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MP 2.04.53

KRAS and BRAF Mutation Analysis in Metastatic Colorectal Cancer


Medical Policy

 

 

Section
Medicine

Original Policy Date
10/2008

Last Review Status/Date
Reviewed with literature review/12:2012

Issue
12:2012

 

Return to Medical Policy Index


Disclaimer
Our medical policies are designed for informational purposes only and are not an authorization, or an explanation of benefits, or a contract.  Receipt of benefits is subject to satisfaction of all terms and conditions of the coverage.  Medical technology is constantly changing, and we reserve the right to review and update our policies periodically.


Description
Cetuximab (Erbitux®, ImClone Systems) and panitumumab (Vectibix®, Amgen) are monoclonal antibodies that bind to the epidermal growth factor receptor (EGFR), preventing intrinsic ligand binding and activation of downstream signaling pathways vital for cancer cell proliferation, invasion, metastasis, and stimulation of neovascularization.

The RAS-RAF-MAP kinase pathway is activated in the EGFR cascade. RAS proteins are G-proteins that cycle between active (RAS-GTP) and inactive (RAS-GDP) forms, in response to stimulation from a cell surface receptor such as EGFR, and act as a binary switch between the cell surface EGFR and downstream signaling pathways. The KRAS gene can harbor oncogenic mutations that result in a constitutively activated protein, independent of EGFR ligand binding, rendering antibodies to the upstream EGFR ineffective. KRAS mutations are found in approximately 30–50% of colorectal cancer tumors and are common in other tumor types. BRAF encodes a protein kinase and is involved in intracellular signaling and cell growth and is a principal downstream effector of KRAS. BRAF mutations occur in less than 10–15% of colorectal cancers and appear to be a marker of poor prognosis.

Cetuximab and panitumumab are approved in the treatment of metastatic colorectal cancer in the refractory disease setting, and ongoing studies are investigating the use of these EGFR inhibitors as monotherapy and as part of combination therapy in first, second, and subsequent lines of therapy. It has been shown that patients with a KRAS mutant tumor do not respond to cetuximab or panitumumab. However, there are still patients with KRAS wild-type tumors that do not respond to these agents, suggesting that other factors, such as alterations in other EGFR effectors could drive resistance to anti-EGFR therapy, and therefore, BRAF mutations are now increasingly being investigated in metastatic colorectal cancer. KRAS and BRAF mutations are considered to be mutually exclusive.

KRAS and BRAF mutation analyses using polymerase chain reaction (PCR) methodology are commercially available as laboratory-developed tests. Such tests are regulated under the Clinical Laboratory Improvement Amendments (CLIA). Premarket approval from the U.S. Food and Drug Administration (FDA) is not required when the assay is performed in a laboratory that is licensed by CLIA for high-complexity testing.

This policy summarizes the evidence for using tumor cell KRAS and BRAF mutational status as a predictor of nonresponse to EGFR-targeted therapy with monoclonal antibodies cetuximab and panitumumab in patients with metastatic colorectal cancer


Policy
KRAS mutation analysis may be considered medically necessary to predict nonresponse to anti-EGFR monoclonal antibodies cetuximab and panitumumab in the treatment of metastatic colorectal cancer.

BRAF mutation analysis is considered investigational to predict nonresponse to anti-EGFR monoclonal antibodies cetuximab and panitumumab in the treatment of metastatic colorectal cancer.


Policy Guidelines
Effective in 2012, there are specific CPT codes for KRAS or BRAF mutation analysis.

81210: BRAF (v-raf murine sarcoma viral oncogene homolog B1) (e.g., colon cancer), gene analysis, V600E variant

81275: KRAS (v-Ki-ras2 Kirsten rat sarcoma viral oncogene) (e.g., carcinoma) gene analysis, variants in codons 12 and 13

Additionally, code 81403 would be reported for KRAS testing for variant(s) in exon 3 (e.g., codon 61).

Prior to 2012, multiple codes describing genetic analysis would likely be used to report this testing (e.g., codes from 83890-83912).

Between October 2009 and April 2012, there was a HCPCS “S” code specific to KRAS testing:

S3713: KRAS mutation analysis testing.

In 2011, a new CPT code was added for using archival tissue for molecular analysis:

88363: Examination and selection of retrieved archival (i.e., previously diagnosed) tissue(s) for molecular analysis (e.g., KRAS mutational analysis).


Benefit Application
BlueCard/National Account Issues

State or federal mandates (e.g., FEP) may dictate that all devices approved by the U.S. Food and Drug Administration (FDA) may not be considered investigational and thus these devices may be assessed only on the basis of their medical necessity.


Rationale

KRAS

This policy is based, in part, on a 2008 TEC Assessment. (1) Additional evidence is available from randomized clinical trials and single-arm studies, organized and outlined below.

Randomized Clinical Trials

Randomized, controlled trials (RCTs) have performed nonconcurrent subgroup analyses of the efficacy of epidermal growth factor receptor (EGFR) inhibitors in patients with wild-type versus mutated KRAS in metastatic colorectal cancer. The data from these trials have consistently shown a lack of clinical response to cetuximab and panitumumab in patients with mutated KRAS, with tumor response and prolongation of progression-free survival (PFS) observed only in wild-type KRAS patients.

Amado et al. (2) performed a subgroup analysis of KRAS tumor mutations in a patient population that had been previously randomly assigned to panitumumab versus best supportive care as third-line therapy for chemotherapy-refractory metastatic colorectal cancer. The original study was designed as a multicenter, RCT but was not blinded because of expected skin toxicity related to panitumumab administration. (3) Patients were randomly assigned 1:1 to receive panitumumab or best supportive care. Random assignment was stratified by Eastern Cooperative Oncology Group (ECOG) performance status (0 or 1 vs. 2) and geographic region. Crossover from best supportive care to the panitumumab arm was allowed in patients who experienced disease progression. Of the 232 patients originally assigned to best supportive care alone, 176 crossed over to the panitumumab arm, at a median time to crossover of 7 weeks (range: 6.6–7.3).

