MEDICAL POLICY

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APPENDIX
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Epidermal Growth Factor Receptor (EGFR) Inhibitors

Number 5.01.603

Effective Date December 9, 2013

Revision Date(s) 12/09/13; 06/12/12; 05/10/11; 03/08/11; 09/14/10; 05/11/10; 01/12/10; 10/13/09; 07/14/09; 8/12/08;12/11/07; 04/10/07; 03/13/07;08/08/06; 02/14/06; 07/01/05;

Replaces N/A

Policy

Small Molecule EGFR inhibitors

Erlotinib (Tarceva®) is the preferred EGFR-TK inhibitor, and may be considered medically necessary for:

  • Treatment of patients with locally advanced or metastatic non-small cell lung cancer (NSCLC); and
  • Treatment of patients with locally advanced, unresectable, or metastatic pancreatic cancer in combination with gemcitabine; and
  • Treatment of patients with recurrent bone cancer – chordoma; and
  • Treatment of patients with relapsed or unresectable stage IV renal cell carcinoma with non-clear cell histology.

Afatinib (Gilotrif®) may be considered medically necessary as second-line therapy for patients with non-small cell lung cancer (NSCLC) with EGFR common mutations (exon 19 del and L858R).

Gefitinib (Iressa®) is considered investigational for the treatment of cancer patients.

Monoclonal Antibodies to EGFR Receptors

Cetuximab (Erbitux®) may be considered medically necessary for the treatment of patients with unresectable, advanced or metastatic colorectal cancer (CRC).

Cetuximab (Erbitux®), in combination with radiation therapy, may be considered medically necessary for the treatment of patients with locally or regionally advanced squamous cell carcinoma of the head and neck (SCCHN).

Cetuximab (Erbitux®) may be considered medically necessary as single agent therapy for SCCHN patients who have received prior radiation therapy, or have resectable locoregional recurrence or have distant metastases.

Cetuximab (Erbitux®), as a single agent or in combination with a platinum-based regimen may be considered medically necessary for the treatment of patients with recurrent, second primary or metastatic squamous cell carcinoma of the head and neck.

Cetuximab (Erbitux®) may be considered medically necessary for the off label treatment of patients with recurrent or metastatic NSCLC.

Cetuximab (Erbitux®) may be considered medically necessary for the treatment of patients with recurrent or distant metastases of squamous cell skin carcinoma.

Panitumumab (Vectibix®) may be considered medically necessary for the treatment of patients with unresectable advanced or metastatic CRC.

Panitumumab (Vectibix®) may be considered medically necessary for the second-line treatment of patients with metastatic penile cancer.

Use of cetuximab (Erbitux®) and panitumumab (Vectibix®) to treat other types of solid tumors and hematological malignancies is considered investigational.

K-RAS

K-RAS mutation analysis may be considered medically necessary for predicting treatment response.

Please refer to the Policy Guidelines section for cetuximab (Erbitux®) and panitumumab (Vectibix®).

BRAF

BRAF mutation analysis may be considered medically necessary to predict nonresponse in the treatment of metastatic colorectal cancer.

Related Policies

5.01.517

Use of Vascular Endothelial Growth Factor Receptor (VEGF) Inhibitors and Other Angiogenesis Inhibitors in Oncology Patients

5.01.518

Bcr-Abl Kinase Inhibitors

5.01.534

Multiple Receptor Tyrosine Kinase Inhibitors

5.01.544

Prostate Cancer Targeted Therapies

5.01.549

Off-Label Use of Drugs and Biologic Agents

9.03.504

Treatment for Age Related Macular Degeneration (AMD), Diabetic Retinopathy and Retinal Vein Occlusion

Policy Guidelines

Small Molecule EGFR Inhibitors

Erlotinib (Tarceva®)

  • Indicated for the treatment of patients with non-small lung cell cancer (NSCLC) when the dose is limited to 150 mg/day p.o., unless concurrent use of a CYP3A4 inducer (i.e., rifampin) is unavoidable.
  • Initial treatment with erlotinib (Tarceva®) will be covered for a period of three months, with further treatment after three months subject to approval, if there is objective (radiographic) measurement of response to therapy.
  • Indicated for the treatment of patients with locally advanced, unresectable, or metastatic pancreatic cancer meeting ALL the following conditions:
  • There is a treatment plan for combination use with gemcitabine; and
  • The dose is limited to 100mg/day p.o. unless concurrent use of a CYP3A4 inducer (i.e., rifampin) is unavoidable; and
  • Initial treatment with erlotinib will be covered for a period of three months, with further treatment after three months subject to approval, if there is objective (radiographic) measurement of response to therapy.
  • Indicated as single agent therapy for treatment of patients with recurrent bone cancer – chordoma or relapsed or unresectable stage IV renal cell carcinoma with non-clear cell histology.
  • Initial treatment with erlotinib will be covered for a period of three months, with further treatment after three months subject to approval, if there is objective measurement of response to therapy.

