Note: The safety and effectiveness of Erbitux in pediatric patients have not been established.

Transcription

1 Original Issue Date (Created): April 26, 2011 Most Recent Review Date (Revised): November 26, 2013 Effective Date: February 01, 2014 I. POLICY Note: Cetuximab (Erbitux) does not require preauthorization. Note: The safety and effectiveness of Erbitux in pediatric patients have not been established. Cetuximab (Erbitux ) may be considered medically necessary for ANY of the following conditions: Head and Neck Cancer Squamous cell carcinoma of head and neck (SCCHN) and ANY of the following indications: In combination with radiation therapy for the initial treatment of locally or regionally advanced disease; In combination with platinum based therapy with 5-FU for the first-line treatment of patients with recurrent locoregional disese or metastatic squamous cell carcinoma of the head and neck; or As a single agent for the treatment of patients with recurrent or metastatic disease for whom platinum based therapy has failed. Colorectal Cancer Erbitux may be considered medically necessary for the treatment of K-RAS mutation negative (wild-type), epidermal growth factor receptor (EGFR)-expressing, metastatic colorectal cancer (mcrc) as determined by FDA-approved tests for this use in any of the following indications: In combination with FOLFORI (irinotecan, 5-fluorouracil, leucovorin) for first-line treatment; In combination with irinotecan in patients who are refractory to irinotecan-based chemotherapy; or As a single agent in patients who have failed oxaliplatin and irinotecan based chemotherapy or who were intolerant to irinotecan. Note: Cetuximab (Erbitux ) is not indicated for treatment of KRAS mutation-positive colorectal cancer. Page 1

2 Cetuximab (Erbitux ) is considered not medically necessary for treatment of colorectal cancer tumors with KRAS mutations in codon 12 or 13. The use of cetuximab (Erbitux ) for indications (including but not limited to lung, breast, cervical, endometrial, esophageal, gastric, glioblastoma multiforme, hepatocellular, ovarian, pancreatic, and renal cell cancers) other than those described in the Policy Section is considered investigational, as there is insufficient evidence to support a conclusion concerning the health outcomes or benefits associated with this treatment for these indications. The use of cetuximab (Erbitux ) in combination with other monoclonal antibodies, and for use in persons who have previously been treated with other anti-egfr therapy (e.g. panitumumab [Vectibix]) is considered investigational, as there is insufficient evidence to support a conclusion concerning the health outcomes or benefits associated with this treatment. ( Cross-reference: MP Clinical Trials MP Off-Label Use of Prescription Drug and Medical Devices MP Monoclonal Antibodies for Cancer Indications MP Genetic Testing for Inherited Susceptibility to Colon Cancer Including KRAS Mutation Analysis II. PRODUCT VARIATIONS [N] = No product variation, policy applies as stated [Y] = Standard product coverage varies from application of this policy, see below [N] Capital Cares 4 Kids [N] PPO [N] HMO [Y] SeniorBlue HMO* [Y] SeniorBlue PPO* [N] Indemnity [N] SpecialCare [N] POS [Y] FEP PPO** * Refer to CMS National Coverage Decision (NCD) , Anti-Cancer Chemotherapy for Colorectal Cancer: ** The FEP program dictates that all drugs, devices or biological products approved by the U.S. Food and Drug Administration (FDA) may not be considered investigational. Therefore, FDA-approved drugs, devices or biological products may be assessed on the basis of medical necessity. III. DESCRIPTION/BACKGROUND Cetuximab (Erbitux ), a monoclonal antibody that binds to epidermal growth factor receptor (EGFR), is an example of a targeted therapy drug. Targeted cancer therapies are drugs or other substances that block the growth and spread of cancer by interfering with specific molecules Page 2