Of the 463 patients in the original study, 427 (92%) were included in the KRAS subgroup mutation analysis. A central laboratory performed the KRAS mutational analysis in a blinded fashion, using formalin-fixed, paraffin-embedded (FFPE) tumor sections and a validated KRAS mutation kit (DxS Ltd, Manchester, U.K.) that identifies 7 somatic mutations located in codons 12 and 13 using real-time polymerase chain reaction (PCR). KRAS mutation status could not be determined in 36 patients because tumor samples were not available or there was insufficient or poor quality DNA. Forty-three percent of the KRAS-evaluable patients had KRAS-mutated tumors, with similar distribution of KRAS mutation types between treatment arms.

Patient demographics and baseline characteristics were balanced between the wild-type (WT) and mutated groups (MT) for panitumumab versus best supportive care including patient age, sex, and ECOG performance status. The interaction between mutational status and PFS was examined, controlling for randomization factors. PFS and tumor response rate was assessed radiographically every 4 to 8 weeks until disease progression using Response Evaluation Criteria in Solid Tumors (RECIST) criteria by blinded, central review. In the KRAS-assessable population, 20% of patients had a treatment-related grade 3 or 4 adverse event. As shown in Table 1, the relative effect of panitumumab on PFS was significantly greater among patients with WT KRAS, compared with patients with MT KRAS in whom no benefit from panitumumab was observed. No responders to panitumumab were identified in the MT group, indicating a 100% positive predictive value for nonresponse in the mutant group.

Table 1. KRAS Status and Efficacy of Panitumumab as Monotherapy in the Treatment of Chemotherapy-Refractory Metastatic Colorectal Cancer(2)

Total n=427

 

KRAS WT

 

KRAS MT

 

WT : MT

243 (57%):184 (43%)

 

P

n=124

 

BSC

n=119

 

P

n=84

 

BSC

n=100

 
mPFS   12.3 weeks  7.3 weeks  7.4 weeks  7.3 weeks 

(HR 0.45; 95% CI: 0.34–0.59)

 

(HR 0.99; 95% CI: 0.73–1.36)

 
Response rate   17%     0%    

WT: wild type; MT: mutated; P: panitumumab; BSC: best supportive care; mPFS: median progression-free survival; HR: hazard ratio; CI: confidence interval

Given the crossover design of the study and the fact that the majority of best supportive care (BSC) patients crossed over to the panitumumab arm early in the trial, conclusions of the effect of KRAS mutational status on PFS and tumor response rate endpoints are limited. However, of the 168 BSC patients that crossed over to panitumumab after disease progression (119 with WT and 77 with MT KRAS), PFS was significantly longer among patients with WT KRAS (mPFS 16.4 weeks for WT vs. 7.9 weeks for MT; hazard ratio (HR) 0.32; 95% confidence interval (CI): 0.22–0.45).

After completion of the CRYSTAL trial, in which 1,198 patients with metastatic colorectal cancer were randomly assigned to receive either cetuximab (C) in combination with folinic acid [leucovorin], 5-FU, and irinotecan (FOLFIRI) or FOLFIRI alone for first-line treatment, a subgroup analysis of response rate and PFS according to KRAS mutational status was performed. (4) The original trial design consisted of a central stratified permuted block randomization procedure with geographic regions and ECOG performance status as randomization strata. Two interim assessments of safety data were conducted by an independent data safety monitoring board (DSMB).

Of the original 1,198 patients, 540 had KRAS-evaluable, archival material. KRAS testing was performed from genomic DNA isolated from archived FFPE tissue, using quantitative PCR to detect the KRAS mutation status of codons 12 and 13. It is not stated whether the KRAS mutation analysis was performed blinded; however, the data available are from a video/slide presentation only. KRAS mutations were present in 192 patients (35.6%). No differences were found in patient demographics or baseline characteristics between the MT and WT populations, including age, sex, ECOG performance status, involved disease sites, and liver-limited disease. PFS and tumor response rate were assessed by a blinded, independent review committee by computed tomography (CT) scan every 8 weeks. A multivariate analysis performed for PFS according to patient characteristics showed a trend for PFS favoring the C plus FOLFIRI combination. The patients with WT KRAS who received C with FOLFIRI showed a statistically significant improvement in median PFS and tumor response rate, whereas the KRAS mutant population did not, as summarized in Table 2.

Table 2. KRAS Status and Efficacy in the First-Line Therapy of Metastatic Colorectal Cancer Treated with FOLFIRI with or without Cetuximab (the CRYSTAL Trial; 4)

ITT*

 

KRAS WT

n=348** (64.4%)

 

KRAS MT

n=192** (35.6%)

 
  C + F  F  C + F  F  C + F  F 
N   599   599   172   176   105   87  
 
Response rate (%)   46.9 (95% CI: 42.9-51.0)   38.7 (95% CI: 34.8-42.8)   59.3 (95% CI: 51.6-66.7%)   43.2 (95% CI: 35.8-50.9%)   36.2 (95% CI: 27.0-46.2%)   40.2 (95% CI: 29.9-51.3%)  

p value 0.0025 0.46

 
 
mPFS (months)***   8.9   8.0   9.9  8.7  7.6  8.1 

(HR 0.68; p=0.017)

 

(HR 1.07; p=0.47)

 

*ITT(intent to treat) in the original CRYSTAL trial assessing C+F versus F alone as first-line therapy for metastatic colorectal cancer.

