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Clinical Colorectal CancerRole of First-Line Anti–Epidermal Growth Factor Receptor Therapy Compared With Anti–Vascular Endothelial Growth Factor Therapy in Advanced Colorectal Cancer: A Meta-Analysis of Randomized Clinical Trials

Clinical Colorectal Cancer, 2, 14, pages 81 - 90

Micro-Abstract

Studies comparing first-line monoclonal antibodies in advanced colorectal cancer (CRC) have yielded conflicting results. The results of our meta-analysis show superior response rates and overall survival (OS) with first-line anti–epidermal growth factor receptor (anti-EGFR) therapy compared with anti–vascular endothelial growth factor (anti-VEGF) therapy but no difference in progression-free survival (PFS). Anti-EGFR monoclonal antibodies in combination with chemotherapy may be an alternative option as initial treatment of CRC.

Abstract

Background

Monoclonal antibodies targeting epidermal growth factor receptor (EGFR) or vascular endothelial growth factor (VEGF) have demonstrated efficacy in combination with chemotherapy in the first-line therapy of advanced colorectal cancer (CRC). Data from randomized studies comparing these monoclonal antibodies as initial therapy is conflicting, and their comparative efficacy remains unclear. We aimed to evaluate the impact of these targeted therapies on patient outcomes by combining the data from randomized clinical trials.

Materials and Methods

MEDLINE, PubMed, EMBASE, and meeting proceedings within the past 12 months were searched to identify relevant studies. All randomized phase II/III clinical trials of advanced CRC comparing an anti-EGFR therapy with an anti-VEGF agent in the first-line setting were included. Data were extracted on sample size, objective response rate (ORR), progression-free survival (PFS), and overall survival (OS).

Results

Three randomized studies comprising 2014 participants were included in the meta-analysis. For patients with KRAS wild type (KRAS-WT) CRC, the ORR was superior in patients who received first-line anti-EGFR therapy compared with those who received anti-VEGF therapy (odds ratio [OR], 1.31; 95% confidence interval [CI], 1.09-1.58; P = .004). This effect was even stronger for all RAS-WT patients (OR, 1.46; 95% CI, 1.13-1.90; P = .004). There was no difference in PFS overall irrespective of the KRAS-WT (HR, 1.03; 95% CI, 0.93-1.13; P = .61) or all RAS-WT (HR, 0.92; 95% CI, 0.71-1.18; P = .50) status. The OS was significantly longer in the patients who received first-line anti-EGFR therapy compared with those who received anti-VEGF therapy (KRAS-WT: HR, 0.79; 95% CI, 0.65-0.97; P = .026; all RAS-WT: HR, 0.77; 95% CI, 0.63-0.95; P = .016).

Conclusion

The results of our research show superior ORR and OS with first-line anti-EGFR therapy compared with anti-VEGF therapy in both KRAS-WT and all RAS-WT patients with advanced CRC. These results suggest that anti-EGFR monoclonal antibodies may be a real alternative to anti-VEGF therapy as initial treatment of advanced CRC.

Keywords: Bevacizumab, Cetuximab, Chemotherapy, Colorectal cancer, Panitumumab.

Introduction

The median survival for patients with advanced colorectal cancer (CRC) has increased from 10 to 12 months with older 5-fluorouracil (5-FU)-based chemotherapy regimens alone to > 24 months with the addition of oxaliplatin/irinotecan and monoclonal antibodies. 1 These targeted agents include the anti–epidermal growth factor receptor (anti-EGFR) inhibitors cetuximab and panitumumab and the anti–vascular endothelial growth factor (anti-VEGF) inhibitor bevacizumab. All these agents have shown a progression-free survival (PFS) benefit as well as an overall survival (OS) benefit compared with chemotherapy alone in randomized clinical trials (RCTs).2, 3, 4, 5, and 6