Afatinib (Gilotrif®)

  • Indicated for the treatment of non-small cell lung cancer (NSCLC) when:
  • The tumor tests positive for EGFR common mutations (exon 19 del and L858R); and
  • The patient has failed a prior trial of erlotinib or gefitinib, unless there are patient-specific reasons why afatinib would be preferable.
  • Initial treatment with afatinib will be covered for a period of three months, with further treatment after three months subject to approval, if there is objective (radiographic) measurement of response to therapy.

Monoclonal Antibodies to EGFR Receptors

Cetuximab (Erbitux®)

  • Indicated for patients with metastatic colorectal tumors only when they express non-mutated (wild-type) K-RAS gene.
  • The initial dose is 400 mg/m2 by IV infusion followed by 250 mg/m2 weekly IV infusion.
  • Patient not previously treated with panitumumab (Vectibix®).
  • Documentation of K-RAS analysis is required.
  • Indicated for patients with squamous cell carcinomas of the head and neck.
  • The initial dose is 400 mg/m2 by IV infusion followed by 250 mg/m2 weekly IV infusion.
  • Documentation of K-RAS analysis is not required as it is relatively uncommon in SCCHN.
  • Indicated for patients with NSCLC who meet ALL of the following conditions:
  • Recurrent or metastatic NSCLC (after surgery or radiation) exists, and
  • No known treated brain metastases are present.
  • Documentation of K-RAS analysis is not required.

Panitumumab (Vectibix®)

  • Indicated for patients with metastatic colorectal tumors only when they express non-mutated (wild-type) K-RAS gene.
  • The recommended dose is 6mg/kg every 14 days by IV infusion.
  • Not previously treated with cetuximab (Erbitux®).
  • Documentation of K-RAS analysis is required.

Description

Cancer is characterized by the uncontrolled growth and spread of malignant cells. Nearly 1.4 million Americans will be diagnosed with cancer this year, and approximately 570,000 will die of the disease. The good news is survival rates for cancer are on the rise, increasing from 50% to 64% over the last 30 years.

Conventional cytotoxic cancer chemotherapy has been one of the major medical advances realized in the last few decades. Although directed toward certain biologic targets thought to be involved in cellular growth and proliferation, typically they have not discriminated well between rapidly dividing normal cells (e.g., bone marrow, gastrointestinal tract) and tumor cells, frequently resulting in toxicities. In addition, tumor responses to traditional cytotoxic cancer chemotherapies can be unpredictable and brief.

“Targeted chemotherapies” (e.g., monoclonal antibodies, small molecule tyrosine kinase inhibitors) are the newest therapeutic approach. These agents have been designed to interfere with Epidermal Growth Factor Receptor proteins, which are molecular targets that have a role in tumor growth and progression. These target proteins are typically preferentially expressed in tumor cells, thus these therapies have a higher specificity for these cells than for normal tissues. The promise of these agents is they will provide a broader therapeutic index with less toxicity. They may also be useful in combination with traditional cytotoxic chemotherapies, immunotherapies or radiation to produce additive or synergistic activity without overlap in toxicity profiles.

The epidermal growth factor receptor (EGFR; ErbB-1; HER1 in humans) is the cell-surface receptor for members of the epidermal growth factor family (EGF-family) of extracellular protein ligands. The epidermal growth factor receptor is a member of the ErbB family of receptors, a subfamily of four closely related receptor tyrosine kinases: EGFR (ErbB-1), HER2/c-neu (ErbB-2), Her 3 (ErbB-3) and Her 4 (ErbB-4). EGFR plays a critical role in the modulation of growth factor signaling. The binding of a ligand such as epidermal growth factor to EGFR induces phosphorylation of several tyrosine residues near the C-terminal end of the EGFR protein and subsequent activation of several tyrosine kinase signal pathways such as the MAPK, Akt and JNK pathways. The induction of these signaling cascades enhances activities such as up regulation of RAS, RAF and mitogen-activated phosphorylation (MAP) which develops cellular growth and invasive capacity. EGFR activation also stimulates vascular endothelial growth factor (VEGF), which is the primary inducer of angiogenesis. As solid tumors cannot grow without the nutritional support provided by a blood supply, angiogenesis plays a key role in progression of these tumors. This feature makes the ErbB family of receptor proteins natural targets for development of novel antitumor compounds.

