August 2014, Vol 3, No 5

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RAS and Colon Cancer: What You’re Missing

Sonia L. Ali, MD


Dr Ali received her medical degree from St. George’s University, St. George’s, Grenada, and is currently practicing as a first-year fellow in the Division of Hematology/Oncology at Scripps Clinic.

Dr Sigal received his medical degree from the University of California, Los Angeles, and is currently practicing in the Division of Hematology/Oncology at Scripps Clinic Medical Group. He is an active investigator in the GI Cancer Program at Scripps Clinic.

When first introduced almost a decade ago, monoclonal antibodies targeting the epidermal growth factor receptor (EGFR) offered patients with unresectable metastatic colorectal cancer (mCRC) new hope. Large phase 3 trials evaluating panitumumab (Vectibix) and cetuximab (Erbitux) in pretreated patients with mCRC showed that the 2 anti-EGFR antibodies produced similar improvements in survival end points measured in weeks and in response rates of up to 10% compared with best supportive care.1,2 Despite the statistical significance of these outcomes, their clinical impact was marginal. An increasingly sophisticated understanding of the EGFR pathway revealed that KRAS played a central role in propagating EGFR signaling and potentially explained the muted impact of panitumumab and cetuximab.3,4 About 40% of patients with mCRC have a mutation in KRAS exon 2 resulting in a constitutively active molecule that drives the EGFR-KRAS-BRAF-MAPK pathway independent of EGFR signaling. Small retrospective studies indicated that mutated KRAS exon 2 was a negative predictive biomarker for anti-EGFR antibodies.5,6 Consistent findings from retrospective analyses of the initial randomized panitumumab and cetuximab trials confirmed that KRAS mutational status was predictive for the use of anti-EGFR antibodies.7,8 Standard of care evolved to restrict anti-EGFR antibody use to patients with a wild-type KRAS exon 2 colorectal cancer.

Incorporating KRAS exon 2 into clinical care improved the selection of patients who would potentially benefit from anti-EGFR antibodies. Again, it was suggested that patient selection could be further optimized. Additional mutations had been reported in KRAS exons 3 and 4, as well as NRAS exons 2, 3, and 4, that were also putative negative predictive biomarkers for anti-EGFR antibodies.9-12 NRAS has structural and functional homology to KRAS, suggesting it, too, had predictive value for anti-EGFR antibodies.13-15 Due to their low prevalence (Table 1), studies supportive of the predictive role for expanded RAS testing were small and retrospective, limiting their clinical impact. Recently, a prospective-retrospective analysis of a large phase 3 trial showed that expanded RAS testing, including KRAS and NRAS exons 2 (codons 12 and 13), 3 (codon 61), and 4 (codons 117 and 146), identified up to an additional 18% of RAS mutations among wild-type KRAS exon 2 patients.16 Expanded RAS testing enhanced the negative and positive predictive value of KRAS exon 2 testing alone for anti-EGFR antibodies.16,17

Finally, BRAF has also been evaluated for its potential predictive role in utilizing anti-EGFR antibodies. Early studies revealed that colorectal cancer cell lines with BRAF V600E mutations were resistant to anti­EGFR antibodies, suggesting that BRAF mutations could also serve as a negative predictive biomarker.4,18 These preclinical findings were supported in small retrospective analyses.14,18 However, larger trials and meta-analyses reveal a much more complicated picture.

This manuscript will review the recent literature of expanded RAS and BRAF testing as predictive biomarkers for anti-EGFR antibodies and address their incorporation into patient care.