3 involved in tumor growth and progression. Inhibition of EGFR prevents activation of downstream signaling pathways vital for cancer cell proliferation, invasion, metastasis, and stimulation of neovascularization. EGFR is overexpressed on the cell surfaces of various solid tumors. Head and Neck Cancer Head and neck cancer refers to cancer that arises in the head or neck region (in the oral cavity, salivary glands, paranasal sinuses and nasal cavity, pharynx, larynx or lymph nodes in the upper part of the neck).. The treatment plan for an individual patient depends on a number of factors, including the exact location of the tumor, the stage of the cancer, and the person's age and general health. Treatment may include surgery, radiation therapy and chemotherapy. Colorectal Cancer Approximately 60%-70% of colorectal tumors express non-mutated ( wild type ) KRAS oncogenes. The remaining colorectal tumors express mutated KRAS oncogenes. The data show that the clinical benefit of using EGFR inhibitors in treating metastatic colorectal cancer, either as monotherapy or in combination with other treatment regimens, is not seen in patients with KRAS-mutated tumors. If mutated, KRAS sends a signal to divide uncontrollably, even if EGFR has been blocked by Cetuximab. Therefore, before cetuximab is used, the standard of care is that the KRAS gene in the cancer cells is tested for mutation. If KRAS is normal (wild type), cetuximab might work. But if KRAS is mutated, indications are that cetuximab will not work, because the mutated KRAS gene continuously sends a KRAS protein signal to divide, even when cetuximab has turned the earlier EGFR signal off. A genetic test for the KRAS mutation was approved by the FDA as an indication for Erbitux treatment of colon cancer in July, 2009 (this also applied to the EGFR antibody panitumumab). Identifying patients whose tumors express mutated KRAS will avoid exposing patients to ineffective drugs, avoid exposure to unnecessary drug toxicities, and expedite the use of the best available alternative therapy. Regulatory Status FDA labeled indications of cetuximab (Erbitux ) are for treatment of colorectal and head and neck cancers. Head and Neck Cancer Cetuximab (Erbitux ) is indicated in combination with radiation therapy for the initial treatment of locally or regionally advanced squamous cell carcinoma of the head and neck. Cetuximab (Erbitux ) is indicated in combination with platinum-based therapy with 5-FU for the first-line treatment of patients with recurrent locoregional disease or metastatic squamous cell carcinoma of the head and neck. Page 3

4 Cetuximab (Erbitux ), as a single agent, is indicated for the treatment of patients with recurrent or metastatic squamous cell carcinoma of the head and neck for whom prior platinum based therapy has failed. Colorectal Cancer Cetuximab (Erbitux ), as a single agent, is indicated for the treatment of KRAS-mutationnegative (wild-type), epidermal growth factor receptor (EGFR)-expressing metastatic colorectal cancer after failure of both irinotecan and oxaliplatin-based regimens. Erbitux, as a single agent, is also indicated for the treatment of EGFR-expressing metastatic colorectal cancer in patients who have failed or are intolerant to irinotecan-based regimens. Cetuximab (Erbitux ), in combination with irinotecan, is indicated for the treatment of EGFR expressing metastatic colorectal carcinoma in patients who are refractory to irinotecan based chemotherapy. The effectiveness of Erbitux in combination with irinotecan is based on objective response rates. Cetuximab (Erbitux ) was recently FDA-approved for the treatment of colorectal cancer in combination with FOLFIRI (ironotecan, 5-fluorouracil, leucovorin) as first-line treatment. Concurrently, the FDA also approved the first KRAS companion diagnostic test, the therascreen KRAS diagnostic kit developed by QIAGEN. Retrospective subset analyses of metastatic or advanced colorectal cancer trials have not shown a treatment benefit for Erbitux in patients whose tumors had KRAS mutations in codon 12 or 13. Use of Erbitux is not recommended for the treatment of colorectal cancer with these mutations. The recommended dosing for head and neck cancer or colorectal cancer is an initial loading dose of 400 mg/m2 infused intravenously and a weekly maintenance dose of 250 mg/m2. Safety Information for Cetuximab (Erbitux ) FDA Black Box Warning Infusion Reactions: Serious infusion reactions occurred with the administration of Erbitux in approximately 3% of patients in clinical trials, with fatal outcome reported in less than 1 in Immediately interrupt and permanently discontinue Erbitux infusion for serious infusion reactions. Cardiopulmonary Arrest: Cardiopulmonary arrest and/or sudden death occurred in 2% patients with squamous cell carcinoma of the head and neck treated with Erbitux and radiation therapy in study 1 and in 3% of patients with squamous cell carcinoma of the head and neck treated with European (EU)-approved cetuximab in combination with plantinum-based therapy with 5- fluorouracil (5-FU) in Study 2.Closely monitor serum electrolytes, including serum magnesium, potassium, and calcium, during and after Erbitux. IV. RATIONALE Page 4

