Adding cetuximab (Erbitux) to adjuvant treatment with mFOLFOX6, the modified sixth version of FOLFOX (leucovorin, fluorouracil, oxaliplatin) did not improve disease-free survival among patients with resected stage III colon cancer, even those with wild-type KRAS, according to a phase III study in the Journal of the American Medical Association. Three-year disease-free survival for mFOLFOX6 alone was 74.6% vs 71.5% with the addition of cetuximab in patients with wild-type KRAS, and 67.1% vs 65% in patients with mutated KRAS, with no evidence of benefit in any individual subgroup. Neither time to recurrence nor overall survival was significantly different between treatment groups.
A total of 2,686 patients comprised the analysis cohort (1,863 patients with wild-type KRAS, 717 patients with mutated KRAS, and 106 patients with indeterminate KRAS). The primary randomized comparison was 12 biweekly cycles of mFOLFOX6 with and without cetuximab.
“Among all patients, grade 3 or higher adverse events (72.5% vs 52.3%) and failure to complete 12 cycles (33% vs 23%) were significantly higher with cetuximab,” the researchers reported. “Increased toxicity and greater detrimental differences in all outcomes were observed in patients aged 70 years or older.”
The authors noted that cetuximab has provided additional benefit above that derived from chemotherapy in the metastatic setting, but that benefit was limited to patients expressing the wild-type form of the KRAS gene as opposed to those with the mutated form of KRAS. The reasons for the lack of benefit of mFOLFOX6 with cetuximab in the adjuvant setting remain unclear.
“New approaches are needed to identify drugs that may be of benefit in adjuvant therapy, because as shown in our trial promising activity in the metastatic setting did not translate into adjuvant therapy benefit and underscores the importance of performing clinical trials,” the researchers concluded.
This theme was echoed in an accompanying editorial by Neil H. Segal, MD, PhD, and Leonard B. Saltz, MD, of Memorial Sloan-Kettering Cancer Center and Weill Cornell Medical College, New York.
“The inescapable conclusion is that efficacy in the metastatic setting does not reliably predict efficacy in the adjuvant setting,” Drs. Segal and Saltz stated. “The role of adjuvant chemotherapy does not involve treating the tumor that the surgeon has removed, but rather attempts to eradicate whatever occult micrometastatic disease may still be present after surgery. If there are no micrometastases, surgery is curative and adjuvant chemotherapy is unnecessary. If micrometastases are present, the long-term health of the patient will depend on whether the chemotherapy can destroy all remaining micrometastases,” they commented.
“The practical implications of the observation that the mechanism by which chemotherapies kill tumor cells in the macrometastatic setting must differ in some fundamental way from how these agents kill tumor cells in the micrometastatic setting are that activity in the macrometastatic setting cannot be used as a surrogate for activity in the adjuvant setting,” they continued. “However, it should not be assumed that agents that are ineffective in the macrometastatic setting will not be active in the adjuvant setting (this may be particularly true of immunomodulating agents). For now, the only way to determine if an approach is useful in the adjuvant setting is by obtaining reliable results from rigorously conducted clinical trials. ■
Alberts SR, et al: JAMA 307:1383-1393, 2012.
Segal NH, Saltz LB: JAMA 307:1431-1432, 2012.