Expanded RAS Analysis

Oxaliplatin-Based Chemotherapy in the Front-Line Setting

Two trials have demonstrated improved predictive value from expanded RAS analysis, including KRAS and NRAS exons 2, 3, and 4, for anti-EGFR antibodies. PRIME was a phase 3 trial that randomized 1183 patients with mCRC to FOLFOX4 (leucovorin, fluorouracil [5-FU], and oxaliplatin) with or without panitumumab, and the first to prospectively perform KRAS testing in the front-line setting.16 Within the wild-type KRAS group, panitumumab improved progression-free survival (PFS) and overall survival (OS) compared with chemotherapy alone (9.6 vs 8.0 months, P=.02 and 23.9 vs 19.7 months, P=.072, respectively). Conversely, patients with mutated KRAS not only failed to derive any benefit from anti-EGFR antibody therapy, they were actually harmed. Mutated KRAS patients who received panitumumab experienced reduced PFS and OS (7.3 vs 8.8 months, P=.02 and 15.5 vs 19.3 months, P=.068, respectively). Prospective-retrospective analysis of PRIME prespecified a statistical design to assess the predictive impact of expanded RAS testing. Among patients with wild-type KRAS exon 2, 108 patients (17%) harbored additional RAS mutations. Wild-type RAS patients had improved PFS and OS (10.1 vs 7.9 months, P=.004 and 26.0 vs 20.2 months, P=.04, respectively) when administered FOLFOX plus panitumumab versus FOLFOX alone. Inferior PFS and OS were observed in the mutated RAS cohort treated with FOLFOX plus panitumumab compared with FOLFOX alone (7.3 vs 8.7 months, P=.008 and 15.5 vs 18.7 months, P=.04, respectively). Expanded RAS testing improved the positive and negative predictive value versus KRAS exon 2 alone for anti­EGFR antibodies. Specifically, the improvement in OS among wild-type KRAS exon 2 patients treated with panitumumab and the reduction in OS among mutated KRAS exon 2 patients treated with panitumumab became statistically significant with expanded RAS testing (Table 2).

Retrospective analysis of the OPUS trial also evaluated the effect of anti-EGFR antibody therapy (cetuximab) combined with oxaliplatin-based chemotherapy in the front-line setting of patients with unresectable mCRC.19 In this study, 337 patients were randomly assigned to either FOLFOX alone or in combination with cetuximab. Of these 337 patients, 317 were included in an unplanned retrospective analysis to determine the predictive value of KRAS. Wild-type KRAS exon 2 patients who received cetuximab had a 23% improvement in overall response rate (ORR; 57% vs 34%, P=.0027) and a 1.1 month improvement in median PFS (8.3 vs 7.2 months, P=.0064) compared with patients receiving chemotherapy alone. No differences were noted for OS. Similar to the results from PRIME, patients with mutated KRAS exon 2 had inferior clinical end points with the addition of cetuximab. Statistical reductions in ORR and PFS were noted (34% vs 54%, P=.0290 and 5.5 vs 8.6 months, P=.0153, respectively), while a numerical decrease in OS occurred (13.4 vs 17.5 months, P=.20). Recently, of 179 wild-type KRAS samples in OPUS, 118 were evaluable for additional RAS mutation screening beyond KRAS exon 2.20 Additional RAS mutations were found in 36 samples (31%). Exclusion of these additional RAS mutations resulted in a statistically significant improvement in response rate and trends toward improved PFS and OS for the group receiving cetuximab (Table 3). Inferior clinical end points were observed in the expanded RAS mutation cohort receiving cetuximab (Table 3).

In a third retrospective study, 148 patients with mCRC wild-type KRAS exon 2 were randomized to FOLFOX with weekly versus every-2-week cetuximab. Ex­­panded RAS analysis uncovered 24 patients (16%) harboring additional RAS mutations with decreased ORR, PFS, and OS compared with the wild-type RAS cohort (ORR, 40% vs 61.3%, P=.1966; median PFS, 7.2 vs 9.7 months, P=.1135; OS, 16.3 vs 28.5 months, P=.0199, respectively).21 Although these results reinforce the 2 studies described above, the absence of a cohort that did not receive cetuximab limits this study’s commentary on the predictive value of expanded RAS testing.

