Cetuximab Combined with Oxaliplatin-Based Chemotherapy May Not Be Effective First-Line Treatment for Metastatic Colorectal Cancer
In a randomized phase III trial, the addition of the targeted therapy cetuximab to oxaliplatin and fluoropyrimidine chemotherapy did not prolong survival or time to disease progression of patients with advanced colorectal cancer. In contrast to previous studies, even patients whose tumors expressed the normal version of the KRAS gene experienced no improvement with cetuximab.
The Lancet, published online June 5, 2011 (see the journal abstract).
Until 10 years ago treatment for metastatic colorectal cancer was limited to a single combination: 5-fluorouracil (5FU) and leucovorin (LV). In the early 2000s, researchers identified several new drugs that were active in treating advanced colorectal cancer. These include the chemotherapy agents irinotecan, oxaliplatin, and capecitabine and the targeted therapies bevacizumab and cetuximab. The best way to use these novel agents to treat metastatic colorectal cancer, however, is not clear.
To address this issue, researchers have initiated numerous clinical trials testing the drugs singly and in various combinations in patients whose disease had progressed on prior therapy or who had not been treated previously. Two of these trials, referred to as CRYSTAL and OPUS, demonstrated that adding cetuximab, a monoclonal antibody that targets the EGFR, to the combination chemotherapy regimens FOLFIRI or FOLFOX, respectively, as a first-line treatment increased the response rate and the time to cancer progression compared to treatment with chemotherapy alone.
However, only patients retrospectively identified as having a wild-type, or normal, KRAS gene, whose product is a component of the EGFR signaling pathway, were found to benefit from cetuximab. This was expected because mutant forms of KRAS send a growth signal whether or not EGFR has activated the pathway; therefore, inhibition of EGFR signaling would be expected to have an effect only in patients with wild-type KRAS. Other studies of cetuximab plus chemotherapy as a second-line treatment have had similar findings.
To determine whether the benefit from the addition of cetuximab to chemotherapy in patients with metastatic colorectal cancer that has not been treated previously would hold up in a larger patient population, researchers randomly assigned 1,630 patients to receive oxaliplatin plus a fluoropyrimidine (either capecitabine or 5FU plus LV, as determined by the patient’s oncologist) with or without cetuximab. Treatment continued until the patient’s disease worsened or the side effects became unacceptable. The patients’ tumors were monitored by CT scan before the start of treatment and every 12 weeks until the end of treatment.
Tumor biopsy samples from 1,065 patients were suitable to be examined by immunohistochemistry to determine EGFR expression. DNA isolated from 1,316 tumor samples was sequenced to identify possible mutations in the KRAS, BRAF, and NRAS genes. Like KRAS, BRAF and NRAS are known to participate in signaling pathways related to EGFR.
The study was led by Timothy S. Maughan, M.D., of the Cardiff University School of Medicine in Wales.
The addition of cetuximab to chemotherapy did not improve overall survival in patients whose tumors expressed wild-type KRAS. The median survival time was 17.9 months in those treated with chemotherapy alone and 17.0 months in those treated with cetuximab plus chemotherapy. In patients whose tumors had a KRAS mutation, the median survival time was 14.8 months for those treated with chemotherapy alone and 13.6 months for those treated with cetuximab plus chemotherapy. The addition of cetuximab to chemotherapy also did not improve the time to disease progression in patients with wild-type KRAS (median time to cancer progression was 8.6 months for both groups).
DNA sequencing analysis revealed mutations in KRAS, BRAF, and NRAS in 43 percent, 8 percent, and 4 percent of tumors, respectively. No patients had mutations in both BRAF and NRAS or BRAF and KRAS. Eleven patients, however, had mutations in both the KRAS and NRAS genes.
Regardless of treatment, the scientists found that overall survival varied depending on the mutations present in a patient’s tumor. Median survival time for patients with tumors expressing a mutated BRAF gene was 8.8 months, for those whose cancers had NRAS mutations was 13.8 months, and for those with KRAS mutated tumors was 14.4 months. Patients without any of these mutations in their tumors survived for a median of 20.1 months.
Treating patients with the combination of cetuximab and oxaliplatin-based chemotherapy increased the skin irritations and gastrointestinal side effects of the chemotherapy drugs without improving patient survival. Some of these toxic effects were specific to the fluoropyrimidine used. For example, patients who received capecitabine plus cetuximab had more diarrhea and numbness and pain in their extremities than patients who received 5FU plus cetuximab.
The finding from this phase III trial that there was no benefit from adding cetuximab to oxaliplatin-based chemotherapy was a surprise given that the OPUS study had shown that combining FOLFOX and cetuximab was beneficial in patients whose tumors expressed wild-type KRAS. The authors raise the possibility that the specific drugs that are combined with cetuximab have important effects on patient survival. If so, the lack of benefit in the current trial could be due to the use of capecitabine rather than 5FU plus LV to treat a majority of the patients.
Whatever the reason for the disparate results, the authors state that “the use of cetuximab in combination with oxaliplatin and capecitabine in first-line chemotherapy...cannot be recommended.” Likewise, in an accompanying editorial, Madeleine Hewish, M.R.C.P., and David Cunningham, M.D., from the Royal Marsden Hospitals in London and Surrey, United Kingdom, propose that oxaliplatin may “not be the best chemotherapy drug for cetuximab.” They suggest that combining cetuximab with irinotecan, 5FU, and LV may improve tumor response and patient survival based on the results of the CRYSTAL study, noting that further trials comparing the efficacies of these combinations are needed.
According to Jack Welch, M.D., Ph.D., of NCI’s Division of Cancer Treatment and Diagnosis, this trial also provided insight into some of the important biomarkers (KRAS, BRAF, and NRAS) that could be used as prognostic indicators in patients with metastatic colorectal cancer. He added that future clinical trials in patients with advanced disease will likely stratify patients by key specific biomarkers.
Finally, the survival times for the patients in this trial are shorter than in those published previously, including the OPUS study. The authors indicate that this may be due to differences in the study populations and to the stage of their disease at the time of diagnosis. Patients with more advanced disease often have shorter survival times.