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.
Introduction
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.
RAS Mutations
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),[1] RAS status emerged as an important biomarker in decision making regarding the use of EGFR antibodies.[2] This retrospective finding emerged from the CRYSTAL[3] and PRIME[4] 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%.[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.[11] However, combinations of an EGFR antibody, BRAF inhibitor, and irinotecan have demonstrated activity in those patients.[12] Notably, genomic sequencing of KRAS, NRAS, and BRAF has demonstrated high mutation status concordance between the primary tumor and matched metastatic sites.[13]
Conflicting Data
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.[8] 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).[14]
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.[7] 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.[15] 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.
1. Chung KY, Shia J, Kemeny NE, et al. Cetuximab shows activity in colorectal cancer patients with tumors that do not express the epidermal growth factor receptor by immunohistochemistry. J Clin Oncol. 2005; 23:1803-10.
2. Amado RG, Wolf M, Peeters M, et al. Wild-type KRAS is required for panitumumab efficacy in patients with metastatic colorectal cancer. J Clin Oncol. 2008;26:1626-34.
3. Van Cutsem E, Köhne CH, Láng I, et al. Cetuximab plus irinotecan, fluorouracil, and leucovorin as first-line treatment for metastatic colorectal cancer: updated analysis of overall survival according to tumor KRAS and BRAF mutation status. J Clin Oncol. 2011;29:2011-9.
4. Douillard JY, Oliner KS, Siena S, et al. Panitumumab–FOLFOX4 treatment and RAS mutations in colorectal cancer. N Engl J Med. 2013; 369:1023-34.
5. Schwartzberg LS, Rivera F, Karthaus M, et al. PEAK: a randomized, multicenter phase II study of panitumumab plus modified fluorouracil, leucovorin, and oxaliplatin (mFOLFOX6) or bevacizumab plus mFOLFOX6 in patients with previously untreated, unresectable, wild-type KRAS exon 2 metastatic colorectal cancer. J Clin Oncol. 2014;32:2240-7.
6. Bokemeyer C, Bondarenko I, Hartmann JT, et al. Efficacy according to biomarker status of cetuximab plus FOLFOX-4 as first-line treatment for metastatic colorectal cancer: the OPUS study. Ann Oncol. 2011; 22:1535-46.
7. Maughan TS, Adams RA, Smith CG, et al. Addition of cetuximab to oxaliplatin-based first-line combination chemotherapy for treatment of advanced colorectal cancer: results of the randomised phase 3 MRC COIN trial. Lancet. 2011;377:2103-14.
8. Venook AP, Niedzwiecki D, Lenz HJ, et al. Effect of first-line chemotherapy combined with cetuximab or bevacizumab on overall survival in patients with KRAS wild-type advanced or metastatic colorectal cancer. JAMA. 2017;317:2392-401.
9. Stintzing S, Modest DP, Rossius L, et al. FOLFIRI plus cetuximab versus FOLFIRI plus bevacizumab for metastatic colorectal cancer (FIRE-3): a post-hoc analysis of tumour dynamics in the final RAS wild-type subgroup of this randomised open-label phase 3 trial. Lancet Oncol. 2016;17:1426-34.
10. Tveit KM, Guren T, Glimelius B, et al. Phase III trial of cetuximab with continuous or intermittent fluorouracil, leucovorin, and oxaliplatin (Nordic FLOX) versus FLOX alone in first-line treatment of metastatic colorectal cancer: the NORDIC-VII study. J Clin Oncol. 2012;30:1755-62.
11. Pietrantonio F, Petrelli F, Coinu A, et al. Predictive role of BRAF mutations in patients with advanced colorectal cancer receiving cetuximab and panitumumab: a meta-analysis. Eur J Cancer. 2015;51:587-94.
12. Kopetz S, McDonough SL, Morris VK, et al. Randomized trial of irinotecan and cetuximab with or without vemurafenib in BRAF-mutant metastatic colorectal cancer (SWOG 1406). J Clin Oncol. 2017;35(4 suppl):abstr 520.
13. Janakiraman M, Vakiani E, Zeng Z, et al. Genomic and biological characterization of exon 4 KRAS mutations in human cancer. Cancer Res. 2010;70:5901-11.
14. Heinemann V, von Weikersthal LF, Decker T, et al. FOLFIRI plus cetuximab versus FOLFIRI plus bevacizumab as first-line treatment for patients with metastatic colorectal cancer (FIRE-3): a randomised, open-label, phase 3 trial. Lancet Oncol. 2014;15:1065-75.
15. Primrose J, Falk S, Finch-Jones M, et al. Systemic chemotherapy with or without cetuximab in patients with resectable colorectal liver metastasis: the New EPOC randomised controlled trial. Lancet Oncol. 2014;15:601-11.
16. Venook AP, Niedzwiecki D, Innocenti F, et al. Impact of primary (1o) tumor location on overall survival (OS) and progression-free survival (PFS) in patients (pts) with metastatic colorectal cancer (mCRC): analysis of CALGB/SWOG 80405 (Alliance). J Clin Oncol. 2016;34(15 suppl):abstr 3504.
17. Tejpar S, Stintzing S, Ciardiello F, et al. Prognostic and predictive relevance of primary tumor location in patients with RAS wild-type metastatic colorectal cancer. JAMA Oncol. 2017;3:194-201.
18. Arnold D, Lueza B, Douillard JY, et al. Prognostic and predictive value of primary tumour side in patients with RAS wild-type metastatic colorectal cancer treated with chemotherapy and EGFR directed antibodies in six randomised trials. Ann Oncol. 2017;28:1713-29.
19. Peeters M, Price TJ, Cervantes A, et al. Randomized phase III study of panitumumab with fluorouracil, leucovorin, and irinotecan (FOLFIRI) compared with FOLFIRI alone as second-line treatment in patients with metastatic colorectal cancer. J Clin Oncol. 2010;28:4706-13.
20. National Comprehensive Cancer Network. NCCN guidelines. Colon cancer. Version 2.2017. https://www.nccn.org/professionals/physician_gls/pdf/colon.pdf. Accessed October 13, 2017.
21. Brulé SY, Jonker DJ, Karapetis CS, et al. Location of colon cancer (right-sided versus left-sided) as a prognostic factor and a predictor of benefit from cetuximab in NCIC CO.17. Eur J Cancer. 2015;51:1405-14.
22. Douillard JY, Siena S, Cassidy J, et al. Randomized, phase III trial of panitumumab with infusional fluorouracil, leucovorin, and oxaliplatin (FOLFOX4) versus FOLFOX4 alone as first-line treatment in patients with previously untreated metastatic colorectal cancer: the PRIME study.
J Clin Oncol. 2010;28:4697-705.
23. Bouchahda M, Macarulla T, Spano JP, et al. Cetuximab efficacy and safety in a retrospective cohort of elderly patients with heavily pretreated metastatic colorectal cancer. Crit Rev Oncol Hematol. 2008;67:255-62.
24. Dotan E, Devarajan K, D’Silva AJ, et al. Patterns of use and tolerance of anti–epidermal growth factor receptor antibodies in older adults with metastatic colorectal cancer. Clin Colorectal Cancer. 2014;13:192-8.
25. Jehn CF, Böning L, Kröning H, et al. Cetuximab-based therapy in elderly comorbid patients with metastatic colorectal cancer. Br J Cancer. 2012;106:274-8.