5 Studies 2 and 4 were conducted outside the U.S. using an EU-approved cetuximab as the clinical trial material. Erbitux provides approximately 22% higher exposure relative to the EU-approved cetuximab used in Studies 2 and 4; these pharmacokinetic data, together with the results of Studies 2, 4, and other clinical trial data establish the efficacy of Erbitux at the recommended dose in SCCHN and mcrc. Squamous Cell Carcinoma of the Head and Neck (SCCHN) Study 1 was a randomized, multicenter, controlled trial of 424 patients with locally or regionally advanced SCCHN. Patients with Stage III/IV SCCHN of the oropharynx, hypopharynx, or larynx with no prior therapy were randomized (1:1) to receive either Erbitux plus radiation therapy or radiation therapy alone. Stratification factors were Karnofsky performance status (60tatus (60tion therapy alone. Stratification fac tumor stage (T1ce status (60tatus (60tion therapy alone. Stratification factors w criteria), and radiation therapy fractionation (concomitant boost versus once-daily versus twice-daily). Radiation therapy was administered for 6 for 6sus once-dailycetwice-daily, or concomitant boost. Erbitux was administered as a 400 mg/m2 initial dose beginning one week prior to initiation of radiation therapy, followed by 250 mg/m2 weekly administered 1 hour prior to radiation therapy for the duration of radiation therapy (6 7 weeks). Of the 424 randomized patients, the median age was 57 years, 80% were male, 83% were Caucasian, and 90% had baseline Karnofsky performance status e status ine Ka 258 patients enrolled in U.S. sites (61%). Sixty percent of patients had oropharyngeal, 25% laryngeal, and 15% hypopharyngeal primary tumors; 28% had AJCC T4 tumor stage. Fifty-six percent of the patients received radiation therapy with concomitant boost, 26% received once-daily regimen, and 18% twice-daily regimen. The main outcome measure of this trial was duration of locoregional control. Overall survival was also assessed. Results are presented in Table 6. Table 6: Study 1: Clinical Efficacy in Locoregionally Advanced SCCHN Erbitux + Radiation Radiation Alone Hazard Ratio (95% CI a ) Stratified Log-rank Page 5

6 (n=211) (n=213) p-value Locoregional Control Median duration (months) ( ) Overall Survival Median duration (months) ( ) 0.03 a CI = confidence interval Study 2 was an open-label, randomized, multicenter, controlled trial of 442 patients with recurrent locoregional disease or metastatic SCCHN. Patients with no prior therapy for recurrent locoregional disease or metastatic SCCHN were randomized (1:1) to receive EU-approved cetuximab plus cisplatin or carboplatin and 5-FU, or cisplatin or carboplatin and 5-FU alone. Choice of cisplatin or carboplatin was at the discretion of the treating physician. Stratification factors were Karnofsky performance status (<80 versus <80 versus ing physician. StratiCisplatin (100 mg/m2, Day 1) or carboplatin (AUC 5, Day 1) plus intravenous 5-FU (1000 mg/m2/day, Days 1day were administered every 3 weeks (1 cycle) for a maximum of 6 cycles in the absence of disease progression or unacceptable toxicity. Cetuximab was administered at a 400 mg/m2 initial dose, followed by a 250 mg/m2 weekly dose in combination with chemotherapy. Patients demonstrating at least stable disease on cetuximab in combination with chemotherapy were to continue cetuximab monotherapy at 250 mg/m2 weekly, in the absence of disease progression or unacceptable toxicity after completion of 6 planned courses of platinum-based therapy. For patients where treatment was delayed because of the toxic effects of chemotherapy, weekly cetuximab was continued. If chemotherapy was discontinued for toxicity, cetuximab could be continued as monotherapy until disease progression or unacceptable toxicity. Of the 442 randomized patients, the median age was 57 years, 90% were male, 98% were Caucasian, and 88% had baseline Karnofsky performance status e status ky performance of patients had oropharyngeal, 25% laryngeal, 20% oral cavity, and 14% hypopharyngeal primary tumors. Fifty-three percent of patients had recurrent locoregional disease only and 47% had metastatic disease. Fifty-eight percent had AJCC Stage IV disease and 21% had Stage III disease. Sixty-four percent of patients received cisplatin therapy and 34% received carboplatin as initial therapy. Approximately fifteen percent of the patients in the cisplatin alone arm switched to carboplatin during the treatment period. The main outcome measure of this trial was overall survival. Results are presented in Table 7 and Figure 1 Page 6

