, M.D., of the Dana-Farber Cancer Institute in Boston, and colleagues decided to examine the effectiveness of another type of drug that targets EGFR–a monoclonal antibody called cetuximab, which is approved for the treatment of metastatic colorectal cancers that overexpress EGFR. Cetuximab targets EGFR by preventing its activation by extracellular signals, or signals occurring outside of the cell, as opposed to the intra-cellular signal blocking of drugs like gefitinib.

The researchers treated seven different NSCLC cell lines with cetuximab or gefitinib, and compared the drugs’ effects on cell growth and cell death or apoptosis. They found that both drugs similarly inhibited the growth of the NSCLC cells containing the normal form of EGFR. However, gefitinib was more effective than cetuximab at inhibiting cell growth and increasing apoptosis in NSCLC cells with mutant EGFR.

The authors note that because these studies were carried out in cell lines, and not in humans, issues such as which drug has more toxicity or negative side effects are still unanswered. However, they did examine the outcomes of four patients with EGFR mutations in their tumors who had been treated with gefitinib and then cetuximab, or vice versa. They found that all patients displayed partial responses to gefitinib in terms of tumor shrinkage, whereas none of them appeared to respond to cetuximab.

“Overall, our results raise the possibility that NSCLC patients with EGFR mutations may derive the greatest benefit, in terms of tumor regression, if treated with gefitinib rather than with cetuximab,” the authors conclude.

“These findings clearly have important clinical implications because both drugs should, theoretically, block EGFR signaling,” writes John D. Minna, M.D., of the Hamon Center for Therapeutic Oncology Research at the University of Texas Southwestern Medical Center in Dallas, and colleagues in an accompanying editorial. “The first round clearly was won by [drugs such as gefitinib].” However, they add that additional research should focus on the effects of cetuximab on certain populations of patients, or used in conjunction with other drugs. “Cetuximab may still have an effective punch if the right circumstances can be identified,” the authors conclude.