The rat sarcoma (RAS) proto-oncogenes (HRAS, KRAS, and NRAS) are involved in the transmission of extracellular signals through guanosine diphosphate/guanosine triphosphate–regulated switches to regulate cellular growth and survival. 7 Mutations in the Kirsten rat sarcoma (KRAS) viral oncogene are common in advanced CRC, with a frequency of up to 40%. 8 Somatic mutations in codons 12 and 13 of KRAS exon 2 can lead to constitutional activation of the mitogen-activated protein kinase pathway and predict a lack of efficacy of anti-EGFR therapies in advanced CRC.3 and 9 Testing for these mutations has become the standard of care over the past decade. 1 In contrast, neuroblastoma RAS (NRAS) mutations are relatively rare in CRC, with a frequency of up to 2.2%. 10 Recent data suggest the negative predictive effect of less common RAS gene mutations outside the traditional KRAS exon 2. These include KRAS exons 3 and 4 and NRAS exons 2, 3, and 4. Douillard et al 11 reported a 5.8-month OS benefit for panitumumab in combination with chemotherapy (FOLFOX4 [5-fluorouracil, leucovorin, oxaliplatin]) compared with chemotherapy alone. These initial data were further supported by the retrospective extended RAS mutational analysis of the first-line CRYSTAL (Cetuximab Combined With Irinotecan in First-line Therapy for Metastatic Colorectal Cancer) and OPUS trials.12 and 13 Furthermore, there is no predictive biomarker for bevacizumab in the management of advanced CRC at this point.

Once the superiority of combination chemotherapy and targeted therapy compared with chemotherapy alone was established in first-line clinical trials in advanced CRC, the next issue of clinical relevance was to determine the best monoclonal antibody and chemotherapy (FOLFOX and FOLFIRI [5-fluorouracil, leucovorin [folinic acid], irinotecan]) combination as the initial treatment for advanced CRC. Results of data from 3 RCTs indicate a superior objective response rate (ORR) favoring anti-EGFR therapy, especially after extended RAS analysis.14, 15, and 16 PFS seems to be similar for first-line anti-EGFR and anti-VEGF therapies. However, the data regarding OS is more supportive of anti-EGFR therapy. Results from the FIRE-3 (Multicenter Randomized Trial Evaluating FOLFIRI Plus Cetuximab Versus FOLFIRI Plus Bevacizumab in First Line Treatment of Metastatic Colorectal Cancer) 14 and PEAK (A Randomized Phase II Study of mFOLFOX6 With Either Panitumumab or Bevacizumab as First-Line Treatment in Patients With Unresectable Wild-Type KRAS Metastatic Colorectal Cancer) 15 studies indicate an OS benefit for first-line anti-EGFR therapy compared with anti-VEGF therapy, especially on extended RAS analysis. However, no statistically significant difference was detected between the 2 monoclonal antibodies in the Cancer and Leukemia Group (CALGB)/SWOG 80405 study. It is unlikely that another RCT will be conducted in the future to address this issue and further clarify the conflicting results from these studies. Therefore, we need to make sense of the existing available data from randomized studies comparing first-line anti-EGFR and anti-VEGF therapies. With this in mind, the aim of our study was to evaluate the existing evidence and investigate the overall impact of first-line anti-EGFR therapy vs. anti-VEGF therapy on ORR, PFS, and OS in advanced CRC.

Methods

The authors agreed on study protocol before literature review and data analysis, although it was not centrally registered. We searched MEDLINE, PubMed, and EMBASE to identify relevant published studies. No restrictions were placed on the search. We also manually searched for abstracts from major oncology conferences since January 2013. Two authors (MK and HM) independently reviewed titles and meeting abstracts and agreed on the articles to be retrieved. The last search was carried out on October 20, 2014.

