ORLANDO — KRAS tumor status has emerged as an important biomarker for the success or failure of therapies for metastatic colorectal cancer and should be assessed before starting treatment, researchers said at a meeting on gastrointestinal cancers sponsored by the American Society of Clinical Oncology.
“Clinicians should definitely start checking for KRAS status in their patients with advanced colorectal cancer. Such testing will become very easy to do in the next few months,” Dr. Josep Tabernero, head of the gastrointestinal tumors unit of Vall d'Hebron University Hospital, Barcelona, said at the meeting, which was also sponsored by the AGA Institute, the American Society for Therapeutic Radiology and Oncology, and the Society of Surgical Oncology.
In an open-label, phase I, multicenter study, Dr. Tabernero and colleagues evaluated the efficacy of cetuximab (Erbitux) given either once a week or once every 2 weeks, in 52 patients with epidermal growth factor receptor (EGF-R)-expressing metastatic colorectal cancer. Cetuximab was administered as a single agent over a 6-week period, and then FOLFIRI (irinotecan/5-fluorouracil [5-FU]/folinic acid [FA]) was added to the regimen.
The researchers also determined KRAS status in tumor samples from 48 of the patients, and correlated this status with overall response and progression-free survival.
The patients had had no prior exposure to EGF-R-targeting therapy, no previous chemotherapy (including adjuvant therapy) for metastatic colorectal cancer within 6 months of study entry, and no surgery or radiation treatment within 4 weeks of study entry.
The results showed that cetuximab 500 mg/m
The 29 patients with wild-type KRAS tumors had an overall response rate of 28%, compared with 0% for the 19 patients with mutant KRAS tumors when cetuximab was given as single agent. Once FOLFIRI was added to cetuximab, patients with wild-type KRAS tumors had an overall response rate of 55%, compared with 32% for those with mutant KRAS tumors.
The median progression-free survival for patients with wild-type KRAS tumors was 9 months, compared with 6 months for patients with mutant KRAS tumors (hazard ratio 0.47).
“This is the first time that the predictive value of the KRAS status has been demonstrated in patients treated with cetuximab and chemotherapy in the first-line setting of patients with advanced colorectal cancer,” Dr. Tabernero said.
In another study presented at the meeting, KRAS status influenced clinical response to treatment with panitumumab (Vectibix) in patients with chemotherapy-refractory metastatic colorectal cancer.
In a phase III trial that randomized 463 patients to panitumumab plus best supportive care (n = 231) or best supportive care alone (n = 232), the benefit of panitumumab was confined to patients with wild-type KRAS tumors. Patients with mutant KRAS tumors showed no benefit, said Dr. Rafael G. Amado at a press briefing. Dr. Amado works for Amgen Inc., which makes panitumumab.
The median progression-free survival for the 124 patients with wild-type KRAS who were treated with panitumumab was 12 weeks, compared with 7 weeks for the 84 patients who had mutant KRAS. The median progression-free survival for patients randomized to best supportive care only was 7 weeks, regardless of KRAS status.
The response rate for wild-type KRAS patients treated with panitumumab was 17%, and 34% had stable disease. In contrast, the response rate for mutant KRAS patients treated with panitumumab was 0%, and 12% had stable disease.
The median overall survival was longer in patients with wild-type KRAS than in those with mutant KRAS tumors, regardless of treatment arm. The median survival of patients with wild-type KRAS tumors receiving panitumumab was 8 months, versus 5 months for those in the mutant KRAS group. In the best-supportive-care arm, the median survival for patients with wild-type and mutant KRAS tumors was 8 months and 4 months, respectively.
“Over 75% of patients in the best-supportive-care arm in both KRAS groups went on to receive panitumumab in a crossover protocol, which likely confounded the survival results,” Dr. Amado noted.
In an interview, he commented on the significance of his study's results. “These findings are important because, by testing for KRAS mutations, physicians may now be able to identify patients who are more likely to respond to panitumumab treatment and avoid unnecessary side effects, as well as expense, to those who are unlikely to respond.”
He added that being able to pinpoint subgroups of patients according to KRAS status or other biomarkers will become increasingly important for directing cancer treatment.
“The field of oncology will continue to undergo further segmentation as diseases are catalogued according to molecular alterations, and drugs will be developed to specifically interdict pathways that are active for specific categories of tumors within the same type of cancer.”