7 Table 7: Study 2: Clinical Efficacy in Recurrent Locoregional Disease or Metastatic SCCHN EU-Approved Cetuximab + Platinumbased Therapy + 5- FU (n=222) Platinumbased Therapy + 5- FU (n=220) Hazard Ratio (95% CI a ) Stratified Log-rank p-value Overall Survival Median duration (months) (0.64, 0.98) Progression-free Survival Median duration (months) (0.46, 0.72) < EU-Approved Cetuximab + Platinumbased Therapy + 5- FU (n=222) Platinumbased Therapy + 5- FU (n=220) Odds Ratio (95% CI a ) CMHb test p-value Objective Response Rate 35.6% 19.5% 2.33 (1.50, 3.60) a CI = confidence interval b CMH = Cochran-Mantel- Haenszel Page 7

8 In exploratory subgroup analyses of Study 2 by initial platinum therapy (cisplatin or carboplatin), for patients (N=284) receiving cetuximab plus cisplatin with 5-FU compared to cisplatin with 5-FU alone, the difference in median overall survival was 3.3 months (10.6 versus 7.3 months, respectively; HR 0.71; 95% CI 0.54, 0.93). The difference in median progression-free survival was 2.1 months (5.6 versus 3.5 months, respectively; HR 0.55; 95% CI 0.41, 0.73). The objective response rate was 39% and 23%, respectively (OR 2.18; 95% CI 1.29, 3.69). For patients (N=149) receiving cetuximab plus carboplatin with 5-FU compared to carboplatin with 5-FU alone, the difference in median overall survival was 1.4 months (9.7 versus 8.3 months; HR 0.99; 95% CI 0.69, 1.43). The difference in median progression-free survival was 1.7 months (4.8 versus 3.1 months, respectively; HR 0.61; 95% CI 0.42, 0.89). The objective response rate was 30% and 15%, respectively (OR 2.45; 95% CI 1.10, 5.46). Study 3 was a single-arm, multicenter clinical trial in 103 patients with recurrent or metastatic SCCHN. All patients had documented disease progression within 30 days of a platinum-based chemotherapy regimen. Patients received a 20-mg test dose of Erbitux on Day 1, followed by a 400 mg/m2 initial dose, and 250 mg/m2 weekly until disease progression or unacceptable toxicity. The median age was 57 years, 82% were male, 100% Caucasian, and 62% had a Karnofsky performance status of year Page 8

9 The objective response rate was 13% (95% confidence interval 7% 21%). Median duration of response was 5.8 months (range 1.295% confidenc Colorectal Cancer Erbitux Clinical Trials in K-Ras Mutation-negative (Wild-type), EGFR-expressing, Metastatic Colorectal Cancer. Study 4 was a randomized, open-label, multicenter, study of 1217 patients with EGFR-expressing, metastatic colorectal cancer. Patients were randomized (1:1) to receive either EU-approved cetuximab in combination with FOLFIRI or FOLFIRI alone as first-line treatment. Stratification factors were Eastern Cooperative Oncology Group (ECOG) performance status (0 and 1 versus 2) and region (sites in Western Europe versus Eastern Europe versus other). FOLFIRI regimen included 14-day cycles of irinotecan (180 mg/m2 administered intravenously on Day 1), folinic acid (400 mg/m2 [racemic] or 200 mg/m2 [L-form] administered intravenously on Day 1), and 5-FU (400 mg/m2 bolus on Day 1 followed by 2400 mg/m2 as a 46-hour continuous infusion). Cetuximab was administered as a 400 mg/m2 initial dose on Day 1, Week 1, followed by 250 mg/m2 weekly administered 1 hour prior to chemotherapy. Study treatment continued until disease progression or unacceptable toxicity occurred. Of the 1217 randomized patients, the median age was 61 years, 60% were male, 86% were Caucasian, and 96% had a baseline ECOG performance status 0e status 0s, 60% were mal localized in colon, 84% had 184% had 1performance status 0e status 0s, 60% were male and/or neoadjuvant chemotherapy. Demographics and baseline characteristics were similar between study arms. K-Ras mutation status was available for 1079/1217 (89%) of the patients: 676 (63%) patients had K-Ras mutation-negative (wild-type) tumors and 403 (37%) patients had K-Ras mutation-positive tumors where testing assessed for the following somatic mutations in codons 12 and 13 (exon 2): G12A, G12D, G12R, G12C, G12S, G12V, G13D. Baseline characteristics and demographics in the K-Ras mutation-negative (wildtype) subset were similar to that seen in the overall population. The main outcome measure of this trial was progression-free survival assessed by an independent review committee (IRC). Overall survival and response rate were also assessed. A statistically significant improvement in PFS was observed for the cetuximab plus FOLFIRI arm compared with the FOLFIRI arm (median PFS 8.9 vs. 8.1 months, HR 0.85 [95% CI 0.74, 0.99], p-value=0.036). Overall survival was not significantly different at the planned, final Page 9