We searched for all randomized phase II/III clinical trials of advanced CRC comparing an anti-EGFR drug with an anti-VEGF agent, both in combination with the newer chemotherapy backbones of FOLFOX or FOLFIRI in the first-line setting. We used the following search terms: “bevacizumab or anti-VEGF,” “cetuximab or panitumumab or anti-EGFR,” “colorectal cancer,” and “chemotherapy’’ in any combination in the titles of published articles or meeting abstracts. Articles for which neither the abstract nor the full text was available in English were excluded after review. The initial search results were checked for any duplicate articles/abstracts and later on screened for the most relevant articles according to the inclusion criteria. Case reports, editorials, letters to the editor, retrospective studies, second- and third-line studies, and review articles were excluded. After exclusion of the nonrelevant articles/abstracts, full-text articles and abstracts were assessed for eligibility. Further detailed review of the full manuscripts/abstracts or meeting presentations was performed to carry out the final qualitative and quantitative analysis. Results were reported according to Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. Data were extracted from the selected studies by 2 authors for sample size, ORR, PFS, and OS for both KRAS-WT and all RAS-WT patients. Final published articles were used to source the data from the FIRE-3 and PEAK studies, whereas data were obtained from the American Society for Clinical Oncology (ASCO) 2014 and European Society of Medical Oncology (ESMO) 2014 meetings proceedings for the CALGB/SWOG 80405 study. The study with the largest sample size was given the greatest percentage weight on meta-analysis.

The meta-analysis was conducted using a random-effects model based on the method of DerSimonian and Laird, and assessment of heterogeneity was based on the inverse variance fixed-effects model. Bootstrapped robust estimation of standard errors was used in the random-effects models because the assumptions underlying regression models could not be assumed. Statistical significance was predetermined to apply if P values were < .05. All the meta-analyses were conducted using the using the user-written “metan” package for Stata, version 13.1(StataCorp, College Station, TX).

Results

A total of 1241 titles were identified from the database and meeting resources. The search results are summarized in Figure 1 . Three randomized studies (1 phase II and 2 phase III trials) comprising a total of 2014 participants who met all the eligibility criteria were eventually selected. These studies are summarized in Table 1 . Quantitative analysis (meta-analysis) was carried out to determine the impact of first-line anti-EGFR (cetuximab or panitumumab) vs. anti-VEGF (bevacizumab) therapy on ORR, PFS, and OS in first-line therapy in KRAS-WT or all RAS-WT patients with advanced CRC. None of the heterogeneity tests was statistically significant, but it should be noted that the test for PFS with RAS had a P value < 0.1 (χ2 = 6.0; P = .051).

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Figure 1 Search Results Summarized According to Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) Guidelines

Table 1 Summary of Randomized Phase II/III Studies Comparing First-Line Anti-EGFR vs. Anti-VEGF Antibodies in Combination With Chemotherapy for the Treatment of Advanced Colorectal Cancer

  KRAS-WT RAS-WT
n PFS OS ORR n PFS OS ORR
FIRE-3 (n = 592)                
 FOLFIRI-cetuximab 297 10.0 mo

(8.8-10.8)
28.7 mo

(24.0-36.6)
62%

(56.2-67.5)
205 10.4 mo

(9.5-12.2)
33.1 mo

(24.5-39.4)
65%

(57.9-72.6)
 FOLFIRI-bevacizumab 295 10.3 mo

(9.8-11.3)
25.0 mo

(22.7-27.6)
58%

(52.1-63.7)
202 10.2 mo

(9.3-11.5)
25.6 mo

(22.7-28.6)
60%

(51.9-67.1)
 Hazard ratio and P value   HR, 1.06

(0.88-1.26)

P = .55
HR, 0.77

(0.62-0.96)

P = .017
OR, 1.18

(0.85-1.64)

P = .18
  HR, 0.93

(0.74-1.17)

P = .54
HR, 0.70

(0.53-0.92)

P = .011
OR, 1.28

(0.83-1.99)

P = 0.32
PEAK (n = 285)                
 FOLFOX-panitumumab 142 10.9 mo

(9.4-13.0)
34.2 mo

(26.6-NR)
57.8%

(49.2-66.0)
88 13.0 mo

(10.9-15.1)
41.3 mo

(28.8-41.3)
63.6%

(52.7-73.6)
 FOLFOX –bevacizumab 143 10.1 mo

(9.0-12.6)
24.3 mo

(21.0-29.2)
53.5%

(45.0-61.9)
82 9.5 mo

(9.0-12.7)
28.9 mo

(23.9-31.3)
60.5%

(49.0-71.2)
 Hazard ratio and P value HR, 0.87

(0.65-1.17)

P = .353
HR, 0.62

(0.44-0.89)