EGFR overexpression has been identified in a variety of solid tumors (e.g., colorectal, lung, breast, kidney, liver). Furthermore, increasing VEGF levels have been correlated with poor prognosis in many of these same pathologies. As a result, EGFR, tyrosine kinase, and VEGF inhibitors have been developed and investigated for the treatment of these conditions. However, much remains to be learned regarding the rational integration of these therapies into cancer treatment regimens and methods to optimize the selection of patients most likely to benefit.

KRAS/BRAF

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 GTPase KRas (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.

Serine/threonine-protein kinase B-Raf (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.

Recent studies have discovered that EGFR inhibition is not effective in treating tumors that have a mutation in the K-RAS gene. It is thought that the mutant gene is in an activated state and therefore does not require signal initiation from the EGF Receptor, which is located earlier in the signaling pathway.

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.

The EGFR inhibiting agents currently available are as follows:

Drug Name

Pharmacology

How Given

FDA-Approved Uses

Small Molecules (acting inside the cell)

Erlotinib (Tarceva®)

EGFR tyrosine

Oral (Rx)

* NSCLC, pancreatic cancer

Gefitinib (Iressa®)

kinase inhibitor

--

FDA revised labeling in 2005 – no longer recommended

Monoclonal Antibodies (acting at the cell membrane surface

Cetuximab (Erbitux®)

EGFR tyrosine

IV (Clinic)

Metastatic *CRC, Head/Neck

Panitumumab (Vectibix®)

kinase MAb

IV (Clinic)

Metastatic CRC

*NSCLC – Non-small cell lung cancer
*RCC – Renal cell carcinoma
*HCC – Hepatocellular carcinoma
*GIST – Gastrointestinal stromal tumor
*CRC – Colorectal cancer

One small molecule EGFR tyrosine kinase inhibitor is currently approved for use in the United States. Erlotinib (Tarceva®) is approved for the treatment of patients with metastatic NSCLC. Although its mechanism of action is not fully characterized, it is believed to selectively and reversibly inhibit the intracellular phosphorylation of EGFR tyrosine kinase. EGFR is expressed in NSCLC, as well as numerous other solid tumors.

Two additional growth factor inhibitors differ mechanistically from these, in that they are monoclonal antibodies to the receptors:

  • Cetuximab (Erbitux®) is a recombinant chimeric monoclonal antibody that binds and inhibits human epidermal growth factor receptor (EGFR, HER1, c-ErbB-1) on normal and tumor cells. This binding prevents the phosphorylation and activation of kinases, resulting in the inhibition of cell growth, induction of apoptosis, and decrease in VEGF production.
  • Panitumumab (Vectibix®) is a recombinant fully human monoclonal antibody that binds and inhibits human epidermal growth factor receptor (EGFR). It is produced in genetically engineered Chinese Hamster ovary cells.

NCCN Compendium

The National Comprehensive Cancer Network (NCCN) Drugs and Biologics Compendium is based directly on the NCCN Clinical Practice Guidelines in Oncology. The compendium lists specific panel recommendations for off-label uses of drugs, and each recommendation is supported by a level of evidence category.

The NCCN Categories of Evidence and Consensus used in the recommendations are:

  • Category 1: The recommendation is based on high level evidence (e.g. randomized controlled trials) and there is uniform NCCN consensus.
  • Category 2A: The recommendation is based on lower level evidence and there is uniform NCCN consensus.
  • Category 2B: The recommendation is based on lower level evidence and there is nonuniform NCCN consensus (but no major disagreement).
  • Category 3: The recommendation is based on any level of evidence but reflects major disagreement.

Scope

Medical policies are systematically developed guidelines that serve as a resource for Company staff when determining coverage for specific medical procedures, drugs or devices. Coverage for medical services is subject to the limits and conditions of the member benefit plan. Members and their providers should consult the member benefit booklet or contact a customer services representative to determine whether there are any benefit limitations applicable to this service or supply.

Benefit Application

N/A

Rationale

Lung Cancer

Non-small cell lung cancer (NSCLC) is potentially curable if diagnosed early (Stage I or II). Unfortunately, approximately 75% of cases are not identified until the patient has locally advanced or metastatic disease (i.e., Stage III or IV). Overall five year survival is only about 15%.