10 analysis based on 838 events [HR=0.93, 95% CI (0.8, 1.1), p-value 0.327]. Results of the planned PFS and ORR analysis in all randomized patients and post-hoc PFS and ORR analysis in subgroups of patients defined by K-Ras mutation status, and post-hoc analysis of updated OS based on additional follow-up (1000 events) in all randomized patients and in subgroups of patients defined by K-Ras mutation status are presented in Table 8 and Figure 2. The treatment effect in the all-randomized population for PFS was driven by treatment effects limited to patients who have K-Ras mutation-negative (wild-type) tumors. There is no evidence of effectiveness in the subgroup of patients with K-Ras mutation-positive tumors. Table 8: Clinical Efficacy in First-line EGFR-expressing, Metastatic Colorectal Cancer (All Randomized and K-Ras Status) K-Ras All Randomized Mutation-negative (Wild-type) K-Ras Mutation-positive EU- Approved Cetuximab plus EU- Approved Cetuximab plus EU- Approved Cetuximab plus FOLFIRI (n=608) FOLFIRI (n=609) FOLFIRI (n=320) FOLFIRI (n=356) FOLFIRI (n=216) FOLFIRI (n=187) Progression-Free Survival Number of Events (%) 343 (56) 371 (61) 165 (52) 214 (60) 138 (64) 112 (60 Median (months) (95% CI) 8.9 (8.0, 9.4) 8.1 (7.6, 8.8) 9.5 (8.9, 11.1) 8.1 (7.4, 9.2) 7.5 (6.7, 8.7) 8.2 (7.4, 9.2) HR (95% CI) 0.88 (0.78, 1.0) 0.80 (0.67, 0.94) 1.04 (0.84, 1.29) p-value a Overall Survival b Number of Events (%) 491 (81) 509 (84) 244 (76) 292 (82) 189 (88) 159 (85) Median (months) (95% CI) 19.6 (18, 21) 18.5 (17, 20) 23.5 (21, 26) 19.5 (17, 21) 16.0 (15, 18) HR (95% CI) 0.88 (0.78, 1.0) 0.80 (0.67, 0.94) 1.04 (0.84, 1.29) Objective Response Rate ORR (95% CI) 46% (42, 50) 38% (34, 42) 57% (51, 62) 39% (34, 44) abased on the Stratified Log-rank test. b Post-hoc updated OS analysis, results based on an additional 162 events. 31% (25, 38) 16.7 (15, 19) 35% (28, 43) Page 10

11 Study 5 was a multicenter, open-label, randomized, clinical trial conducted in 572 patients with EGFR-expressing, previously treated, recurrent mcrc. Patients were randomized (1:1) to receive either Erbitux plus best supportive care (BSC) or BSC alone. Erbitux was administered as a 400 mg/m2 initial dose, followed by 250 mg/m2 weekly until disease progression or unacceptable toxicity. Of the 572 randomized patients, the median age was 63 years, 64% were male, 89% were Caucasian, and 77% had baseline ECOG performance status of 0of 0were male, 8 and baseline characteristics were similar between study arms. All patients were to have received and progressed on prior therapy including an irinotecan-containing regimen and an oxaliplatin-containing regimen. K-Ras status was available for 453/572 (79%) of the patients: 245 (54%) patients had K-Ras mutation-negative (wild-type) tumors and 208 (46%) patients had K-Ras mutation-positive tumors where testing assessed for the following somatic mutations in codons 12 and 13 (exon 2): G12A, G12D, G12R, G12C, G12S, G12V, G13D. The main outcome measure of the study was overall survival. Results are presented in Table 9 and Figure 3. Table 9: Overall Survival in Previously Treated EGFR-expressing, Metastatic Colorectal Cancer (All Randomized and K-Ras Status) Page 11