P = .009
HR, 0.65

(0.44-0.96)

P = .029
HR, 0.63

(0.39-1.02)

P = .058
CALGB/SWOG 80405 (n = 1137)                
 Chemotherapy (FOLFOX [∼75%]/FOLFIRI [∼25%]-cetuximab 578 10.4 mo

(9.6-11.3)
29.9 mo

(27.0-32.9)
65.6% 270 11.4 mo

(9.6-12.9)
32.0 mo

(27.6-38.5)
68.8%
 Chemotherapy (FOLFOX [∼75%]/FOLFIRI [∼25%]-bevacizumab 559 10.8 mo

(9.7-11.4)
29.0 mo

(25.7-31.2)
57.2% 256 11.3 mo

(10.3-12.6)
31.2 mo

(26.9-34.3)
56%
 Hazard ratio and P value HR, 1.04

(0.91-1.17)

P = .55
HR, 0.925

(0.78-1.09)

P = .34
P = .02 HR, 1.10

(0.90-1.30)

P = .31
HR, 0.90

(0.70-1.10)

P = .40
P < .01

Abbreviations: HR = hazard ratio; NR = not reported; OR = odds ratio; ORR = objective response rate; OS = overall survival; PFS = progression-free survival; WT = wild type.

Objective Response Rate

For patients with KRAS-WT CRC, the ORR was superior in patients who received first-line anti-EGFR therapy compared with those who received anti-VEGF therapy (OR, 1.31; 95% CI, 1.09-1.58; P = .004) ( Figure 2 ). This effect was even stronger for patients with more extensive RAS analysis who were found to be all RAS-WT after exclusion of rare RAS mutations (KRAS exons 3 and 4 and NRAS exons 2, 3, and 4) (OR, 1.46; 95% CI, 1.13-1.90; P = .004) ( Figure 3 ).

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Figure 2 Forest Plot for Objective Response Rate (ORR) for KRAS Wild Type (KRAS-WT) Patients

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Figure 3 Forest Plot for Objective Response Rate (ORR) for All RAS Wild Type (RAS-WT) Patients

Progression-Free Survival

There was no difference in PFS overall irrespective of the KRAS-WT (hazard ratio [HR], 1.03; 95% CI, 0.93-1.13; P = .61) or all RAS-WT (HR, 0.92; 95% CI, 0.71-1.18; P = .50) status between first-line anti-EGFR and anti-VEGF therapy in combination with cytotoxic chemotherapy ( Figures 4 and 5 ).

gr4

Figure 4 Forest Plot for Progression-Free Survival (PFS) for KRAS Wild Type (KRAS-WT) Patients

gr5

Figure 5 Forest Plot for Progression-Free Survival (PFS) for all RAS Wild Type (RAS-WT) Patients

Overall Survival

For KRAS-WT patients, the OS was significantly longer in patients who received first-line anti-EGFR compared with those who received anti-VEGF therapy (HR, 0.79; 95% CI, 0.65-0.97; P = .026). This effect was even more pronounced in the all RAS-WT patients (HR, 0.77; 95% CI, 0.63-0.95; P = .016) ( Figures 6 and 7 ).

gr6

Figure 6 Forest Plot for Overall Survival (OS) for KRAS Wild Type (KRAS-WT) Patients

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Figure 7 Forest Plot for Overall Survival (OS) for All RAS Wild Type (RAS-WT) Patients

Discussion

This is the first study, to our knowledge, evaluating the overall impact of first-line anti-EGFR therapy (cetuximab or panitumumab) compared with anti-VEGF therapy (bevacizumab) on ORR, PFS, and OS in advanced CRC by combining the results of 3 randomized studies.14, 15, and 16 These trials have reported conflicting results regarding PFS, OS, and ORR. The FIRE-3 study did not meet its primary end point of ORR, without any significant difference in ORR or PFS between first-line anti-EGFR vs. anti-VEGF therapy in advanced CRC. 14 The PEAK study, which was a phase II study with a relatively smaller sample size, showed improvement in ORR only for KRAS-WT patients. 15 However, there was a significant difference favoring anti-EGFR therapy over anti-VEGF therapy in ORR as well as PFS for the all RAS-WT patients with a trend toward better OS. These results need to be interpreted with caution because of the small number of patients in both subgroups. The CALGB/SWOG 80405 study 16 has not been published yet, but updated results were presented at the ESMO 2014 meeting in Madrid. This study did not detect any significant differences in PFS or OS between the 2 treatment approaches. However, the ORR results favored first-line anti-EGFR therapy. Our results indicate that first-line anti-EGFR monoclonal antibody therapy improves the ORR and OS compared with anti-VEGF therapy, without any significant impact on PFS.