Irinotecan-Based Chemotherapy in the Front-Line Setting
CRYSTAL was a phase 3 trial that randomized 1198 mCRC patients to irinotecan-based chemotherapy with or without the addition of cetuximab.2 An updated retrospective analysis of CRYSTAL had an ascertainment rate of 89% (n=1063) of samples for KRAS testing from the intention-to-treat population and identified mutated KRAS exon 2 in 37%.22 Statistically significant improvements in OS (23.5 vs 20.0 months, P=.0093), PFS (9.9 vs 8.4 months, P=.0012), and ORR (57.3% vs 39.7%, P?.001) were observed for wild-type KRAS exon 2 patients in the cetuximab-containing treatment arm versus the chemotherapy-alone group (Table 4). A retrospective expanded RAS analysis of CRYSTAL among 430 (65%) of the wild-type KRAS exon 2 patients was presented at ASCO 2014.23 New RAS mutations were identified in an additional 63 patients (15%). Cetuximab did not confer any benefit to patients with any RAS mutation and those with wild-type KRAS exon 2 with a new RAS mutation. However, patients with wild-type RAS had clinically and statistically significant improvements in response and survival end points when administered FOLFIRI (leucovorin, 5-FU, and irinotecan) plus cetuximab compared with FOLFIRI alone. Wild-type RAS patients also had improved clinical end points when compared with wild-type KRAS exon 2 patients (Table 4). Expanded RAS testing also resulted in incremental improvements in end points with irinotecan-based chemotherapy and cetuximab in the FIRE-3 trial, which will be discussed later.24

Salvage Setting

In the first phase 3 second-line trial that prospectively assessed KRAS status, 1186 patients who had progressed on 1 prior line of therapy were randomized to FOLFIRI with or without panitumu­mab. Of the 1083 patients with wild-type KRAS exon 2, those administered FOLFIRI plus panitumumab had improved PFS (5.9 vs 3.9, P=.004) and ORR (35% vs 10%, P<.001) compared with those receiving FOLFIRI alone. A nonstatistical OS trend also favored the panitumumab-containing arm.17 These data have been confirmed with longer follow-up (median PFS, 6.7 vs 4.9 months, P=.023; ORR 36% vs 10%, P?.0001).25 Recently, a retrospective-prospective biomarker analysis of this trial identified an additional 18% of patients with mutated RAS among those with known wild-type KRAS exon 2.26 Wild-type RAS patients treated with FOLFIRI plus panitumumab had improved PFS and OS outcomes compared with those with wild-type KRAS exon 2 alone. In contrast, patients with any RAS mutation, including those with wild-type KRAS exon 2, derived no additional benefit from the use of panitumu­mab (Table 5).

Mutated RAS and Anti-EGFR Antibodies
Despite the positive predictive value of wild-type KRAS exon 2 for anti-EGFR antibodies described in the previous trials, these results have not been universal. The NORDIC-VII and MRC COIN trials showed no benefit from the addition of anti-EGFR antibodies to an oxaliplatin-based chemotherapy regimen in a cohort of wild-type KRAS exon 2 patients in the first-line setting.27,28 MRC COIN was a phase 3 trial that prospectively randomized 729 wild-type KRAS (at exons 2 and 3) patients to front-line FOLFOX or XELOX (capecitabine plus oxaliplatin) with or without cetuximab. The primary end point was OS. No advantage was identified from the use of cetuximab according to survival end points (OS, 17 vs 17.9 months, P=.67; PFS, 8.6 vs 8.6 months, P=.8) compared with chemotherapy alone. Cetuximab also conferred no advantage among a cohort of wild-type RAS patients (at KRAS codons 12, 13, and 61; NRAS codons 12 and 61) prospectively assessed in this study. NORDIC-VII was a 3-arm randomized study evaluating the benefit of adding cetuximab to front-line oxaliplatin-based chemotherapy. In an unplanned retrospective analysis of 194 wild-type KRAS exon 2 patients, the addition of cetuximab again did not improve clinical outcomes.