Two chemotherapy agents (doublet) are recommended by NCCN for first-line therapy of patients with advanced NSCLC and good performance status (i.e., ECOG performance status 0-2). Patients with poor performance status (i.e., 3 or 4) generally do not benefit from chemotherapy. Specifically, platinum-based regimens are recommended. Newer agents in combination with platinum agents have generated a plateau in overall response rate (ORR) of ≥25-35%, time to progression (TTP) of four to six months, median survival of eight to 10 months, and one-year survival of 30-40%. None of these newer combinations have been shown to be clearly superior.

As understanding of the pathophysiology of NSCLC has improved, and because most patients with advanced disease continue to progress following first-line chemotherapy and ultimately die within a year, newer therapies have been developed that have demonstrated value in prolonging survival in this setting. Single-agent docetaxel is considered the standard for comparison for second-line therapy of advanced or recurrent metastatic NSCLC. A large randomized head-to-head study showed pemetrexed 500 mg/m2 provided similar response and survival rates with less severe adverse events and fewer hospitalizations compared to docetaxel 75 mg/m2.

A large phase 3 trial [Iressa Survival Evaluation in Lung Cancer (ISEL)] showed that gefitinib (Iressa®) failed to significantly prolong survival when compared to placebo in patients with advanced NSCLC who had received at least one chemotherapy regimen and could no longer tolerate their most recent regimen. The FDA revised the labeling for gefitinib in June 2005. The new labeling for geritinib states the medicine should be used only in cancer patients who have already taken the medicine and whose doctor believes it is helping them. New patients should not be given gefitinib because in a large study gefitinib did not prolong survival.

Erlotinib (Tarceva®) has proven survival benefit as a seond- or third-line therapy for the treatment of patients with chemotherapy refractory (typically a platinum-based regimen) advanced or recurrent metastatic NSCLC compared to basic supportive care. It has a unique and milder side effect profile compared with traditional cytotoxics (e.g., docetaxel) recommended for use in this setting. It also offers the convenience and potential advantages of oral versus invasive administration as a second-line therapy.

Use of cetuximab (Erbitux®), a monoclonal antibody targeting the epidermal growth factor receptor (EGFR), has the potential to increase survival in patients with advanced NSCLC. (43) A 1125 patient multinational, multicenter, open-label, phase 3 trial, chemotherapy-naïve patients with advanced EGFR-expressing histologically or cytologically proven Stage wet IIIB or Stage IV NSCLC were randomly assigned in a 1:1 ratio to chemotherapy plus cetuximab (n=557) or just chemotherapy (n=568). Patients given chemotherapy plus cetuximab survived longer than those in the chemotherapy-alone group.

A retrospective study of patients treated with first-line chemotherapy with and without erlotinib found that the median overall survival for all patients with mutations was significantly better (>20 months, P<.001) than overall survival for patients without mutations (10 months).

Afatinib

One single arm phase II study and two phase III open label studies compared afatinib with standard chemotherapies as a first line treatment for patients with advanced or metastatic NSCLC. All patients were newly diagnosed treatment naïve stage IIIB or IV with activating EGFR mutations. The results showed modest efficacy of afatinib compared with standard chemotherapy. There are no comparative efficacy data for afatinib vs. previous TKIs in common mutations (exon 19 deletion/L858R), or in preventing T790M resistance.

In the LUX-Lung 3 study, afatinib significantly prolonged PFS (11.1 months) vs. cisplatin/pemetrexed (6.9 month) (HR: 0.58 [95% CI: 0.43, 0.78]; P<0.001), but not overall survival. Median PFS was longer (13.6 months, HR: 0.47 [95% CI: 0.34, 0.65]; P<0.0001) with common EGFR mutations (Del19 and L858R). Afatinib significantly delayed the time to deterioration for cough (HR: 0.60 [95% CI 0.41 to 0.87]; P= 0.007) and dyspnea (HR: 0.68 [95% CI 0.50 to 0.93]; P =0.015), but not pain (HR: 0.83 [95% CI 0.62 to 1.10]; P =0.19). However, the study included no maintenance therapy in chemotherapy group, and there was potential investigator bias due to the awareness of new NCCN guidelines and high cross over rates.