The OS of advanced CRC has increased over the past decade, with the median OS approaching 30 months according to recent data.14 and 16 A number of cytotoxic as well as targeted agents have been approved for the treatment of patients with advanced CRC, and the best sequencing of these agents is an issue of paramount importance. On 1 hand, while we move toward management of some advanced cancers as chronic diseases—eg, breast, CRC, and renal cancers—it is suggested that as long as patients get access to all the active drugs, sequencing probably does not matter so much. On the other hand, an even more important observation is that patients might miss out on active treatment options in second- and third-line settings, especially if they have deterioration in their performance status Besides this, the response rates, PFS, and OS in second-line therapy and beyond are generally modest compared with first-line therapy. The latter scenario, seen more commonly in the real world setting, suggests an approach of initiating treatment with the most active agent to ensure patients get the maximum benefit rather than risking missing out on such active drugs in subsequent lines of therapy.

The data from the 3 randomized studies used for this meta-analysis are relatively easy to understand for ORR but are somewhat puzzling for PFS and OS. The FIRE-3 study reported an OS benefit of 2.7 months, favoring anti-EGFR therapy in the absence of improvement of ORR or PFS. 14 Once the all RAS-WT data were available, the OS difference was exaggerated even further to 8.1 months. Because the study was initially presented last year at the American Society of Clinical Oncology (ASCO) meeting, a number of hypotheses have been put forward in an effort to explain the late separation of curves. This could be a second-line treatment effect, but then approximately 40% of patients switched to the alternative monoclonal antibody in both arms of this study. This is especially important because this study included KRAS-WT patients only, a subgroup of patients who are most likely to benefit from anti-EGFR therapy in a first-, second-, or third-line setting. Therefore, lower rates of cetuximab use in the second-line setting for the FOLFIRI-bevacizumab arm could have contributed to the inferior OS. Prespecified second-line treatment was recommended but not mandatory in the FIRE-3 study in contrast to the CALGB/SWOG 80405 study.

It has also been suggested that anti-EGFR therapy resistance leads to VEGF upregulation,17 and 18 making a more conducive tumor microenvironment for anti-VEGF therapy. An update of FIRE-3 data from the 2014 ESMO meeting after independent radiological review seems to demonstrate an improvement in ORR with anti-EGFR therapy compared with anti-VEGF therapy (KRAS-WT: ORR, 66.5% vs. 55.6%; OR, 1.58; 95% CI, 1.10-2.28; P = .016; all RAS-WT: ORR, 72% vs. 56.1%; OR, 2.01; 95% CI, 1.27-3.19; P = .003). 19 Besides this, the results favored early tumor shrinkage (tumor shrinkage ≥ 20% at 6 weeks) and depth of response (percentage of maximal tumor shrinkage observed at the nadir compared with baseline) with anti-EGFR therapy compared with anti-VEGF monoclonal antibody therapy.

The CALGB/SWOG 80405 study, 16 which is the largest RCT to date of first-line anti-EGFR vs. anti-VEGF therapy in the first-line setting of advanced CRC, did not show any significant difference in PFS or OS between the 2 treatment approaches. The primary end point of the FIRE-3 study was ORR, in contrast to the more meaningful end point of OS in the larger CALGB/SWOG 80405 study. We also know that an improvement in ORR might not necessarily lead to an improvement in OS. However, further data on second-line therapy, median duration of treatment, BRAF mutational analysis, and further RAS analysis (< 60% had full RAS analysis performed at the time of the ESMO 16 2014 presentation) is needed before we can draw any definite conclusions.