**540 patients had available archival pathology material for the KRAS mutation subset analysis.

***Confidence intervals for mPFS were not provided in the presentation slides.

C: cetuximab; F: FOLFIRI; WT: wild type; MT: mutated; mPFS: median progression-free survival; HR: hazard ratio

In a third trial, the randomized, Phase II OPUS trial, the intention-to-treat (ITT) population consisted of 337 patients randomly assigned to C and folinic acid [leucovorin], 5-FU, oxaliplatin (FOLFOX) versus FOLFOX alone in the first-line treatment of metastatic colorectal cancer. (5) A 10% higher response rate (assessed by independent reviewers) was observed in the population treated with C, but no difference in PFS was seen between the two groups. The researchers then re-evaluated the efficacy in the 2 treatment arms with consideration of KRAS mutational status of the patients’ tumors. Of the original ITT population, 233 subjects had evaluable material for KRAS testing, and 99 (42%) were KRAS mutant. There was no difference in demographics or baseline characteristics between the WT and MT groups, including patient age, sex, ECOG performance status, involved disease sites, and liver-limited disease. The study showed that the addition of C to FOLFOX resulted in a significant improvement in response rate and PFS only in the WT KRAS group. The study findings are summarized in Table 3.

Table 3. KRAS Status and Efficacy in the First-Line Therapy of Metastatic Colorectal Cancer Treated with FOLFOX with or without Cetuximab (OPUS Study, 5)

 

KRAS WT

n=134 (58%)

 

KRAS MT

n=99 (42%)

 
 

C + Fx

 

Fx

 

C + Fx

 
Fx 
n (KRAS evaluable)  

61

 

73

 

52

 
47  
       
Response rate (%)  

60.7%

(95% CI:

47.3-72.9%)

 

37.0%

(95% CI:

26.0-49.1%)

 

32.7%

(95% CI:

20.3-47.1)

 
48.9%
 
(95% CI:
 
34.1-63.9%)  
p value  

p=0.011

 

p=0.106

 
Odds ratio  

2.54 (95% CI: 1.24-5.23)

 

0.51 (95% CI: 0.22-1.15)

 
       
mPFS (months)*  

7.7

 

7.2

 

5.5

 
8.6  
p value  

p=0.016

 

p=0.0192

 
hazard ratio  

0.57

 

1.83

 

*Confidence intervals for mPFS were not provided in the presentation slides.

C: cetuximab; Fx: FOLFOX; WT: wild type; MT: mutated; mPFS: median progression-free survival

In the CAIRO2 study, Tol and colleagues analyzed tumor samples from 528 of 755 previously untreated patients with metastatic colorectal cancer who were randomly assigned to receive capecitabine, oxaliplatin and bevacizumab (CB regimen n=378) or the same regimen plus C (CBC regimen n=377). (6) A KRAS mutation was found in 40% of tumors (108 from patients in the CB group and 98 from the CBC group). Patients with KRAS mutations treated with C had significantly shorter PFS than the KRAS WT patients who received C (8.1 vs. 10.5 months, respectively, p=0.04). In addition, patients who had MT KRAS tumors who received C had significantly shorter PFS than patients with MT KRAS tumors who did not receive C (8.1 vs. 12.5 months, respectively, p=0.003) and overall survival (OS) (17.2 versus 24.9 months, respectively, p=0.03). For patients with WT tumors, there were no significant PFS differences between the 2 groups. Overall, patients treated with C who had tumors with a mutated KRAS gene had significantly decreased PFS as compared with C-treated patients with WT KRAS tumors or patients with mutated KRAS tumors in the CB group.

Karapetis and colleagues analyzed tumor samples from 394 of 572 patients (69%) with colorectal cancer who were randomly assigned to receive C plus BSC (n=287) versus BSC alone (n=285) for KRAS mutations and assessed whether mutation status was associated with survival. (7) The patients had advanced colorectal cancer, had failed chemotherapy and had no other standard anticancer therapy available. Of the tumors that were evaluated (198 from the C group and 196 from the BSC group), 41% and 42% had a KRAS mutation, respectively. In patients with WT KRAS tumors, treatment with C as compared to best supportive care alone improved OS (median, 9.5 months versus 4.8 months, respectively; hazard ratio [HR] for death 0.55; 95% CI: 0.41-0.74; p<0.001) and PFS (median, 3.7 months versus 1.9 months, respectively; HR for progression to death, 0.40; 95% CI: 0.30-0.54; p<0.001). For patients with MT KRAS tumors, there were no significant differences between those treated with C versus BSC alone with respect to OS (HR, 0.98; p=0.89) or PFS (HR, 0.99; p=0.96).

Douillard and colleagues reported the results of a multicenter, Phase III trial, in which patients with no prior chemotherapy for metastatic colorectal cancer (mCRC), ECOG performance status of 0 to 2, and available tissue for biomarker testing were randomly assigned 1:1 to receive panitumumab-FOLFOX4 versus FOLFOX4. (8) The primary endpoint was PFS; OS was a secondary endpoint. Results were prospectively analyzed on an intent-to-treat basis by tumor KRAS status. KRAS results were available for 93% of the 1,183 patients randomly assigned. In the WT KRAS group panitumumab-FOLFOX4 significantly improved PFS compared with FOLFOX4 alone (median PFS, 9.6 vs. 8.0 months, respectively; hazard ratio [HR]: 0.80; 95% CI: 0.66 to 0.97; p=0.02). A nonsignificant increase in OS was also observed for panitumumab-FOLFOX4 versus FOLFOX4 (median OS: 23.9 vs. 19.7 months, respectively; HR: 0.83; 95% CI: 0.67 to 1.02; p=0.072). In the mutant KRAS group, PFS was significantly reduced in the panitumumab-FOLFOX4 arm versus the FOLFOX4 arm (HR: 1.29; 95% CI: 1.04 to 1.62; p=0.02), and median OS was 15.5 months versus 19.3 months, respectively (HR: 1.24; 95% CI: 0.98 to 1.57; p=0.068). Adverse event rates were generally comparable across arms with the exception of toxicities known to be associated with anti-EGFR therapy. The study demonstrated that panitumumab-FOLFOX4 was well-tolerated and significantly improved PFS in patients with WT KRAS tumors.