The LUX-Lung 6 study compared efficacy and safety of afatinib to gemcitabine/cisplatin as first-line treatment in an Asian population with EGFR positive mutations. The design and results were similar to LUX-Lung 3. Afatinib prolonged PFS as compared to gemcitabine/cisplatin (11 months vs. 5.6 months, HR 0.28 [95% CI 0.20, 0.39]; P=0.0001). LUX-Lung 2 is a single arm, phase II study of afatinib as first and second line therapy in patients from Taiwan and USA. Two doses of afatinib (50 mg and 40 mg) were tested in this study. The results were similar compared to LUX-Lung 3 and LUX-Lung 6: ORR was 61%, median PFS was 10.1 month and overall survival was 24.8 months for all patients.

The most common adverse events (AE) with afatinib were diarrhea (95.2%), rash (90%), dryness, and irritation of the skin, mucosa and nails. Although the discontinuation rate was lower in afatinib (8%) versus chemotherapy (12%), almost half of afatinib patients required dose reduction to less than 40 mg per day and 14% discontinued therapy due to AE. Diarrhea and rash occurred in more than 90% of patients. Serious AE included several cases of interstitial lung disease and 4 deaths potentially due to treatment related fatal toxicity. This suggests that afatinib may not be well tolerated, and more data are needed to ensure its safe use in a wider population. Afatinib improved PFS and quality of life as a first-line treatment for patients with metastatic NSCLC whose tumors have activating EGFR mutations. It is not metabolized by CYP450 enzymes as are other EGFR TKIs.

Colorectal Cancer

Cetuximab has been studied as both a single agent and in combination with irinotecan in the treatment of metastatic colorectal cancer. (28)

Pancreatic Cancer

In pancreatic cancer symptoms are typically minor until the disease has significantly progressed, and following diagnosis the tumor is often resistant to standard anticancer therapies. These factors contribute to a high mortality rate, with only 20% of patients surviving to one year. In patients with advanced pancreatic cancer, one-year survival drops to approximately 10%. The current standard of therapy in unresectable, advanced, and metastatic disease is gemcitabine.

A randomized, double-blind, placebo-controlled clinical trial added erlotinib 100 mg/day to gemcitabine in patients with inoperable advanced pancreatic cancer. (19) The results showed modest survival benefit compared to those receiving gemcitabine alone. There was a significant difference in overall survival [p=0.025] that favored the erlotinib plus gemcitabine group with a hazard ratio of 0.81 [95% CI 0.67 - 0.97). The corresponding one-year survival rates were 24% versus 17%. PFS was also significantly improved in the gemcitabine plus erlotinib treatment group with a hazard ratio of 0.76, p=0.003. The RR [CR/PR/SD] were 58% [CR/PR=9%] and 49% [CR/PR=8%] for the erlotinib and placebo groups, respectively. No unexpected adverse events or safety signals were reported.

Hepatocellular Carcinoma

Hepatocellular carcinoma is the third leading cause of cancer deaths worldwide. Surgical resection and liver transplantation are the only cures for hepatocellular carcinoma, but benefit only 15% of patients. Most cases are fatal within one year of diagnosis. Soratenib the only pharmacotherapy option available for advanced, inoperable hepatocellular carcinoma (HCC).

One phase 2 study, N=137 patients, looked at the safety and efficacy of four week cycles of 400 mg twice daily soratenib to patients with inoperable HCC, no prior systemic treatment and Child-Pugh A or B scores. After independent assessment three patients (2.2%) had a partial response, eight patients (5.8%) had minor response and 46 patients (33.6%) had stable disease for at least 16 weeks. The median time to progression was 4.2 months and median overall survival was 9.2 months. Adverse events included fatigue, diarrhea, and hand-foot skin reaction.

One phase 3 study (N=602), looked at the efficacy and safety of 400 mg soratenib twice daily compared to placebo in patients with advanced HCC, no prior systemic treatment, ECOG 0-2 and Child-Pugh A. Primary endpoints were median overall survival (OS) and time to symptomatic progression (TTSP). The hazard ratio for OS was 0.69 for sorafenib versus placebo which represented 44% improvement in OS. This was the basis for early stopping criteria. The median overall survival advantage was 10.7 months for sorafenib versus 7.9 months for placebo. The hazard ratio for TTSP was 0.58 and median TTP was 5.5 months for sorafenib vs 2.8 months for placebo. Adverse events incidences were similar between the two groups; however, more serious adverse events of diarrhea and hand-foot skin reactions were seen in the sorafenib group.

The 2008 NCCN Practice Guidelines for hepatocellular carcinoma reflects the results of the phase 3 study and recommends sorafenib for patients with Child-Pugh Class A or B status as first line treatment for unresectable or inoperable HCC and in cases of HCC metastatic disease.