In contrast to the previous first-line studies with anti-VEGF in combination with chemotherapy in advanced CRC, the median OS of the bevacizumab arm in the CALGB/SWOG 80405 trial seems to be an outlier, as was also agreed on by the authors of the study at the ESMO 2014 meeting.4 and 5 It was suggested that this could be related to early and aggressive management of low-volume metastatic disease in the United States and Canada in contrast to Europe, where a more conservative management approach might be taken for patients with low-volume asymptomatic metastasis from CRC. The chemotherapy backbone was predominantly FOLFOX (75%) in contrast to FOLFIRI (100%) in the FIRE-3 study. Results from the Medical Research Council COIN (A Three-Arm Randomised Controlled Trial Comparing Either Continuous Chemotherapy Plus Cetuximab or Intermittent Chemotherapy With Standard Continuous Palliative Combination Chemotherapy With Oxaliplatin and a Fluoropyrimidine in First Line Treatment of Metastatic Colorectal Cancer) trial 20 suggest that oxaliplatin might not be the best chemotherapy drug to use in combination with cetuximab, because this trial did not confirm a benefit of adding cetuximab to oxaliplatin-based chemotherapy in first-line therapy for advanced CRC. A recent meta-analysis also showed superior efficacy for anti-EGFR therapy when used in combination with an irinotecan-based regimen compared with an oxaliplatin-based regimen. 21 Therefore, the greater use of oxaliplatin-based chemotherapy in the CALGB/SWOG 80405 study could have attenuated any OS difference between the 2 groups. It will be useful to have data from the 2 phase III studies about the nonsurgical targeted interventions like radiofrequency ablation, selective internal radiotherapy, and stereotactic radiotherapy for the management of oligometastatic disease.

Maintenance chemotherapy with 5-FU–based chemotherapy and bevacizumab is routine in clinical practice, shown by a number of studies demonstrating a modest but definitive PFS and OS advantage.22 and 23 It is unclear how to incorporate maintenance therapy into the approach taken by the 3 first-line anti-EGFR vs. anti-VEGF therapy studies in which patients were treated until disease progression or intolerable toxicity. Patient choice is also extremely important and relevant here, because an acneiform rash and continuous Skin Toxicity Evaluation Protocol With Panitumumab (STEPP) regimen 24 to minimize the toxicity of anti-EGFR therapy might be less acceptable to patients, especially in the first-line setting. Patients in the cetuximab arm had a significant decline in the dermatology-specific quality of life skin satisfaction scores in the CALGB/SWOG 80405 study. 25 Besides this, the 3 weekly treatment schedule favors anti-VEGF therapy with regard to patient convenience and minimizing the “chemotherapy chair time.”

Our results further support extended RAS testing for all patients with advanced CRC to better identify patients who are less likely to benefit from anti-EGFR therapy. The prognostic and predictive significance of the rare RAS mutations (KRAS exons 3 and 4 and NRAS exons 2, 3, and 4) needs to be determined in prospective studies. However, given that the incidence of these rare mutations is relatively low (10%-18%),11, 12, and 26 data from trials may need to be pooled to evaluate their biomarker significance. It will also be useful to carry out BRAF analysis for the FIRE-3 and CALGB/SWOG 80405 studies to look for any potential differences between the study arms.

There are several limitations of our study. Data was extracted from published studies and meeting abstracts rather than being based on an individual patient data meta-analysis. This meta-analysis included the CALGB/SWOG 80405 study, which has not been published yet and has only been presented at conferences in the past 12 months. However, we expect the differences compared with the final published results to be relatively modest. Common meta-analysis–associated biases—including publication bias, time lag bias, and selection bias—were minimized through a comprehensive search of the literature and conference proceedings by 2 separate authors.

Conclusion

The results of our research support the use of first-line anti-EGFR therapy as an alternative option to anti-VEGF therapy in all RAS-WT patients with advanced CRC on the basis of superior ORR and OS benefit. Further data regarding duration of initial treatment and second-line therapy given, as well as data from patients who underwent surgical resection and full RAS analysis from the FIRE-3 and CALGB/SWOG 80405 studies is awaited to determine the best monoclonal antibody combination with chemotherapy. Future research should focus on detailed molecular profiling of CRC tissue with full RAS and BRAF analysis along with biomarkers predictive of response to anti-VEGF therapy.