The CRYSTAL trial (4) demonstrated that the addition of cetuximab to a combined first-line chemotherapy regimen of irinotecan, infusional fluorouracil and leucovorin (FOLFIRI) statistically significantly reduced the risk of disease progression and increased the chance of response in patients with metastatic colorectal cancer that was KRAS wild-type, compared with chemotherapy alone. An updated analysis of the CRYSTAL trial reported increased follow-up time and an increased number of patients evaluable for tumor KRAS status and considered the clinical significance of the tumor mutation status of BRAF in the expanded population of patients with KRAS wild-type tumors. (9) Subsequent to the initial published analysis, which had a cutoff for OS of December 2007, and an associated overall median duration of follow-up of 29.7 months, additional tumor analysis allowed for the typing of an additional 523 tumors for KRAS mutation status, representing an increase in the ascertainment rate from 45% of intent to treat population patients in the original analysis to 89% (540 to 1,063) in the current analysis, with mutations detected in 37% of tumors. The updated analysis of OS was carried out with a new cutoff date of May 2009, giving an overall median duration of follow-up of 46 months. The addition of cetuximab to FOLFIRI in patients with KRAS wild-type disease resulted in significant improvements in OS (median, 23.5 vs. 20.0 months; hazard ratio [HR]: 0.796; p=0.0093), PFS (median, 9.9 vs. 8.4 months; HR: 0.696; p=0.0012), and response (rate 57.3% vs. 39.7%; odds ratio: 2.069; p<0.001) compared with FOLFIRI alone. Significant interactions between KRAS status and treatment effect were noted for all key efficacy endpoints. KRAS mutation status was confirmed as a powerful predictive biomarker for the efficacy of cetuximab plus FOLFIRI. BRAF V600E mutations were detected in 60 (6%) of 999 tumor samples evaluable for both BRAF and KRAS. In all but one case, BRAF mutations were identified in tumors which were wild type for KRAS. The impact of BRAF tumor mutation status in relation to the efficacy of cetuximab plus FOLFIRI was examined in the population of patients with KRAS wild-type disease (n=625). There was no evidence of an independent treatment interaction by tumor BRAF mutation status. The authors concluded that BRAF mutation status was not predictive of treatment effects of cetuximab plus FOLFIRI but that BRAF tumor mutation was a strong indicator of poor prognosis for all efficacy endpoints compared with those whose tumors were WT.

Peeters and colleagues reported the results of a Phase III study in which 1,186 patients with metastatic CRC were randomized to receive panitumumab with FOLFIRI versus FORFIRI alone as second-line treatment. (10) The study endpoints were PFS and OS, which were independently tested and prospectively analyzed by KRAS status. KRAS status was available for 91% of patients: 597 (55%) with wild-type (WT) KRAS tumors, and 486 (45%) with mutant (MT) KRAS tumors. In the WT KRAS subpopulation, when panitumumab was added to chemotherapy, a significant improvement in PFS was observed (hazard ratio [HR]: 0.73; 95% CI: 0.59 to 0.90; p=0.004); median PFS was 5.9 months for panitumumab-FOLFIRI versus 3.9 months for FOLFIRI. A nonsignificant trend toward increased OS was observed; median OS was 14.5 months versus 12.5 months, respectively (HR: 0.85, 95% CI: 0.70 to 1.04; p=0.12); response rate was improved to 35% versus 10% with the addition of panitumumab. In patients with MT KRAS, there was no difference in efficacy. Adverse events were comparable across arms. The authors concluded that panitumumab plus FOLFIRI significantly improved PFS and is well-tolerated as second-line treatment in patients with WT KRAS mCRC.

Maughan and colleagues reported the results of a Phase III, multicenter trial (MRC COIN trial) which randomized patients with advanced colorectal cancer who had not received previous chemotherapy to oxaliplatin and fluoropyrimidine chemotherapy (arm A) or the same combination plus cetuximab. (11) The comparison between arms A and B (for which the primary outcome was OS) was in patients with KRAS wild-type tumors. Baseline characteristics were well balanced between the trial groups. Analysis was by intention to treat and treatment allocation was not masked. Further analysis with respect to other mutations, including BRAF, was done. 1,630 patients were randomly assigned to treatment groups (n=815 to standard therapy and 815 to the addition of cetuximab). Tumor samples from 1,316 (81%) of patients were used for somatic mutation analyses; 43% had KRAS mutations. In patients with KRAS wild-type tumors, OS did not differ between treatment groups (median survival, 17.9 months in the control group versus 17.0 months in the cetuximab group (HR: 1.04, 95% CI: 0.87-1.23, p=0.67). BRAF mutations were detected in 8% of patients; wild-type BRAF did not show any evidence of a benefit from the addition of cetuximab. Contrary to other trials that have assessed KRAS mutation status and the benefit of the addition of cetuximab to the regimen of wild-type KRAS patients, this trial did not show a benefit of the addition of cetuximab to oxaliplatin-based chemotherapy.

Systematic Reviews

Qiu and colleagues conducted a meta-analysis of 22 studies on the predictive and prognostic value of KRAS mutations in metastatic colorectal cancer (mCRC) patients treated with cetuximab. (12) The overall KRAS mutation rate was 38% (829 of 2,188 patients). The results of the meta-analysis were consistent with previous reports on the use of cetuximab and KRAS mutation status, that patients with tumors that harbor mutant-type KRAS are more likely to have a worse response, PFS and OS when treated with cetuximab when compared to those with wild type KRAS.

Dahabreh and colleagues conducted a systematic review of randomized, controlled trials that assessed the use of KRAS mutation testing as a predictive biomarker for treatment of advanced colorectal cancer with cetuximab and panitumumab. (13) The authors concluded that, compared to patients with wild type KRAS, KRAS mutations are consistently associated with reduced OS and PFS and increased treatment failure rates among patients with advanced colorectal cancer who are treated with anti-EGFR antibodies.