2008 Update

K-RAS Mutations and their impact on the clinical effectiveness EGFR inhibitors

Many retrospective observational studies have been performed to evaluate the contribution of mutations downstream of the epithelial growth factor receptor (EGFR) on the efficacy of the anti-EGFR tyrosine kinase inhibitor oncology therapies such as cetuximab, panitumumab, and gefitinib. Studies differ in design, patient demographics, and therapeutic regimens. The majority of studies evaluating the association of K-RAS mutation with treatment resistance conclude that wild type status is associated with a more favorable response to treatment. Higher efficacy is often seen among tumors with wild-type K-RAS, including a higher percent and degree of response, overall survival, and time-to-progression. However, no single outcome is consistently statistically significant among all studies. Currently available evidence suggests that K-RAS mutation is associated with poor response to TKI therapy, with the most evidence being for cetuximab. At this time, K-RAS mutation status neither predicts resistance to therapy, nor does the presence of wild-type allele predict good efficacy.

A statistically significant difference in overall response was seen in ten of 13 studies in which response was an outcome. Response rates among K-RAS mutants ranged from 0% to 33%. Only five of 13 studies that measured response reported any response to TKI treatment, ranging from 9.5% to 33%. No studies assessing response to panitumumab reported any response to therapy in the K-RAS mutant group. In general, the presence of K-RAS mutation is associated with decreased response to TKI treatment. However, studies presenting response rates of approximately 10-30% suggest that the existence of K-RAS mutation is not the sole determinant of treatment response. In addition, the percent of K-RAS wild-type subjects with partial or complete response is still relatively low, ranging from 26-68%. This suggests that while K-RAS likely contributes the TKI resistance, other factors are involved.

Seven of 15 studies assessed overall survival as an outcome. Three of these found no statistically significant difference, and one found a difference in overall survival only among patients taking combination therapy of cetuximab with irinotecan, while no difference in overall survival was seen in the same patients taking cetuximab monotherapy. The remaining three found statistically significant differences in overall survival between K-RAS mutants and K-RAS wild-type. All three assessed response to cetuximab. Comparison of the overall survival of mutants versus wild-type found an overall median response rate of 6.9 months and 16.3 months, respectively (p<0.001), 27.3 weeks versus 44.7 weeks, respectively (p=0.003), and 10.1 months versus 14.3 months, respectively (p=0.026). Overall, half of the studies that measured overall survival as an outcome reported a difference between K-RAS mutants and K-RAS wild type. The largest study performed with overall survival as an outcome, consisting of 427 patients, found that there was no difference in overall survival between K-RAS mutants and K-RAS wild type after treatment with panitumumab.

Eleven of 15 studies assessed progression-free-survival (PFS) or time-to-progression (TTP). Three of these directly compared TTP or PFS between K-RAS mutants and K-RAS wild type after treatment with cetuximab found no statistically significant difference. However, six studies directly comparing them confirmed that there was a difference. After treatment with cetuximab, TTP for K-RAS mutants and K-RAS wild type were 10.1 weeks [95% CI, 8 to 16 weeks] and 31.4 weeks [95% CI, 19.4 to 36 weeks], respectively. PFS was 6.9 months versus 16.3 months for mutants and wild-type, respectively (p=0.016). One study found a statistically significant difference in progression-free survival only with cetuximab combined with irinotecan (12 weeks versus 34 weeks, p=0.016), but not for cetuximab monotherapy. When randomized to best supportive care or best supportive care and panitumumab, subjects with K-RAS mutations showed no difference in PFS between the two treatment arms. In K-RAS wild-type patients, a statistically significant difference in PFS was seen (HR 0.45, 95%CI -.34-0.59). One study with patients taking either cetuximab or panitumumab reported difference in PFS of 8.6 weeks in K-RAS mutants versus 32 weeks in K-RAS wild type (p<0.001). Two abstracts presented at the American Society of Clinical Oncology (ASCO) 2008 Annual Meeting evaluated the benefit of cetuximab as adjunct therapy to the standard regimen for metastatic colorectal cancer, FOLFIRI. Both studies found that the addition of cetuximab to standard therapy only resulted in increased median PFS in K-RAS wild-type patients. K-RAS mutants showed no improvement in PFS. Overall, the evidence shows that K-RAS mutation is associated with shorter TTP and PFS after treatment with TKI than K-RAS wild type. However, K-RAS mutation has been independently associated with disease progression and this may contribute to differences in disease progression regardless of therapy.