Clinical Practice Points

 

  • Meta-analysis of randomized clinical trials comparing first-line anti-EGFR therapy with anti-VEGF therapy in advanced colorectal cancer indicates better response rates and overall survival (OS) with anti-EGFR therapy but no difference in progression-free survival (PFS).
  • Full RAS analysis should be carried out for all newly diagnosed patients with advanced colorectal cancer (CRC).
  • First-line anti-EGFR therapy may be a real alternative to anti-VEGF therapy as initial treatment of advanced CRC.

Disclosures

Dr Khattak: Merck Serono sponsored attendance/registration for ESMO 2014; Dr Martin: Nil; Dr Davidson: Nil; Mr Phillips: Nil.

References

  • 1 D. Cunningham, W. Atkin, H.J. Lenz, et al. Colorectal cancer. Lancet. 2010;375:1030-1047 Crossref
  • 2 E. Van Cutsem, C.H. Kohne, E. Hitre, et al. Cetuximab and chemotherapy as initial treatment for metastatic colorectal cancer. N Engl J Med. 2009;360:1408-1417 Crossref
  • 3 E. Van Cutsem, C.H. Kohne, I. Lang, 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;29:2011-2019 Crossref
  • 4 H. Hurwitz, L. Fehrenbacher, W. Novotny, et al. Bevacizumab plus irinotecan, fluorouracil, and leucovorin for metastatic colorectal cancer. N Engl J Med. 2004;350:2335-2342 Crossref
  • 5 L.B. Saltz, S. Clarke, E. Diaz-Rubio, et al. Bevacizumab in combination with oxaliplatin-based chemotherapy as first-line therapy in metastatic colorectal cancer: a randomized phase III study. J Clin Oncol. 2008;26:2013-2019 Crossref
  • 6 J.Y. Douillard, S. Siena, J. Cassidy, 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;28:4697-4705 Crossref
  • 7 M. Malumbres, M. Barbacid. RAS oncogenes: the first 30 years. Nat Rev Cancer. 2003;3:459-465 Crossref
  • 8 C.P. Vaughn, S.D. Zobell, L.V. Furtado, C.L. Baker, W.S. Samowitz. Frequency of KRAS, BRAF, and NRAS mutations in colorectal cancer. Genes Chromosomes Cancer. 2011;50:307-312 Crossref
  • 9 R.G. Amado, M. Wolf, M. Peeters, et al. Wild-type KRAS is required for panitumumab efficacy in patients with metastatic colorectal cancer. J Clin Oncol. 2008;26:1626-1634 Crossref
  • 10 N. Irahara, Y. Baba, K. Nosho, et al. NRAS mutations are rare in colorectal cancer. Diagn Mol Pathol. 2010;19:157-163 Crossref
  • 11 J.Y. Douillard, K.S. Oliner, S. Siena, et al. Panitumumab-FOLFOX4 treatment and RAS mutations in colorectal cancer. N Engl J Med. 2013;369:1023-1034 Crossref
  • 12 F. Ciardiello, H. Lenz, C. Kohne, et al. Treatment outcome according to tumor RAS mutation status in CRYSTAL study patients with metastatic colorectal cancer (mCRC) randomized to FOLFIRI with/without cetuximab. J Clin Oncol. 2014;32 abstract 3506
  • 13 S. Tejpar, H. Lenz, C. Köhne, et al. Effect of KRAS and NRAS mutations on treatment outcomes in patients with metastatic colorectal cancer (mCRC) treated first-line with cetuximab plus FOLFOX4: new results from the OPUS study. J Clin Oncol. 2014;32 abstract LBA444
  • 14 V. Heinemann, L.F. von Weikersthal, T. Decker, 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;15:1065-1075
  • 15 L.S. Schwartzberg, F. Rivera, M. Karthaus, 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;32:2240-2247