A pooled analysis of the CRYSTAL and OPUS randomized clinical trial data was performed to further investigate the findings of these trials in patients with KRAS wild-type tumors, using extended survival data and following an enhancement in the ascertainment rate of KRAS and BRAF tumor mutation status. (14) Pooled individual patient data from each study were analyzed for OS, PFS and best objective response rate (ORR) in patients evaluable for KRAS and BRAF mutation status. Treatment arms were compared according to mutation status using log-rank and Cochran-Mantel-Haenszel tests. In 845 patients with KRAS wild-type tumors, adding cetuximab to chemotherapy led to a significant improvement in OS (hazard ratio [HR]: 0.81; p=0.0062), PFS (HR: 0.66; p<0.001), and ORR (odds ratio: 2.16; p<0.0001). BRAF mutations were detected in 70 of 800 (8.8%) evaluable tumors. No significant differences were found in outcome between the treatment groups in these patients. However, prognosis was worse in each treatment arm for patients with BRAF tumor mutations compared with those with BRAF wild-type tumors. This analysis of pooled data from the CRYSTAL and OPUS studies confirms the consistency of the benefit obtained across all efficacy endpoints from adding cetuximab to first-line chemotherapy in patients with KRAS wild-type mCRC. It further suggests that BRAF mutation does not appear to be a predictive biomarker in this setting, but is a marker of poor prognosis.

Single-Arm Studies (Cetuximab or Panitumumab)

In addition to the 3 randomized trials outlined here, several single-arm studies that retrospectively evaluated KRAS mutational status and treatment response, showed similar nonresponse to anti-EGFR monoclonal antibodies in patients with MT KRAS tumors in metastatic colorectal cancer. (15-19) These studies are summarized in Table 4.

Table 4. Single-Arm Studies Showing Objective Response Rate (n [%]) to Anti-EGFR Monoclonal Antibodies in Chemotherapy-Refractory Metastatic Colorectal Cancer

Study

 

Treatment

 

Total patients

(WT:MT)

 

WT

n (%)

 

MT

n (%)

 
Lievre et al. 2008 (6)   C +/- CT   89 (65:24)   34 (44)   0 (0)  
De Roock et al. 2008 (7)   C +/- CT   113 (57:46)   27 (41)   0 (0)  
Khambata-Ford et al. 2007 (8)   C   80 (50:30)   5 (10)   0 (0)  
Di Fiore et al. 2007 (9)   C + CT   59 (43:16)   13 (28)   0 (0)  
Benvenuti et al. 2007 (10)   P or C or C + CT   48 (32:16)   10 (31)   1 (6)  

C: cetuximab; CT: chemotherapy; P: panitumumab; WT: wild type; MT: mutated

Two of these single-arm studies also reported a difference in progression-free survival (PFS) and overall survival (OS), as summarized in Table 5.

Table 5. Single-Arm Studies of Treatment of Metastatic Colorectal Cancer with Anti-EGFR Monoclonal Antibodies and KRAS Mutational Status

Study/Year

 

Description

 

Results

 
   

Outcome

 

WT

 

MT

 

p value

 
De Roock et al. 2008 (7)   113 patients with irinotecan (I) –refractory mCRC treated with cetuximab (C) with or without I
 
WT:MT:
 
67 (59.3%):46 (40.7%)  
Overall response (n=108), C+I and C   27/66 (41%)   0/42 (0%)   p=0.000001 (C+I)
 
p=0.126 (C alone)  
mPFS (C+I)   34 weeks (95% CI: 28.5–40.0)   12 weeks (95% CI: 5.4–18.7)   p=0.016  
mPFS (C)   12 weeks (95% CI: 4.2–20.0)   12 weeks (95% CI: 7.0–17.0)   p=0.351  
mOS (C+I)   44.7 weeks (95% CI: 28.4–61.0)   27.3 weeks (95% CI: 9.5–45.0)   p=0.003  
mOS (C)   27 weeks (95% CI: 8.9–45.1)   25.3 weeks (95% CI: 0.0-70.0)   p=0.330  
           
Lievre et al. 2008 (6)   89 patients treated with C monotherapy after treatment failure with I
 
WT:MT:
 
65 (73%):24 (27%)  
Response rate   40%   0%   p<0.001  
mPFS   31.4 weeks (95% CI: 19.4–36)   10.1 weeks (95% CI: 8–16)   p=0.0001  
mOS   14.3 months (95% CI: 9.4–20)   10.1 months (95% CI: 5.1–13)   p=0.026  

C: cetuximab; I: irinotecan; mCRC: metastatic colorectal cancer; WT: wild type; MT: mutated; mPFS: median progression-free survival; mOS: median overall survival

BRAF

A meta-analysis of BRAF mutation and resistance to anti-EGFR monoclonal antibodies in patients with metastatic colorectal cancer was performed. (20) The primary endpoint of eligible studies was objective response rate (ORR), defined as the sum of complete and partial tumor response (CR and PR). There were a total of 11 studies (21-30), with sample sizes ranging from 31 to 259 patients. All studies were conducted retrospectively (one study was a nonconcurrent analysis of response in a population previously randomized (30)). Anti-EGFR therapy was given as first-line treatment in one study and as second-line or greater in the other 10. In 2 studies, the anti-EGFR monoclonal antibody was given as monotherapy, and in 9 studies, patients received various chemotherapies. Seven studies were performed in unselected patients (i.e., KRAS mutational status was unknown) totaling 546 patients, for whom 520 were assessable for tumor response. In the unselected population, a BRAF mutation was detected in 8.8% of patients, and the ORR for patients with mutant BRAF was 29.2% (14/48) and for WT BRAF was 33.5% (158/472; p=0.048). Four studies were performed in patients with WT KRAS metastatic colorectal cancer. BRAF mutational status was performed on 376 KRAS WT tumors. BRAF mutation was detected in 10.6% (n=40) of primary tumors. Among the 376 analyzed, all patients were assessable for tumor response. ORR of patients with mutant BRAF was 0% (0 of 40), whereas the ORR of patients with WT BRAF was 36.3% (122 of 336). Only 3 studies presented data on PFS and OS; and therefore, a pooled analysis was not performed. The authors conclude that although the meta-analysis provided evidence that BRAF mutation is associated with lack of response to anti-EGFR monoclonal antibodies in WT KRAS metastatic colorectal cancer, the number of studies and number of patients included in the meta analysis were relatively small and that large studies are needed to confirm the results of the meta-analysis using homogenous metastatic colorectal cancer patients with assessors blinded to the clinical data.