Karapetis et al. published a study that used tissue samples from the CO.17 trial of cetuximab versus supportive care in treating refractory advanced stage metastatic colorectal cancer patients. Five hundred seventy-two patients were enrolled in the original clinical trial, of which tissue samples were examined for 394 patients (69%). The remainder was unavailable for logistic reasons, or due to lack of consent. The authors observed a five-month improvement in median overall survival (9.5 months in the cetuximab group versus 4.8 months with supportive care) for patients with wild type K-RAS. There was no difference in survival between cetuximab and supportive care groups for patients with K-RAS mutations.

2009 Update

The NCCN Drug Compendium

The Company recognizes indications and uses of drugs listed in the NCCN Drugs and Biologics Compendium with Categories of Evidence and consensus of 1 and 2A as proven and Categories of Evidence and Consensus of 2B and 3 as unproven. However, Category 2B uses may be considered for coverage if they are substantiated by provider submission of significant peer-reviewed phase 2 or phase 3 studies demonstrating treatment effectiveness.

Schneider et al. studied the effect of various polymorphisms involving the EGFR signaling pathway in 311 patients receiving erlotinib in NSCLC. None of 17 patients with a KRAS mutation had a tumor response, but the impact of KRAS mutation status on survival outcomes was of borderline statistical significance. Similarly, Miller et al. studied a series of 101 patients with bronchioalveolar carcinoma, of which no patient (zero of 18; 95% CI, 0% to 19%) whose tumor harbored a KRAS mutation responded to erlotinib.

2010 Update

This policy is updated in agreement with March 2010 NCCN Drugs and Biologics Compendium recommendations of 1 and 2A.

2011 Update – KRAS/BRAF

Technology Assessments, Guidelines and Position Statements

The National Comprehensive Cancer Network (NCCN) guidelines (1.2011) 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 indicate that cetuximab and panitumumab are only indicated for patients with tumors that express the wild-type KRAS gene (category 2A recommendation). The guidelines state that there is the option of BRAF genotyping of tumor tissue at the diagnosis of KRAS wild-type stage IV disease, but that data regarding BRAF as a predictor of response (or lack of) to anti-EGFR therapy remain inconclusive.

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 expedite the use of alternative therapies. Thus, 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.

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 PFS and OS regardless of treatment. The data for a BRAF mutation predicting response to anti-EGFR therapy are limited by small numbers of patients and conflicting results among studies. However, recent data (currently unpublished) from the CRYSTAL trial suggest that patients with KRAS wild-type/BRAF mutant tumors may respond to anti-EGFR therapy. Therefore, it may be considered an option in the diagnosis of KRAS wild-type Stage IV disease. Nonconcurrent subgroup analyses of BRAF mutations in patients previously randomized in the large trials in which KRAS mutations predicted nonresponsiveness to anti-EGFR therapy will be helpful to confirm the current data available for BRAF mutations.

2013 Update

This policy is updated in agreement with November 2013 NCCN Drugs and Biologics Compendium recommendations of 1 and 2A. Criteria for afatinib, a new oral EGFR inhibitor, were added. A literature search from January 1, 2013 did not identify further required changes.

References

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  2. Arteaga C. The epidermal growth factor receptor: from mutant oncogene in nonhuman cancers to therapeutic target in human neoplasia: J Clin Onc. 2001; 19:32s-40s,
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  4. Herbst RS, Prager D, Hermann R et al. TRIBUTE-A: Phase III trial of erlotinib HCl (OSI-774) combined with carboplatin and paclitaxel (CP) chemotherapy in advanced non-small cell lung cancer. Proc Am Soc Clin Oncol. 2004; 23: ASCO Abstract #7011.
  5. Gatzemeier U, Pluzanska A, Szczesna A et al. Results of a phase 3 trial of erlotinib (OSI-774) combined with cisplatin and gemcitabine (GC) chemotherapy in advanced non-small cell lung cancer. Proc Am Soc Clin Oncol. 2004; 23:ASCO Abstract #7010.
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  26. Khambata-Ford S, Garrett CR, Meropol NJ. 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;25:3230-3237.
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Coding

Codes

Number

Description

CPT

81403

Molecular pathology procedure, Level 4, gene analysis, if performed KRAS (v-Ki-ras2 Kirsten rat sarcoma viral oncogene) (e.g., carcinoma)

ICD-9 Procedure

   

ICD-9 Diagnosis

   

HCPCS

J8565

Gefitinib (Iressa®), oral, 250 mg

 

J8999

Prescription drug, oral, chemotherapeutic, NOS (includes: Erlotinib)

 

J9055

Injection, cetuximab, 10 mg (Erbitux)

 

J9303

Injection, panitumumab, 10mg (Vectibix)

Type of Service

   

Place of Service

   

Appendix

N/A

History

Date

Reason

03/08/05

Add to Prescription Drug Section - New Policy. Hold for notification, publish June 1, 2005

10/01/05

Replace Policy - Medco issue resolved, approved text being added back into Policy Statement and Policy Guidelines. No review needed by MPC.

