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Two treatments with same target have different effects on NSCLC tumors
Gefitinib may more effectively block signaling of epidermal growth factor receptor than cetuximab, researchers say.
The gene mutation that identifies lung cancer patients most likely to respond to gefitinib (Iressa, AstraZeneca) is not associated with a response to cetuximab (Erbitux; ImClone, Bristol-Myers Squibb), according to a study that appeared in the Journal of the National Cancer Institute. Both drugs target the same gene but through different mechanisms, researchers concluded.
“Overall, our results raise the possibility that patients with non-small-cell lung cancer (NSCLC) with epidermal growth factor receptor (EGFR) mutations may derive the greatest benefit, in terms of tumor regression, if treated with gefitinib rather than with cetuximab,” said lead researcher Toru Mukohara, MD, in a press release.
Some patients with NSCLC have mutant versions of 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, OSI) work by blocking signals in the intracellular domain of EGFR. Additionally, many NSCLC patients with mutations in this intracellular domain of EGFR appear to benefit from these drugs.
Mukohara and his colleagues from the Dana-Farber Cancer Institute in Boston decided to examine the effectiveness of another type of drug that targets EGFR – a monoclonal antibody called cetuximab, which the FDA approved for the treatment of metastatic colorectal cancers that overexpresses EGFR. Cetuximab targets EGFR by preventing its activation by extracellular signals, or signals occurring outside of the cell, as opposed to the intracellular 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 apoptosis. They found that both drugs similarly inhibited the growth of the NSCLC cells containing the normal form of EGFR. Gefitinib, however, was more effective than cetuximab at inhibiting cell growth and increasing apoptosis in NSCLC cells with mutant EGFR.
Questions unanswered
The researchers noted that because these studies were carried out in cell lines, and not in humans, issues such as drug toxicity or negative side effects are still unanswered. However, they did examine the outcomes of four patients with EGFR mutations whom they had treated with gefitinib and then cetuximab, or vice versa. The researchers found that all patients displayed partial responses to gefitinib in terms of tumor shrinkage, whereas none of them appeared to respond to cetuximab.
“These findings clearly have important clinical implications because both drugs should, theoretically, block EGFR signaling,” wrote John D. Minna, MD, from the Hamon Center for Therapeutic Oncology Research at The University of Texas Southwestern Medical Center at Dallas, in an accompanying editorial. “The first round clearly was won by [drugs such as gefitinib].”
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,” Minna added.
For more information:
- Minna JD, Peyton MJ, Gazdar AF. Gefitinib versus cetuximab in lung cancer: round one. J Natl Cancer Inst. 2005;97:1168-1169.
- Mukohara T, Engelman JA, Hanna NH, et al. Differential effects of gefitinib and cetuximab on non-small-cell lung cancers bearing epidermal growth factor receptor mutations. J Natl Cancer Inst. 2005;97:1185-1194.