In this randomized phase 3 trial for patients with resected stage III colon cancer expressing wild-type KRAS
mutations, the addition of cetuximab to mFOLFOX6 did not improve disease-free or overall survival in contradistinction to the original study of cetuximab combined with FOLFOX in metastatic colorectal cancer.5
Multiple trials combining cetuximab with chemotherapy in the metastatic setting have been reported. The first-line trials Cetuximab Combined with Irinotecan in First-Line Therapy for Metastatic Colorectal Cancer (CRYSTAL)5
and Oxaliplatin and Cetuximab in the First-Line Treatment of Metastatic Colorectal Cancer (OPUS)19
both demonstrated significant improvements in outcomes with cetuximab in patients with wild-typeKRAS
. However, the first-line trials Continuous Chemotherapy plus Cetuximab or Intermittent Chemotherapy (COIN)20
and NORDIC for the trial VII of the Nordic Colorectal Cancer Biomodulation Group (NORDIC VII)21
did not show benefit with the addition of cetuximab.
The reasons for the lack of benefit of mFOLFOX6 with cetuximab in the adjuvant setting remain unclear. The observed 3-year disease-free survival in the mFOLFOX6 alone group, pooled over patients with mutated KRAS
and wild-type KRAS
, is 72% (95% CI, 69%–75%), identical to that observed in the Multicenter International Study of Oxaliplatin/Fluorouracil/Leucovorin in the Adjuvant Treatment of Colon Cancer (MOSAIC) trial2
that established FOLFOX as the standard of care. The overall rates of death within 60 days of treatment initiation were 0.1% for the mFOLFOX6 alone group and 0.6% for the mFOLFOX6 with cetuximab group, consistent with the 0.3% rate reported for the FOLFOX group of the MOSAIC trial.2
The patients enrolled in NCCTG N0147 were from the entire North American cooperative group system. Thus, it is unlikely that the results could be explained by a problem with patient selection. Other potential explanations include toxicity limiting administration of planned therapy, differential effect related to age, adverse effect of cetuximab on the activity of chemotherapy, effect of a specific subgroup on overall results, and an alteration in the mechanism of action of cetuximab in the setting of micrometastatic disease.
In the COIN trial,22
the addition of cetuximab resulted in dose reductions of chemotherapy at twice the rate observed in patients receiving chemotherapy alone, regardless of age. The ability of patients with wild-type KRAS
in NCCTG N0147 to complete the planned course of therapy was reduced in those receiving cetuximab, most notably in patients aged 70 years or older. The inability to give either the planned duration of therapy or dose intensity was primarily related to gastrointestinal symptoms and fatigue. For older patients, the addition of neutropenia further limited therapy with the mFOLFOX6 with cetuximab protocol.
Only 51% of patients with wild-type KRAS aged 70 years or older completed 12 cycles of therapy when receiving cetuximab vs 78% of those receiving mFOLFOX6 alone. Toxicity therefore may have had a direct effect in reducing the potential benefit derived from cetuximab added to mFOLFOX6. Smaller differences were observed by treatment for patients with mutated KRAS than were observed for the patients with wild-type KRAS, suggesting that the ability to complete cetuximab-containing therapy is more challenging in patients with wild-type KRAS vs with mutated KRAS.
The ability of cetuximab to enhance the benefit of chemotherapy appears to be complex. Phase 3 trials assessing the activity of cetuximab in combination with a fluoropyrimidine for metastatic disease have only shown a benefit when an infusional fluoropyrimidine regimen was used. In the COIN20
and NORDIC VII21
clinical trials, the lack of benefit from cetuximab was primarily restricted to patients receiving either capecitabine or bolus fluorouracil as opposed to infusional fluorouracil. A subgroup analysis in the COIN trial demonstrated a benefit to the addition of cetuximab to infusional fluorouracil and oxaliplatin. However, the mFOLFOX6 regimen used in our trial should have overcome this negative interaction, if it exists.
Specific subgroups of patients were evaluated in a posthoc analysis. When disease-free survival outcomes were assessed using other age categories, sex, performance status, grade of the tumor, and T and N status, no subgroup showed benefit (eFigure 2). In addition, with the recognition that patients with a mutated BRAF
tumor have a potential worse outcome,23
the disease-free survival for the subgroup of patients with tumors expressing both wild-type KRAS
and wild-type BRAF
was assessed. This subgroup also showed no benefit and disease-free survival rates were fairly consistent in patients with wild-type KRAS
. Additional subgroup analyses are under way using other molecular markers.
The role of adjuvant therapy is to eradicate micrometastatic disease. Molecular characteristics of micrometastases appear to differ from established metastases.24,25
The evolution from the appearance of a tumor with malignant potential to the development of metastatic disease and ultimately the establishment of distant metastatic foci is a dynamic and complex process, exemplified by the epithelial-mesenchymal transition and its reverse mesenchymal-epithelial transition. As the tumor evolves, cell-cell adherence is reduced along the invasion front allowing the migration and spread of tumor cells by epithelial-mesenchymal transition, through repression of E-cadherin.26
Once the metastasizing cells reach its final site, the cells undergo mesenchymal-epithelial transition as they regain the ability to form cell-cell adherence.27
Assessment of signaling pathways suggest that epidermal growth factor has a significant role during epithelial-mesenchymal transition in the change that occurs in Ecadherin.28
Cross talk that develops during this phase between the receptor for epidermal growth factor and other signaling pathways may provide an escape mechanism from anti–epidermal growth factor receptor therapy.29,30
Additional preclinical research is required to establish the importance of these observations in colon cancer.
In addition, the activity of cetuximab on metastatic disease occurs through a variety of mechanisms.31
Cetuximab leads to cell-cycle arrest in G1 phase, as well as induces apoptosis, inhibits tumor angiogenesis, and activates antibody-dependent cellular toxicity. Although these mechanisms of activity have been defined, little is known about acquired or intrinsic resistance to cetuximab beyond mutations in KRAS
and possibly BRAF
was mutated in 18% of the wild-type KRAS
tumors from patients enrolled in our trial. When analyzed by BRAF
status, no effect on cetuximab benefit was observed.
In conclusion, in this randomized phase 3 trial for patients with resected stage III colon cancer, no benefit was observed from the addition of cetuximab to mFOLFOX6 therapy, even when restricted to patients with tumors expressing wild-type KRAS and wild-type BRAF. 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.