Phillips and colleagues analyzed the data from 4 studies which reported tumor response and survival in patients with mCRC treated with anti-EGFR monoclonal antibodies as related to BRAF mutational status. (31) Di Nicolantonio and colleagues looked retrospectively at 113 patients with mCRC who had received cetuximab or panitumumab. (22) None of the BRAF-mutated tumors responded to treatment (0 of 11), whereas 32.4% (22 of 68) of the BRAF WT did. Loupakis and colleagues retrospectively assessed 87 patients receiving I and C. (25) Of the 87 patients in the study, BRAF was mutated in 13 cases, and none of them responded to chemotherapy, compared to 32% (24 of 74) with WT BRAF who did. In the CAIRO2 study, a retrospective analysis of BRAF mutations was performed in 516 available tumors from patients previously randomized to CB regimen or the same regimen plus cetuximab (CBC regimen). (30) A BRAF mutation was found in 8.7% (n=45) of the tumors. Patients with a BRAF mutation had a shorter median PFS and OS compared to WT BRAF tumors in both treatment arms. The authors concluded that a BRAF mutation is a negative prognostic marker in patients with mCRC and that this effect, in contrast to KRAS mutations, is not restricted to the outcome of cetuximab treatment. In the CRYSTAL trial, Van Cutsem and colleagues randomized 1,198 patients with untreated mCRC to FOLFIRI with or without cetuximab. (4) A recent analysis of BRAF mutations in this patient population and the influence on outcome was presented at the 2010 American Society of Clinical Oncology (ASCO) Gastrointestinal Cancers Symposium. (32) The authors showed that of the KRAS WT/BRAF-mutated patients, the OS for FOLFIRI plus cetuximab and FOLFIRI alone was 14.1 and 10.3 months, respectively (p=0.744). Although this was not statistically significant, it showed a trend toward improved OS, PFS, and response, suggesting that KRAS wild-type/BRAF-mutant patients may benefit from anti-EGFR therapy. This unpublished analysis is the first to show a possible benefit of anti-EGFR therapy in patients with BRAF-mutant tumors.

De Roock and colleagues reported the effects of 4 mutations, including BRAF, on the efficacy of cetuximab and chemotherapy in chemotherapy-refractory metastatic colorectal cancer in 773 primary tumor samples. (33) Tumor samples were from fresh frozen or FFPE tissue, and the mutation status was compared to retrospectively collected clinical outcomes including objective response, PFS, and OS. BRAF mutations were found in 36 of 761 tumors (4.7%). In patients with WT KRAS, carriers of BRAF mutations had a significantly lower response rate (8.3% or 2 of 24 patients) than BRAF WT (38.0% or 124 of 326 patients; odds ratio [OR]: 0.15; 95% CI: 0.02-0.51; p=0.0012). PFS for BRAF-mutated versus WT was a median of 8 weeks versus 26 weeks, respectively (HR: 3.74; 95% CI: 2.44-5.75; p<0.0001) and OS median 26 weeks versus 54 weeks, respectively (HR: 3.03; 1.98-4.63; p<0.0001).

Mao and colleagues conducted a meta-analysis of BRAF mutation V600E and resistance to anti-EGFR monoclonal antibodies in patients with metastatic colorectal cancer. (20) Eleven studies were included, with sample sizes ranging from 31 to 259; all of the studies were retrospective analyses. Seven of the studies included unselected patients, and 4 included only patients with wild-type KRAS. The primary endpoint was objective response rate (ORR). In the 7 studies with unselected patients, BRAF mutational status was performed successfully on 546 mCRC. BRAF mutation was detected in 8.8% of primary tumors. The ORR of mCRC patients with mCRC with mutant BRAF was 29.2% versus 33.5% in patients with wild-type BRAF. In the 4 studies that included patients with wild-type KRAS, BRAF mutational status was performed successfully on 376 KRAS wild-type mCRC. BRAF mutations were detected in 10.6% of primary tumors. The ORR of patients with mutant BRAF was 0.0%, whereas the ORR of patients with wild-type BRAF was 36.3%. The authors concluded that the results of their meta-analysis provided evidence that BRAF mutation is associated with lack of response in wild-type KRAS mCRC treated with anti-EGFR monoclonal antibodies.

An updated analysis of the CRYSTAL trial reported increased follow-up time and an increased number of patients evaluable for tumor KRAS status and considered the clinical significance of the tumor mutation status of BRAF in the expanded population of patients with KRAS wild-type tumors. (9) The impact of BRAF tumor mutation status in relation to the efficacy of cetuximab plus FOLFIRI was examined in the population of patients with KRAS wild-type disease (n=625). There was no evidence of an independent treatment interaction by tumor BRAF mutation status. The authors concluded that BRAF mutation status was not predictive of treatment effects of cetuximab plus FOLFIRI but that BRAF tumor mutation was a strong indicator of poor prognosis for all efficacy endpoints compared with those whose tumors were WT.

At the latest review of this policy (December 2012), no additional clinical trials were identified on the clinical use of BRAF mutation analysis to guide anti-EGFR therapy in patients with metastatic CRC.