12 Median (months) (95% CI) All Randomized Erbitux plus BSC BSC (N=287) (N=285) (5.4, 6.7) (4.2, 4.9) K-Ras Mutation-negative (Wild-type) Erbitux plus BSC BSC (N=117) 8.6 (7.0, 10.3) (N=128) 5.0 (4.3, 5.7) K-Ras Mutation-positive Erbitux plus BSC BSC (N=108) (N=100) (3.9, 5.6) (3.6, 4.9) HR (95% CI) 0.77 (0.64, 0.92) 0.63 (0.47, 0.84) 0.91 (0.67, 1.24) p-valuea a Based on the Stratified Log-rank test. Study 6 was a multicenter, clinical trial conducted in 329 patients with EGFR-expressing recurrent mcrc. Tumor specimens were not available for testing for K-Ras mutation status. Patients were randomized (2:1) to receive either Erbitux plus irinotecan (218 patients) or Erbitux monotherapy (111 patients). Erbitux was administered as a 400 mg/m2 initial dose, followed by 250 mg/m2 weekly until disease progression or unacceptable toxicity. In the Erbitux plus irinotecan arm, irinotecan was added to Erbitux using the same dose and schedule for irinotecan as the patient had previously failed. Acceptable irinotecan schedules were 350 mg/m2 every 3 weeks, 180 mg/m2 every 2 weeks, or 125 mg/m2 weekly times four doses every 6 weeks. Of the 329 patients, the Page 12

13 median age was 59 years, 63% were male, 98% were Caucasian, and 88% had baseline Karnofsky performance status e 0. Approximately two-thirds had previously failed oxaliplatin treatment. The efficacy of Erbitux plus irinotecan or Erbitux monotherapy, based on durable objective responses, was evaluated in all randomized patients and in two pre-specified subpopulations: irinotecan refractory patients, and irinotecan and oxaliplatin failures. In patients receiving Erbitux plus irinotecan, the objective response rate was 23% (95% confidence interval 18%terval 18%e rate was 23% (95%s 23% (95%% (95%3% (95%as 23% (9 time to progression was 4.1 months. In patients receiving Erbitux monotherapy, the objective response rate was 11% (95% confidence interval 6%terval 6%% (95%as 23% of response was 4.2 months, and median time to progression was 1.5 months. Similar response rates were observed in the pre-defined subsets in both the combination arm and monotherapy arm of the study. V. DEFINITIONS CODON refers to a sequence of 3 consecutive nucleotides in DNA or RNA that codes for a specific amino acid or signals the termination of gene translation (stop or termination codon). COLORECTAL CANCER refers to cancer that develops in the colon (the longest part of the large intestine) and/or the rectum (the last several inches of the large intestine before the anus). EPIDERMAL GROWTH FACTOR (EGFR) refers to the protein found on the surface of some cells and to which epidermal growth factor binds, causing the cells to divide. It is found at abnormally high levels on the surface of many types of cancer cells, so these cells may divide excessively in the presence of epidermal growth factor. KRAS GENE refers to a gene that may cause cancer when it is mutated. The Kras gene makes the KRAS protein, which is involved in cell signaling pathways, cell growth, and apoptosis (cell death). Agents that block the activity of the mutated Kras gene or its protein may stop the growth of cancer. KRAS WILD-TYPE: The normal or typical form of the KRAS gene, as distinguished from any mutant forms of KRAS; KRAS lacking mutation. VI. BENEFIT VARIATIONS The existence of this medical policy does not mean that this service is a covered benefit under the member's contract. Benefit determinations should be based in all cases on the applicable contract language. Medical policies do not constitute a description of benefits. A member s individual or group customer benefits govern which services are covered, which are excluded, and which are subject to benefit limits and which require preauthorization. Members and providers should consult the member s benefit information or contact Capital for benefit information. Page 13