Two main explanations can be proposed for the discrepant outcomes between MRC COIN and NORDIC-VII and the other anti-EGFR antibody trials. First, the method of 5-FU delivery may affect the beneficial impact of anti-EGFR antibodies. In an exploratory analysis of MRC COIN, cetuximab only improved PFS among the one-third of patients who received infusional 5-FU (FOLFOX) and not among the two-thirds of patients treated with capecitabine (XELOX).29 With a two-third reduction in the pool of patients who could benefit from cetuximab, the study lost statistical power to identify a difference. NORDIC-VII utilized bolus 5-FU (Nordic FLOX regimen) instead of the more standard infusional 5-FU (FOL­FOX), but no subgroup analysis was performed in this trial according to 5-FU delivery.

Second, patients with mutated KRAS exon 2 and RAS mutations had inferior outcomes when administered anti-EGFR antibodies in combination with oxa­liplatin-based chemotherapy. In PRIME, patients with mutated KRAS exon 2 administered panitumumab had a statistical decrease in PFS (7.3 vs 8.8 months, P=.02) and trended to worse OS (15.5 vs 19.3 months, P=.068) compared with chemotherapy alone. Similar outcomes were noted in OPUS among mutated KRAS exon 2 patients treated with cetuximab, with a statistical decrease in PFS (5.5 vs 8.6 months, P=.0153) and numerical decline in OS (13.4 vs 17.5 months, P=.20). Anti­EGFR antibodies also proved to be harmful among patients with any RAS mutation, as part of expanded RAS testing (KRAS and NRAS exons 2, 3, and 4), who also received oxaliplatin-based chemotherapy, with reduced survival end points (Table 2). Finally, even in MRC COIN, mutated KRAS patients had worse survival outcomes when treated with cetuximab. These results may partially be due to a putative suppressive effect of wild-type RAS over mutated RAS where anti-EGFR antibodies block wild-type RAS, disinhibiting RAS and driving tumor progression.30 This would not explain why anti-EGFR antibodies are not deleterious when administered to patients with mutated KRAS exon 2 or RAS in combination with FOLFIRI.17,22,26 Nevertheless, because MRC COIN and NORDIC-VII did not test for a complete expanded RAS panel, up to 18% of mutated RAS patients may have been missed. Since this unidentified group of mutated RAS patients would have deleterious outcomes when treated with anti-EGFR antibodies, they would actively have averaged out any benefits from them.

Anti-EGFR Antibodies Versus Bevacizumab in Wild-Type KRAS and RAS Patients
FIRE-3 was a phase 3 trial that randomized 592 previously untreated wild-type KRAS exon 2 patients to FOLFIRI with either bevacizumab (Avastin) or cetuximab.31 The primary end point was ORR, with PFS and OS serving as secondary end points. Despite similar ORR and PFS results between the 2 groups, patients treated with cetuximab had improved OS (28.8 vs 25 months, P=.0164). For reasons that are not clear, differences in OS did not appear until nearly 2 years after randomization. Since a similar percentage of patients in each group received second-line therapy, one explanation for this phenomenon may have been the lack of a standardized second-line therapy. It is also possible that the impact of second-line therapy was affected by the front-line therapy, suggesting that appropriate monoclonal antibody sequencing needs further investigation. Updated results from a preplanned analysis of expanded RAS testing in 488 patients (82%) confirmed the OS benefit in wild-type RAS patients (33.1 vs 25.9 months, P=.01) treated with cetuximab compared with bevacizumab.24

PEAK was a randomized phase 2 study that evaluated the use of FOLFOX with either panitumumab or bevacizumab in 285 previously untreated patients with wild-type KRAS exon 2 mCRC.32 As with FIRE-3, improvements in OS were seen with panitumumab compared with bevacizumab (34.2 vs 24.3 months, P=.009). Again, as in FIRE-3, PFS was similar between arms. In a prespecified expanded RAS subgroup analysis of PEAK, wild-type RAS patients in the panitumumab cohort achieved statistical improvements in PFS (13 vs 9.5 months, P=.029) and increased the numerical benefit for OS (41 vs 29 months, P=.058).