  • 16 Lenz H, Niedzwiecki D, Innocenti F, et al. PHASE III trial of irinotecan/5-FU/leucovorin (FOLFIRI) or oxaliplatin/5-FU/leucovorin (mFOLFOX6) with bevacizumab (BV) or cetuximab (CET) for patients (pts) with expanded RAS analyses untreated metastatic adenocarcinoma of the colon or rectum (mCRC). Paper presented at: European Society of Medical Oncology (ESMO); Jan 26-30, 2014; Madrid, Spain.
  • 17 F. Ciardiello, R. Bianco, R. Caputo, et al. Antitumor activity of ZD6474, a vascular endothelial growth factor receptor tyrosine kinase inhibitor, in human cancer cells with acquired resistance to antiepidermal growth factor receptor therapy. Clin Cancer Res. 2004;10:784-793 Crossref
  • 18 A. Viloria-Petit, T. Crombet, S. Jothy, et al. Acquired resistance to the antitumor effect of epidermal growth factor receptor-blocking antibodies in vivo: a role for altered tumor angiogenesis. Cancer Res. 2001;61:5090-5101
  • 19 Stintzing S, Modest DP, von Weikersthal LF, et al. Independent radiological evaluation of objective response, early tumor shrinkage, and depth of response in FIRE-3 (AIO KRK-0306) in the final RAS evaluable population. Paper presented at: European Society of Medical Oncology (ESMO); Jan 26-30, 2014; Madrid, Spain.
  • 20 T.S. Maughan, R.A. Adams, C.G. Smith, 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;377:2103-2114 Crossref
  • 21 D. Chan, N. Pavlakis, T. Price, et al. Impact of chemotherapy partner on efficacy of targeted therapy in metastatic colorectal cancer (mCRC): a meta-analysis. J Clin Oncol. 2014;32 abstract 3552
  • 22 M. Koopman, L. Simkens, A. Tije, et al. Maintenance treatment with capecitabine and bevacizumab versus observation after induction treatment with chemotherapy and bevacizumab in metastatic colorectal cancer (mCRC): the phase III CAIRO3 study of the Dutch Colorectal Cancer Group (DCCG). J Clin Oncol. 2013;31 abstract 3502
  • 23 B. Chibaudel, F. Maindrault-Goebel, G. Lledo, et al. Can chemotherapy be discontinued in unresectable metastatic colorectal cancer? The GERCOR OPTIMOX2 Study. J Clin Oncol. 2009;27:5727-5733 Crossref
  • 24 M.E. Lacouture, E.P. Mitchell, B. Piperdi, et al. Skin toxicity evaluation protocol with panitumumab (STEPP), a phase II, open-label, randomized trial evaluating the impact of a pre-emptive skin treatment regimen on skin toxicities and quality of life in patients with metastatic colorectal cancer. J Clin Oncol. 2010;28:1351-1357 Crossref
  • 25 Venook A, Niedzwiecki D, Lenz H-J, et al. CALGB/SWOG 80405: phase III trial of irinotecan/5-FU/leucovorin (FOLFIRI) or oxaliplatin/5-FU/leucovorin (mFOLFOX6) with bevacizumab (BV) or cetuximab (CET) for patients (pts) with KRAS wild-type (wt) untreated metastatic adenocarcinoma of the colon or rectum (MCRC). Paper presented at: annual meeting of the American Society of Clinical Oncology (ASCO); May 30-June 3, 2014; Chicago, IL.
  • 26 T. Price, M. Bruhn, C. Lee, et al. Correlation of PI3KCA and extended RAS gene mutation status with outcomes from the phase III AGITG MAX involving capecitabine (C) alone or in combination with bevacizumab (B) with or without mitomycin C (M) in advanced colorectal cancer (CRC). J Clin Oncol. 2014;32 abstract 3539

Footnotes

1 Royal Perth Hospital, Perth, Western Australia

2 University of Western Australia, Crawley, Western Australia

Address for correspondence: Muhammad A. Khattak, MBBS, FRACP, Royal Perth Hospital, 197 Wellington Street, Perth, Western Australia. Fax: +61-8-9224-3126

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