The first studies of epidermal growth factor receptor (EGFR) inhibitors in metastatic colorectal cancer were begun before the predictive role of RAS mutations had been elucidated. Secondary analyses of many large randomized trials have shown that mutations in exons 2–4 of KRAS and NRAS, BRAF V600E mutation, and right-sided primary tumor all predict lack of response to EGFR inhibition in the first-line setting. However, even in patient populations defined by a lack of these negative predictors, there is still not uniform response to anti-EGFR therapy. Additionally, although older adults have been shown to have the potential to both tolerate and respond to anti-EGFR therapy, the criteria for selecting the most appropriate older patients for treatment remain unclear.
Cetuximab and panitumumab, both monoclonal antibodies targeting the epidermal growth factor receptor (EGFR), were initially developed for use in second-line or subsequent-line treatment of colorectal cancer, administered either as single agents or in combination with irinotecan; the early studies, however, used tumor expression of EGFR as a criterion for treatment eligibility. By the time clinicians had ascertained the importance of RAS mutations in informing the use of anti-EGFR agents in colorectal cancer, studies of these agents in first-line treatment were well underway, and the patterns of care were fairly established. This accounts, at least in part, for the lack of consensus or conviction about when in the continuum of care anti-EGFR agents should be used.
Shortly after EGFR expression was recognized as irrelevant in the management of colorectal cancer (since patients lacking EGFR expression were shown to be able to respond to cetuximab-based therapies), RAS status emerged as an important biomarker in decision making regarding the use of EGFR antibodies. This retrospective finding emerged from the CRYSTAL and PRIME studies of first-line colorectal cancer treatment that included cetuximab and panitumumab, respectively, and which had each enrolled an unselected cohort of patients with metastatic disease. Secondary analyses of both studies[3,4] showed that a virtual lack of benefit of anti-EGFR therapy was correlated with mutations at codons 12 and 13 in KRAS exon 2. However, even with enrichment for KRAS exon 2 wild-type status, the overall response rate in CRYSTAL rose to just 57.3%. This spurred further analyses of other trials of first-line anti-EGFR agents (Table)[3-10] and led to a broadening of the list of activating mutations in KRAS exons that are most predictive of lack of response to these agents.[4,9]
Although proof is lacking that specific mutations in an individual patient absolutely preclude that patient’s ability to respond to anti-EGFR therapy, mutations in KRAS or NRAS exon 2 (at codons 12 and 13), exon 3 (at codons 59 and 61), and exon 4 (at codons 117 and 146) have generally been accepted as biomarkers that predict a lack of response to these drugs. In our practice, RAS mutations outside of these locations are not considered to be contraindications to anti-EGFR therapy, since regarding other mutations as contraindications could exclude patients from receiving potentially beneficial therapy. Similarly, patients with BRAF V600E mutations—although mutations in BRAF, KRAS, and NRAS are mutually exclusive—are also unlikely to benefit from any of the standard anti-EGFR therapy combinations. A large meta-analysis of 10 randomized trials failed to demonstrate a progression-free survival (PFS) or overall survival (OS) benefit for anti-EGFR therapy in BRAF V600E–mutant patients. However, combinations of an EGFR antibody, BRAF inhibitor, and irinotecan have demonstrated activity in those patients. Notably, genomic sequencing of KRAS, NRAS, and BRAF has demonstrated high mutation status concordance between the primary tumor and matched metastatic sites.
The Cancer and Leukemia Group B (CALGB)/Southwest Oncology Group (SWOG) 80405 trial was a phase III study of first-line chemotherapy for metastatic colorectal cancer with either FOLFOX (folinic acid, fluorouracil [5-FU], and oxaliplatin) or FOLFIRI (folinic acid, 5-FU, and irinotecan) per the treating physician’s discretion plus either cetuximab or bevacizumab. The study found no difference in OS between the bevacizumab and cetuximab treatment arms, either in the KRAS exon 2 wild-type population or in the subset of patients with extended RAS wild-type tumors. This outcome was somewhat different from the results seen in KRAS exon 2 wild-type patients in the FIRE-3 study, which showed an OS benefit of 28.7 months in patients who received chemotherapy in combination with cetuximab compared with 25 months in those treated with chemotherapy plus bevacizumab (hazard ratio [HR], 0.77; 95% CI, 0.62–0.96). An even greater survival difference was seen in patients with extended RAS wild-type tumors, with OS of 33.1 months in patients who received cetuximab vs 25.6 months in those treated with bevacizumab (HR, 0.70; 95% CI, 0.53–0.92).
Methodologic differences between the CALGB/SWOG 80405 and FIRE-3 studies could account for the disparate results. Notably, the chemotherapy backbones were not the same; FOLFIRI was used in the FIRE-3 study, and in the CALGB/SWOG 80405 study, some patients were treated with FOLFOX and others received FOLFIRI. The findings of MRC COIN—a UK multicenter, randomized, controlled, three-arm trial by the Medical Research Council that evaluated oxaliplatin and fluoropyrimidine vs oxaliplatin and fluoropyrimidine plus cetuximab vs intermittent oxaliplatin and fluoropyrimidine in previously untreated advanced colorectal cancer—suggest that the chemotherapy backbone may have an impact on the efficacy of the EGFR antibodies. The precise clinical scenario may also be important; for example, the New EPOC (Eloxatin Peri-Operative Chemotherapy) trial in the United Kingdom showed that use of cetuximab prior to the resection of isolated KRAS wild-type liver metastases was actually harmful. Similarly, differences in the patterns of care between centers in Europe and the United States introduced variability in patient management after the study-mandated first-line treatment was completed, which had effects on outcomes.
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