Recently presented at ASCO 2014, CALGB 80405 was a phase 3 trial that randomized 1137 patients with previously untreated wild-type KRAS exon 2 mCRC to either bevacizumab or cetuximab in combination with either FOLFOX or FOLFIRI according to physician’s choice.33 This study began accruing unselected patients in 2005, but based on accumulating data, study amendments mandated inclusion of only wild-type KRAS exon 2 patients, and a combination bevacizu­mab plus cetuximab treatment arm was eliminated. OS was the primary end point. No differences were found between the chemotherapy/bevacizumab and chemotherapy/cetuximab cohorts for OS (29.04 vs 29.93 months, P=.34) or PFS. Two key weaknesses of this study were that FOLFOX was the preferred chemotherapy backbone in nearly 75% of cases, and that expanded RAS analysis was not performed. As described earlier in this review, about 18% of wild-type KRAS exon 2 patients will have additional RAS mutations. These additional RAS mutations have been shown to be deleterious when patients are administered oxaliplatin-based chemotherapy in combination with an anti-EGFR antibody. Inclusion of these unidentified mutated RAS patients could have concealed any survival benefit from cetuximab.

In contrast to FIRE-3 and PEAK, which showed improved OS among wild-type KRAS and RAS patients administered an anti-EGFR antibody, CALGB 80405 did not. It is hard to discount the survival advantage seen in FIRE-3 and PEAK, but they were secondary end points, and it had been difficult to explain the lack of improvement in PFS. Also, a meta-analysis did not identify differences in OS between anti-EGFR antibodies and bevacizumab.34 In addition, a randomized phase 2 second-line trial that assigned 182 wild-type KRAS patients to FOLFIRI with either panitumumab or bevacizumab did not show any differences between the study arms for any clinical end points.35 CALGB 80405 was the largest phase 3 trial, and its primary end point was OS. Based on the totality of these data, there probably is no difference in survival outcomes among wild-type KRAS exon 2 patients treated with either bevacizumab or an anti-EGFR antibody. However, lack of expanded RAS testing in CALGB 80405 still makes preferential anti-EGFR antibody use among wild-type RAS patients reasonable.

BRAF is a proto-oncogene encoding a serine-threonine kinase that acts as a downstream effector of KRAS in the EGFR-KRAS-BRAF-MAPK signaling pathway. The BRAF V600E mutation accounts for approximately 90% of BRAF mutations, occurring in less than 15% of colon adenocarcinomas.18,36,37 In a small retrospective analysis of 11 patients with mCRC possessing both wild-type KRAS exon 2 and mutated BRAF, none responded to anti-EGFR antibodies.18 Similar results were also noted in a separate small report.14 Since anti-EGFR antibodies had a response rate of less than 20% in all wild-type KRAS exon 2 patients, it was not clear if these results reflected predictive or prognostic value of mutated BRAF V600E.

Retrospective analyses of much larger well-designed prospective trials reinforced the negative prognostic power of BRAF V600E mutation. CAIRO2 was a phase 3 trial that randomized 755 previously untreated patients with mCRC to the combination of XELOX plus bevacizumab with or without cetuximab.38 Retrospective review identified 45 patients with wild-type KRAS exon 2 and mutated BRAF. These patients had decreased PFS and OS independent of whether they received cetuximab.39 Similar results were noted upon retrospective studies of the CRYSTAL and PRIME trials, pointing to the powerful negative prognostic value of mutated BRAF.16,22 The limited prevalence of BRAF mutations makes demonstrating statistical significance difficult, but mutated BRAF patients did appear to have numerical improvements in response and survival end points when treated with anti-EGFR antibodies, suggesting that they may still be of benefit.