14 VII. DISCLAIMER Capital s medical policies are developed to assist in administering a member s benefits, do not constitute medical advice and are subject to change. Treating providers are solely responsible for medical advice and treatment of members. Members should discuss any medical policy related to their coverage or condition with their provider and consult their benefit information to determine if the service is covered. If there is a discrepancy between this medical policy and a member s benefit information, the benefit information will govern. Capital considers the information contained in this medical policy to be proprietary and it may only be disseminated as permitted by law. VIII. REFERENCES Adam R, Haller DG, Poston G, et al. Toward optimized front-line therapeutic strategies in patients with metastatic colorectal cancer--an expert review from the International Congress on Anti-Cancer Treatment (ICACT) Ann. Onc., March 10, Allegra CJ, Jessup JM, Somerfield MR, et al, American Society of Clinical Oncology Provisional Clinical Opinion: Testing for KRAS Gene Mutations in Patients With Metastatic Colorectal Carcinoma to Predict Response to Anti-Epidermal Growth Factor Receptor Monoclonal Antibody Therapy, J Clin Oncol, 2009, 27(12): Au HJ, et al. Health-related quality of life in patients with advanced colorectal cancer treated with cetuximab: overall and KRAS-specific results of the NCIC CTG and AGITG CO.17 Trial. Journal of Clinical Oncology 2009;27(11): Blue Cross Blue Shield Association (BCBSA) Technology Evaluation Center ( TEC) Assessment: KRAS Mutations and Epidermal Growth Factor Receptor Inhibitor Therapy in Metastatic Colorectal Cancer. Assessment Program Volume 23, No. 6 January Bernier J. Drug Insight: cetuximab in the treatment of recurrent and metastatic squamous cell carcinoma of the head and neck. Nature Clinical Practice. Oncology 2008;5(12): Brockstein B, Vokes E. Locally advanced squamous cell carcinoma of the head and neck: Approaches combining chemotherapy and radiation therapy.in: UpToDate Online Journal [serial online]. Waltham, MA: UpToDate; updated Febuary 6, 2012.[Website] : Accessed July 27, Cascinu S, et al. Cetuximab plus gemcitabine and cisplatin compared with gemcitabine and cisplatin alone in patients with advanced pancreatic cancer: a randomised, multicentre, phase II trial. Lancet Oncology 2008;9(1): Centers for Disease Control (CDC).United States Cancer Statistics [Website]: Accessed July 27, Centers for Medicare and Medicaid Services (CMS) National Coverage Determination (NCD) Anti-Cancer Chemotherapy for Colorectal Cancer. Effective 01/28/05. CMS [Website]: Accessed September 25, Clark J, Grothey A. Systemic chemotherapy for metastatic colorectal cancer : Completed clinical trials. In: UpToDate Online Journal [serial online]. Waltham, MA: UpToDate; updated July [Website] : Accessed July 27, Clark J, Grothey A. Systemic chemotherapy for non-operable metatastic colorectal cancer : Treatment recommendations. In: UpToDate Online Journal [serial online]. Waltham, MA: UpToDate; updated April 10, [Website] : Accessed. July 27, Page 14

15 ImClone LLC and Bristol-Myers Squibb. Erbitux (Cetuximab) prescribing information. Révise July 2012 [Website]: Accessed September 25, Mancl EE, Kolesar JM, Vermeulen LC. Clinical and economic value of screening for Kras mutations as predictors of response to epidermal growth factor receptor inhibitors. Am J Health Syst Pharm Dec 1;66(23): National Cancer Institute (NCI) Dictionary of Cancer Terms. [Website]: Accessed September 25, National Cancer Institute (NCI) Dictionary of Genetic Terms. [Website]: Accessed September 25, National Comprehensive Cancer Network (NCCN). Clinical Practice Guidelines in Oncology : Colon Cancer. V.1 : [Website]: Accessed September 25, National Comprehensive Cancer Network (NCCN). Clinical Practice Guidelines in Oncology : Head and Neck Cancer V [Website]: Accessed September 25, National Comprehensive Cancer Network (NCCN). Clinical Practice Guidelines in Oncology : Rectal Cancer. V [Website]: Accessed September 25, Razak AR, Siu LL, Le Tourneau C. Molecular targeted therapies in all histologies of head and neck cancers: an update. Curr Opin Oncol Feb 18. Salgia R, Skarin A. Investigational approaches for advanced non-small lung cancer. In: UpToDate Online Journal [serial online]. Waltham, MA: UpToDate; updated February 28, [Website] : Accessed July 27, Shankaran V, Obel J, Benson III AB. Predicting Response to EGFR Inhibitors in Metastatic Colorectal Cancer: Current Practice and Future Directions. Oncologist, February 1, 2010; 15(2): U.S. National Institutes of Health (NIH). National Cancer Institute (NCI). Drug Information: Cetuximab. Updated 7/9/12,[Website]: Accessed September 25, Van Cutsem E, Köhne CH, Hitre E, et al.cetuximab and chemotherapy as initial treatment for metastatic colorectal cancer. N Engl J Med Apr 2;360(14): IX. CODING INFORMATION Note: This list of codes may not be all-inclusive, and codes are subject to change at any time. The identification of a code in this section does not denote coverage as coverage is determined by the terms of member benefit information. In addition, not all covered services are eligible for separate reimbursement. Page 15