02/14/06

Replace Policy - Policy reviewed and revised per Pharmacy and Therapeutics Committee on 1/31/06. Title changed from Epidermal Growth Factor Receptor Inhibitors

06/16/06

Update Scope and Disclaimer - No other changes.

06/21/06

Update codes only. - No other changes.

08/08/06

Replace Policy - Policy reviewed by Pharmacy and Therapeutics Committee on 7/25/06; no changes in policy statement; policy guidelines updated.

03/13/07

Replace Policy - Policy updated with literature review; references updated. Indications for Sprycel, Nexavar, Sutent and Vectibix added to policy statement; indications for Avastin in the treatment of ovarian cancer added as an investigational policy statement, and medically necessary in the treatment of diabetic retinopathy. Policy Guidelines and Rationale updated.

04/10/07

Replace Policy - Policy reviewed by P&T March 27, 2007. Policy statement updated to clarify the indications and criteria for medically necessary treatment with Gleevec and Sprycel. Policy Guidelines updated.

12/11/07

Replace Policy - Policy updated with literature review; policy statement updated to include bullet point “treatment of patients with advanced hepatocellular carcinoma (HCC)” as medically necessary under Sorafenib (Nexavar®). Rationale and references updated to support change in statement.

08/12/08

Replace Policy - Policy updated with literature search. Policy statement revised to indicate that Erbitux may be considered medically necessary for head and neck cancer. Comment on testing for K-RAS mutations added to Policy Guidelines. Rationale section updated, references added. Reviewed by P&T July 24, 2008

11/11/08

Update Description Section - No other changes.

07/14/09

Replace Policy - Policy updated with literature search. Policy statements extensively revised. References added.

09/15/09

Minor updates, code updates - 3rd bullet added under Tarceva’s policy statement “documentation of susceptibility to EGFR mutation or gene amplification”. No other changes.Code S3713 added.

10/13/09

Replace Policy - Policy updated with literature search. Two bullets added under the Nexavar medically necessary statement regarding gastrointestinal stromal tumors and soft-tissue sarcoma. References added.

01/12/10

Replace Policy - Policy updated with literature search; no change to the policy statement. Policy guidelines updated.

05/11/10

Replace Policy - Policy updated with literature search. Policy statement updated to include med nec statement for Erbitux. Reference added. Reviewed by OAP on February 18, 2010. Reviewed by P&T committee on March 2010.

9/14/10

Replace Policy - Policy statement for Erbitux updated with removal of IIIB pleural effusion/IV. Policy guidelines for Erbitux updated with removal of guidelines under NSCLC in accordance with NCCN guidelines. Reviewed by OAP on 8/19/10.

03/08/11

Replace Policy - Policy updated with literature search. BRAF, previously not addressed, may now be considered medically necessary in colon cancer. Reviewed by OAP 02/17/11.

05/10/11

Replace Policy - Policy updated with the abstraction of soratenib (Nexavar®) and sinitinib (Sutent®) which are now addressed in 5.01.534; reference to these drugs and their ability to treat renal cell and thyroid cancers have been removed, along with associated references.

06/26/12

Replace policy. Literature review; no change in policy statements.

06/29/12

Coding update: CPT codes, 81275, 81403 and 88363 added to the policy.

12/19/12

Update Related Policy to add 5.01.01 and 9.03.504.

12/09/13

Replace policy. Policy updated in agreement with November 2013 NCCN Drugs and Biologics Compendium recommendations of 1 and 2A. Criteria for afatinib, a new oral EGFR inhibitor, were added. References 50 – 55 added. CPT codes 81275 and 88363 removed; they are not specific to this policy. Deleted code S3713 removed.


Disclaimer: This medical policy is a guide in evaluating the medical necessity of a particular service or treatment. The Company adopts policies after careful review of published peer-reviewed scientific literature, national guidelines and local standards of practice. Since medical technology is constantly changing, the Company reserves the right to review and update policies as appropriate. Member contracts differ in their benefits. Always consult the member benefit booklet or contact a member service representative to determine coverage for a specific medical service or supply. CPT codes, descriptions and materials are copyrighted by the American Medical Association (AMA).
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