A meta-analysis that compiled the results of the OPUS and CRYSTAL trials did not demonstrate statistical differences in outcomes between cohorts with both wild-type KRAS exon 2 and mutated BRAF that did, or did not, receive anti-EGFR antibodies.40 However, those patients administered anti-EGFR antibodies experienced important trends of improved outcomes for OS, PFS, and ORR that approached statistical significance. Despite the lack of statistical significance in this meta-analysis, the numerical improvements in outcome are clinically important. When considering these results together with the lack of BRAF V600E predictive value for anti-EGFR antibodies in the CAIRO2, CRYSTAL, and PRIME trials, 2 conclusions can be made. First, BRAF V600E is a very poor negative prognostic marker. Second, patients with BRAF V600E mutations can still benefit from anti-EGFR antibodies and should not be excluded from their use. However, recently presented at ASCO 2014, preliminary reports with promising results for coinhibition of BRAF and other targets, such as EGFR, MEK, or PI3K/AKT, may resurrect the predictive role of BRAF.41-45


This manuscript reviewed the rapidly evolving role of expanded RAS testing as a predictive biomarker for anti-EGFR antibodies in patients with mCRC. Expanded RAS analysis involved assessing for tumor mutations in KRAS or NRAS at exons 2 (codons 12 and 13), 3 (codons 61), and 4 (codons 117 and 146). Multiple retrospective and retrospective-prospective studies determined that expanded RAS analysis improved the negative and positive predictive value compared with KRAS exon 2 alone. Although preplanned expanded RAS analysis made panitumumab studies the most rigorous, expanded RAS testing also conferred increased predictive value for cetuximab. It is important to highlight that expanded RAS analysis was beneficial among patients administered either an irinotecan- or oxaliplatin-based chemotherapy regimen.

These results have 2 main implications for patient care. First, expanded RAS testing should be performed prior to the use of panitumumab and cetuximab. Second, patients who are wild-type KRAS exon 2 can receive either front-line bevacizumab or an anti-EGFR antibody. However, patients with wild-type RAS may still benefit preferentially from the use of a front-line anti-EGFR antibody.

Future biomarker clinical study design is now confronted with the challenge of essentially peering into the future. As evidenced by the KRAS/RAS story, not only can new biomarkers emerge, but well-accepted biomarkers can also assume new roles. A prescient clinical trial will continue to focus on excellent study design with specimen storage for an almost certain future retrospective analysis.


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  43. Hong DS, Morris VK, Fu S, et al. Phase 1B study of vemurafenib in combination with irinotecan and cetuximab in patients with BRAF-mutated advanced cancers and metastatic colorectal cancer. J Clin Oncol. 2014;32(suppl). Abstract 3516.
  44. Corcoran RB, Atreya CE, Falchook GS, et al. Phase 1-2 trial of the BRAF inhibitor dabrafenib (D) plus MEK inhibitor trametinib (T) in BRAF V600 mutant colorectal cancer (CRC): updated efficacy and biomarker analysis. J Clin Oncol. 2014;32(suppl). Abstract 3517.
  45. Tabernero J, Chan E, Baselga J, et al. VE-BASKET, a Simon 2-stage adaptive design, phase II, histology-independent study in nonmelanoma solid tumors harboring BRAF V600 mutations (V600m): activity of vemurafenib (VEM) with or without cetuximab (CTX) in colorectal cancer (CRC). J Clin Oncol. 2014;32(suppl). Abstract 3518.

Uncategorized - August 18, 2014

Bevacizumab Not Cost-Effective in Metastatic Colorectal Cancer

The addition of bevacizumab to chemotherapy for metastatic colorectal cancer is not cost-effective,” according to Daniel A. Goldstein, MD, of Emory University, Atlanta, GA, who led a cost-effectiveness analysis that earned an ASCO Merit Award at the annual meeting. The lack of cost-effectiveness was demonstrated at a willingness-to-pay threshold of [ Read More ]

The Last Word - August 18, 2014

The Case for Personalized Medicine: Defining the Field and Envisioning the Future of Healthcare

“In a time of unprecedented scientific breakthroughs and technological advancements, personalized health care has the capacity to detect the onset of disease at its earliest stages, pre-empt the progression of disease, and, at the same time, increase the efficiency of the health care system by improving quality, accessibility, and affordability.” [ Read More ]