Summary

In summary, clinical trial data show that patients with KRAS-mutated metastatic colorectal cancer do not benefit from cetuximab or panitumumab, either as monotherapy or in combination with other treatment regimens. These data support the use of KRAS mutation analysis of tumor DNA before considering use of cetuximab or panitumumab in a treatment regimen. Identifying patients whose tumors express mutated KRAS will avoid exposing patients to ineffective drugs and unnecessary drug toxicities and expedites the use of alternative therapies. Thus, KRAS mutation analysis may be considered medically necessary to predict nonresponse to anti-epidermal growth factor receptor (EGFR) monoclonal antibodies in the treatment of metastatic colorectal cancer.

The data for patients with metastatic colorectal cancer and a BRAF mutation have shown consistently that a BRAF mutation is a poor prognostic marker, as it is associated with shorter progression-free survival (PFS) and overall survival (OS), regardless of treatment. Most of the data for a BRAF mutation predicting response to anti-EGFR therapy are limited by small numbers of patients and conflicting results among studies. The large, randomized CRYSTAL trial, with nonconcurrent subgroup analyses of BRAF mutations in patients previously randomized, reported the impact of BRAF tumor mutation status in relation to the efficacy of cetuximab plus FOLFIRI in the population of patients with KRAS wild-type disease. There was no evidence of an independent treatment interaction by tumor BRAF mutation status, and the trial showed that BRAF mutation status was not predictive of treatment effects of cetuximab plus folinic acid [leucovorin], 5-FU, and irinotecan (FOLFIRI). BRAF tumor mutation was a strong indicator of poor prognosis for all efficacy endpoints compared with those whose tumors were BRAF wild type (WT). Thus, BRAF mutation analysis is considered investigational to predict nonresponse to anti-EGFR monoclonal antibodies in the treatment of metastatic colorectal cancer.

Practice Guidelines and Position Statements

The National Comprehensive Cancer Network (NCCN) guidelines (v 3.2013) on the treatment of colon cancer recommend that tumor KRAS gene status testing be performed for all patients with metastatic colon cancer, on archived specimens of primary tumor or a metastasis, at the time of diagnosis of metastatic disease. The guidelines further state that if KRAS is non-mutated, consider testing for BRAF mutation status. The guidelines indicate that cetuximab and panitumumab are only indicated for patients with tumors that express the WT KRAS gene.

The guidelines state that patients with a BRAF V600E mutation appear to have a poorer prognosis. Data are insufficient to guide the use of anti-EGFR therapy in the first-line setting with active chemotherapy based on BRAF V600E mutation status. Limited data suggest lack of antitumor activity from anti-EGFR monoclonal antibodies in the presence of a BRAF V600E mutation when used after a patient has progressed on first-line therapy. (34)

References:

    1. Blue Cross and Blue Shield Association Technology Evaluation Center (TEC). KRAS mutations and epidermal growth factor receptor inhibitor therapy in metastatic colorectal cancer. TEC Assessments 2008; Volume 23, Tab 6.
    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(10):1626-34.
    3. Van Cutsem E, Peeters M, Siena S et al. Open-label phase III trial of panitumumab plus best supportive care compared with best supportive care alone in patients with chemotherapy-refractory metastatic colorectal cancer. J Clin Oncol 2007; 25(13):1658-64.
    4. Van Cutsem E, Kohne CH, Hitre E et al. Cetuximab and chemotherapy as initial treatment for metastatic colorectal cancer. N Engl J Med 2009; 360(14):1408-17.
    5. Bokemeyer C, Bondarenko I, Makhson A et al. Fluorouracil, leucovorin, and oxaliplatin with and without cetuximab in the first-line treatment of metastatic colorectal cancer. J Clin Oncol 2009; 27(5):663-71.
    6. Tol J, Koopman M, Cats A et al. Chemotherapy, bevacizumab, and cetuximab in metastatic colorectal cancer. N Engl J Med 2009; 360(6):563-72.
    7. Karapetis CS, Khambata-Ford S, Jonker DJ et al. K-ras mutations and benefit from cetuximab in advanced colorectal cancer. N Engl J Med 2008; 359(17):1757-65.
    8. 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(31):4697-705.
    9. 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(15):2011-9.
    10. Peeters M, Price TJ, Cervantes A et al. Randomized phase 3 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(31):4706-13.
    11. 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 randomized phase 3 MRC COIN trial. Lancet 2011; 377(9783):2103-14.
    12. Qui LX, Mao C, Zhang J et al. Predictive and prognostic value of KRAS mutations in metastatic colorectal cancer patients treated with cetuximab: a meta-analysis of 22 studies. Eur J Cancer 2010; 46(15):2781-7.
    13. Dahabreh IJ, Terasawa T, Castaldi PJ et al. Systematic review: anti-epidermal growth factor receptor treatment effect modification by KRAS mutations in advanced colorectal cancer. Ann Intern Med 2011; 154(1):37-49.
    14. Bokemeyer C, Cutsem EV, Rougier P et al. Addition of cetuximab to chemotherapy as first-line treatment for KRAS wild-type metastatic colorectal cancer: pooled analysis of the CRYSTAL and OPUS randomised clinical trials. Eur J Cancer 2012; 48(10):1466-75.
    15. Benvenuti S, Sartore-Bianchi A, Di Nicolantonio F et al. Oncogenic activation of the RAS/RAF signaling pathway impairs the response of metastatic colorectal cancers to anti-epidermal growth factor receptor antibody therapies. Cancer Res 2007; 67(6):2643-8.
    16. De Roock W, Piessevaux H, De Schutter J et al. KRAS wild-type state predicts survival and is associated to early radiological response in metastatic colorectal cancer treated with cetuximab. Ann Oncol 2008; 19(3):508-15.
    17. Di Fiore F, Blanchard F, Charbonnier F et al. Clinical relevance of KRAS mutation detection in metastatic colorectal cancer treated by cetuximab plus chemotherapy. Br J Cancer 2007; 96(8):1166-9.
    18. Khambata-Ford S, Garrett CR, Meropol NJ et al. Expression of epiregulin and amphiregulin and K-ras mutation status predict disease control in metastatic colorectal cancer patients treated with cetuximab. J Clin Oncol 2007; 25(22):3230-7.
    19. Lievre A, Bachet JB, Boige V et al. KRAS mutations as an independent prognostic factor in patients with advanced colorectal cancer treated with cetuximab. J Clin Oncol 2008; 26(3):374-9.
    20. Mao C, Liao RY, Qiu LX et al. BRAF V600E mutation and resistance to anti-EGFR monoclonal antibodies in patients with metastatic colorectal cancer: a meta-analysis. Mol Biol Rep 2011; 38(4):2219-23.
    21. Cappuzzo F, Varella-Garcia M, Finocchiaro G et al. Primary resistance to cetuximab therapy in EGFR FISH-positive colorectal cancer patients. Br J Cancer 2008; 99(1):83–9.
    22. Di Nicolantonio F, Martini M, Molinari F et al. Wild-type BRAF is required for response to panitumumab or cetuximab in metastatic colorectal cancer. J Clin Oncol 2008; 26(35):5705–12.
    23. Freeman DJ, Juan T, Reiner M et al. Association of K-ras mutational status and clinical outcomes in patients with metastatic colorectal cancer receiving panitumumab alone. Clin Colorectal Cancer 2008; 7(3):184–90.
    24. Laurent-Puig P, Cayre A, Manceau G et al. Analysis of PTEN, BRAF, and EGFR status in determining benefit from cetuximab therapy in wild-type KRAS metastatic colon cancer. J Clin Oncol 2009; 27(35):5924–30.
    25. Loupakis F, Ruzzo A, Cremolini C et al. KRAS codon 61, 146 and BRAF mutations predict resistance to cetuximab plus irinotecan in KRAS codon 12 and 13 wild-type metastatic colorectal cancer. Br J Cancer 2009; 101(4):715–21.
    26. Molinari F, Martin V, Saletti P et al. Differing deregulation of EGFR and downstream proteins in primary colorectal cancer and related metastatic sites may be clinically relevant. Br J Cancer 2009; 100(7):1087–94.
    27. Moroni M, Veronese S, Benvenuti S et al. Gene copy number for epidermal growth factor receptor (EGFR) and clinical response to antiEGFR treatment in colorectal cancer: a cohort study. Lancet Oncol 2005; 6(5):279-86.
    28. Perrone F, Lampis A, Orsenigo M et al. PI3KCA/PTEN deregulation contributes to impaired responses to cetuximab in metastatic colorectal cancer patients. Ann Oncol 2009; 20(1):84–90.
    29. Sartore-Bianchi A, Di Nicolantonio F, Nichelatti M et al. Multi-determinants analysis of molecular alterations for predicting clinical benefit to EGFR-targeted monoclonal antibodies in colorectal cancer. PLoS One 2009; 4(10):e7287.
    30. Tol J, Nagtegaal ID, Punt CJ. BRAF mutation in metastatic colorectal cancer. N Engl J Med 2009; 361(1):98–9.
    31. Phillips B, Kalady M, Kim R. BRAF testing in advanced colorectal cancer: is it ready for prime time? . Clin Adv Hematol Oncol 2010; 8(6):437-44.
    32. Van Cutsem E, Lang I, Folprecht G et al. Cetuximab plus FOLFIRI in the treatment of metastatic colorectal cancer (mCRC): the influence of KRAS and BRAF biomarkers on outcome: updated data from the CRYSTAL trial. American Society of Clinical Oncology 2010 Gastrointestinal Cancers Symposium (GCS) . Orlando, FL.
    33. De Roock W, Claes B, Bernasconi D et al. Effects of KRAS, BRAF, NRAS and PIK3CA mutations on the efficacy of cetuximab plus chemotherapy in chemotherapy-refractory metastatic colorectal cancer: a retrospective consortium analysis. Lancet Oncol 2010; 11(8):753-62.
    34. National Comprehensive Cancer Network. Clinical Practice Guidelines in Oncology. Colon cancer. Version 3.2013. Available online at: http://www.nccn.org/professionals/physician_gls/f_guidelines.asp#colon. Last accessed November, 2012.

Codes

Number

Description

CPT   See Policy Guidelines section
ICD-9-CM Diagnosis 153.0-153.9 Malignant neoplasm of colon code range
  154.0-154.8 Malignant neoplasm of rectum code range
  197.5 Secondary malignant neoplasm of respiratory and digestive systems: large intestine and rectum
HCPCS S3713 KRAS mutation analysis testing
ICD-10-CM (effective 10/1/14) C18.0-C18.9 Malignant neoplasm of colon code range
  C19 Malignant neoplasm of rectosigmoid junction
  C20 Malignant neoplasm of rectum
  C78.5 Secondary malignant neoplasm of large intestine and rectum
ICD-10-PCS (effective 10/1/14)   Not applicable. ICD-10-PCS codes are only used for inpatient services. There are no ICD procedure codes for laboratory tests.

Index
BRAF Mutation Testing
KRAS Mutation Testing


Policy History

Date

Action

Reason

10/07/08

Add policy

New policy

01/08/09

Replace policy – correction only

Policy updated to reflect Section & subsection

11/11/10 Replace policy Policy updated with literature search. Title changed to indicate inclusion of BRAF testing to the policy; BRAF testing policy statement added as investigational to predict nonresponse to anti-EGFR monoclonal antibodies cetuximab and panitumumab in the treatment of metastatic colorectal cancer; KRAS policy statement unchanged. References 4, 5, 11-27 added; reference 28 updated
12/08/11 Replace policy Policy updated with literature search. References 27-34 added. Policy statements unchanged
12/13/12 Replace Policy Policy updated with literature search. Reference 14 added. Policy statements unchanged.