16 Covered when medically necessary: HCPCS Description Code J9055 Injection, cetuximab, mg ICD-9-CM Diagnosis Code* Description Malignant neoplasm of lip Malignant neoplasm of tongue Malignant neoplasm of major salivary glands Malignant neoplasm of gum Malignant neoplasm of floor of mouth Malignant neoplasm of other and unspecified parts of mouth Malignant neoplasm of oropharynx Malignant neoplasm of nasopharynx Malignant neoplasm of hypopharynx Malignant neoplasm of other and ill-defined sites within the lip, oral cavity, and pharynx Malignant Neoplasm of hepatic flexure Malignant Neoplasm of rectum, rectosigmoid junction and anus Malignant neoplasm of nasal cavities, middle ear, and accessory sinuses Malignant neoplasm of larynx Malignant neoplasm of trachea Other malignant neoplasm of skin of lip Malignant neoplasm of head, face, and neck Lymph nodes of head, face, and neck Secondary Malignant neoplasm respirator and digestive system Malignant carcinoid tumors of the appendix, large intestine, and rectum *If applicable, please see Medicare LCD or NCD for additional covered diagnoses and procedures. The following ICD-10 diagnosis codes will be effective October 1, 2014 ICD-10-CM Diagnosis Description Code* C18.3 Malignant neoplasm of hepatic flexure C18.4 Malignant neoplasm of transverse colon C18.6 Malignant neoplasm of descending colon C18.7 Malignant neoplasm of sigmoid colon C18.0 Malignant neoplasm of cecum C18.1 Malignant neoplasm of appendix C18.2 Malignant neoplasm of ascending colon Page 16

17 ICD-10-CM Diagnosis Description Code* C18.5 Malignant neoplasm of splenic flexure C18.8 Malignant neoplasm of overlapping sites of colon C18.9 Malignant neoplasm of colon, unspecified C19 C20 Malignant neoplasm of rectosigmoid junction Malignant neoplasm of rectum C21.1 Malignant neoplasm of anal canal C21.0 Malignant neoplasm of anus, unspecified C21.2 Malignant neoplasm of cloacogenic zone C21.8 Malignant neoplasm of overlapping sites of rectum, anus and anal canal C76.0 Malignant neoplasm of head, face and neck *If applicable, please see Medicare LCD or NCD for additional covered diagnoses. X. POLICY HISTORY MP CAC 4/26/2011 New Policy CAC February New FDA indications approved for head and neck has been added to the medical policy as medically necessary. CAC 10/30/12 Minor revision. Policy being revised to add new FDA-approved indication for colorectal cancer for use in combination with FOLFORI (ironotecan, 5-fluorouracil, leucovorin) for first-line treatment. Colorectal cancer must be K- RAS mutation-negative (wild-type), EGFR-expressing as determined by FDAapproved tests. Codes reviewed 9/24/12 klr CAC 11/26/13 Consensus. No change to policy statements. Rationale added. References updated. Health care benefit programs issued or administered by Capital BlueCross and/or its subsidiaries, Capital Advantage Insurance Company, Capital Advantage Assurance Company and Keystone Health Plan Central. Independent licensees of the BlueCross BlueShield Association. Communications issued by Capital BlueCross in its capacity as administrator of programs and provider relations for all companies. Page 17