September 11, 2008 — The large trial showing a significant improvement in survival in head and neck cancer when cetuximab (Erbitux, ImClone/Bristol-Myers Squibb) was added to cisplatin-based chemotherapy has been published in the September 11 issue of the New England Journal of Medicine. These results were first reported at the 2007 meeting of the American Society of Clinical Oncology and, at the time, experts in the field predicted that they would change clinical practice, as reported by Medscape Oncology.
This is the first time in 30 years — since cisplatin was first used in head and neck cancer — that any regimen has improved on its success, say the researchers. The improved survival that was seen after the addition of cetuximab (at a median of 2.7 months) is "therefore notable," they comment.
"I think these data support the notion that we have a new standard treatment for patients with recurrent and/or metastatic head and neck cancer," lead researcher Jan Vermorken, MD, PhD, professor of oncology at Antwerp University Hospital, in Ghent, Belgium, commented to Medscape Oncology. "I would recommend that every patient with recurrent head and neck cancer who is not a candidate for radiation or surgery now receive platinum-based chemotherapy plus cetuximab, if their condition allows them to tolerate this."
Cetuximab is approved for use in head and neck cancer, but only for specific indications (i.e., as a single agent in patients with platinum-resistant disease) or in combination with radiation in previously untreated patients. The way cetuximab was used in the current study — the Erbitux in First-Line Treatment of Recurrent or Metastatic Head and Neck Cancer (EXTREME) trial — is not yet approved, although the manufacturer has applied for a license extension on the basis of these results.
The trial involved 442 patients with untreated recurrent or metastatic squamous-cell carcinoma of the head and neck (approximately 60% of these patients had not received any previous chemotherapy). All patients received chemotherapy with a platinum agent (cisplatin or carboplatin, chosen by the investigator) together with infusional 5-fluorouracil. Half of the patients also received cetuximab.
After a maximum of 6 cycles of chemotherapy, patients in the chemotherapy-plus-cetuximab group who had at least stable disease received cetuximab monotherapy; those in the chemotherapy group received no further active treatment.
The median overall survival increased from 7.4 months in the chemotherapy group to 10.1 months in the chemotherapy-plus-cetuximab group (hazard ratio for death, 0.80; P = .04).
The addition of cetuximab also significantly improved median progression-free survival from 3.3 to 5.6 months (hazard ratio for progression, 0.54; P < .001), and significantly increased the response rate, from 20% to 36% (P < .001).
However, it also significantly increased the adverse effect of sepsis, which occurred in 9 patients in the chemotherapy-plus-cetuximab group but in only 1 patient in the chemotherapy group (P = .02). The incidence of hypomagnesemia also increased (11 patients in the chemotherapy-plus-cetuximab group and 3 patients in the chemotherapy group; P = .05). Other adverse events, such as neutropenia, were reported at similar rates in both groups, but the cetuximab-treated patients also had skin reactions (9%) and infusion-related reactions (3%). These are consistent with the adverse-effect profile of cetuximab, the researchers comment.
Other Drugs With Similar Actions
Cetuximab is an inhibitor of the epidermal growth-factor receptor (EGFR), which is often expressed on head and neck cancer cells. Other drugs that target EGFR have been studied in this setting, said Dr. Vermorken, including monoclonal antibodies (such as panitumumab, matuzumab, nimotuzumab, and zalutumumab) and tyrosine kinase inhibitors (such as gefitinib, erlotinib, lapatinib, and canertinib). These agents are in various stages of development, but so far none have shown results as good as those seen with cetuximab. One additional aspect of cetuximab is that it has been shown to enhance the cytotoxicity of a number of chemotherapeutic agents, including cisplatin.
The 2 agents that have been studied the most are gefitinib and erlotinib, but both appear to have only modest antitumor activity in head and neck cancer, according to a review article published in the same issue of the New England Journal of Medicine (2008;359:1143-1154). It notes that in a recently completed large phase 3 trial comparing 2 dose levels of gefitinib with methotrexate, the standard cytotoxic agent, gefitinib did not show superiority over methotrexate in terms of survival.
Cetuximab has been in the news recently because of the finding that KRAS mutations affect its efficacy in the treatment of colorectal cancer, as reported by Medscape Oncology. In that patient population, testing cancer tissue for KRAS mutations can identify patients who are likely to respond to the drug and those who would likely not derive any benefit. However, this is not the case with head and neck cancer, Dr. Vermorken commented. "The incidence of KRAS mutations in head and neck cancer is extremely low — in the order of 5%," he said. "So, contrary to what has been observed in colorectal cancer, enrichment of the patient group selecting those who might have a higher benefit of this treatment is not possible, at least with KRAS."
The EXTREME trial was supported by Merck (Darmstadt), which originally developed cetuximab under license from ImClone. Some of the coauthors of the paper are employees of Merck (Darmstadt). Dr. Vermorken and several coauthors report serving on advisory boards and receiving lecture fees from Merck (Darmstadt). Dr. Vermorken also reports serving on advisory boards for Amgen and Genmab.
N Engl J Med. 2008;359:1116-1127.
Medscape Medical News © 2008 Medscape
Cite this: Zosia Chustecka. Cetuximab Improves Survival in Head and Neck Cancer - Medscape - Sep 11, 2008.