Clinical UM Guideline

 

Subject: Cetuximab (Erbitux®)
Guideline #: CG-DRUG-67 Publish Date:    06/28/2018
Status: New Last Review Date:    05/03/2018

Description

This document addresses the treatment of oncologic conditions with cetuximab (Erbitux; Eli Lilly and Company, Indianapolis, IN), a recombinant human and mouse chimeric monoclonal IgG1 antibody that binds to and inhibits the biologic activity of the human epidermal growth factor receptor (EGFR). 

Note: For additional information, please refer to the following related documents:

Clinical Indications

Medically Necessary:

Notes:
*A course of panitumumab discontinued because of adverse reaction, not progressive disease, is not considered prior treatment.
** If cetuximab is recommended as initial therapy, it should not be used in second or subsequent lines of therapy.

  1. Colorectal and Anal Adenocarcinoma:
    Cetuximab is considered medically necessary for treatment of individuals with Stage IV, KRAS wild-type+ colon, rectal, colorectal, small bowel, appendix or anal adenocarcinoma when all of the following criteria are met:
    1. The individual has not received prior treatment with panitumumab* (Vectibix, Amgen, Thousand Oaks, CA); and
    2. Cetuximab is not used in combination with anti-VEGF agents (for example, bevacizumab); and
    3. Cetuximab may be used for only one line of therapy;** and
    4. Cetuximab is used as a single agent or as part of combination therapy.

Note: +KRAS wild-type means the gene is normal or lacking mutations                                       

  1. Head and Neck Cancer:
    Cetuximab is considered medically necessary for treatment of individuals with squamous cell carcinoma of the head and neck (SCCHN) when the following criteria are met:
    1. The individual has not received prior treatment with panitumumab;* and
    2. Cetuximab is not used in combination with anti-VEGF agents (for example, bevacizumab); and
    3. Cetuximab may be used for only one line of therapy;** and
    4. Cetuximab is used in one of the following indications:
      1. In combination with radiation therapy, for the initial treatment of locally or regionally advanced disease; or
      2. As a single agent for the treatment of individuals with recurrent or metastatic disease for whom prior platinum-based therapy has failed; or
      3. In combination with platinum-based therapy with 5-FU (fluorouracil) as first-line treatment for individuals with recurrent locoregional disease or metastatic SCCHN; or
      4. Single agent or in combination therapy with or without radiation therapy for any of the following indications:
        1. Unresectable locoregional recurrence; or
        2. Second primary in individuals who have received prior radiation therapy; or
        3. Resectable locoregional recurrence in individuals who have not received prior radiation therapy; or
        4. Distant metastases.
  1. Squamous Cell Carcinoma of the Skin:
    Cetuximab is considered medically necessary for treatment of individuals with unresectable regional recurrence or distant metastatic squamous cell skin carcinoma when all of the following criteria are met:
    1. The individual has not received prior treatment with panitumumab*; and
    2. Cetuximab is not used in combination with anti-VEGF agents (for example, bevacizumab); and
    3. Cetuximab may be used for only one line of therapy**.

Not Medically Necessary:

Cetuximab is considered not medically necessary when the above criteria are not met including, but not limited to:

Cetuximab is considered not medically necessary when used in combination with other monoclonal antibodies.

Coding

The following codes for treatments and procedures applicable to this guideline are included below for informational purposes. Inclusion or exclusion of a procedure, diagnosis or device code(s) does not constitute or imply member coverage or provider reimbursement policy. Please refer to the member's contract benefits in effect at the time of service to determine coverage or non-coverage of these services as it applies to an individual member.

HCPCS

 

J9055

Injection, cetuximab, 10 mg [Erbitux]

 

 

ICD-10 Diagnosis

 

C00.0-C14.8

Malignant neoplasm of lip, oral cavity and pharynx

C17.0-C17.9

Malignant neoplasm of small intestine

C18.0-C20

Malignant neoplasm of colon, rectosigmoid junction, rectum

C21.0-C21.8

Malignant neoplasm of anus and anal canal

C30.0-C32.9

Malignant neoplasm of nasal cavities, ear, sinuses, larynx

C39.0

Malignant neoplasm of upper respiratory tract, part unspecified

C44.02

Squamous cell carcinoma of skin of lip

C44.121-C44.129

Squamous cell carcinoma of skin of eyelid, including canthus

C44.221-C44.229

Squamous cell carcinoma of skin of ear and external auricular canal

C44.320-C44.329

Squamous cell carcinoma of skin of nose and other/unspecified parts of face

C44.42

Squamous cell carcinoma of skin of scalp and neck

C44.520-C44.529

Squamous cell carcinoma of anal skin, skin of breast and other part of trunk

C44.621-C44.629

Squamous cell carcinoma of skin of upper limb, including shoulder

C44.721-C44.729

Squamous cell carcinoma of skin of lower limb, including hip

C44.82

Squamous cell carcinoma of overlapping sites of skin

C44.92

Squamous cell carcinoma of skin, unspecified

C49.0

Malignant neoplasm of connective and soft tissue of head, face and neck

C76.0

Malignant neoplasm of head, face and neck

C77.0

Secondary and unspecified malignant neoplasm of lymph nodes of head, face and neck

C78.5

Secondary malignant neoplasm of large intestine and rectum

C79.2

Secondary malignant neoplasm of skin

D00.00-D00.08

Carcinoma in situ of lip, oral cavity and pharynx

D02.0

Carcinoma in situ of larynx

Z51.11-Z51.12

Encounter for antineoplastic chemotherapy and immunotherapy

Z85.038

Personal history of other malignant neoplasm of large intestine

Z85.048

Personal history of other malignant neoplasm of rectum, rectosigmoid junction, and anus

Z85.810-Z85.819

Personal history of malignant neoplasm of lip, oral cavity and pharynx

Discussion/General Information

Colorectal cancer refers to malignancies originating from the large intestine (colon) or the rectum.  The term colorectal cancer does not include anal cancer.  Anal cancer refers to malignancies developing from anal tissue (e.g., anus, anal canal or anorectum) which include the opening of the rectum to the outer body.  Anal cancer occurs infrequently and represents 3% of all cancers of the lower gastrointestinal tract (National Cancer Institute [NCI], 2018; NCCN, 2018).

According to the NCI (2018), head and neck carcinomas account for approximately 4% of all cancers in the United States and are twice as common in men compared to women.  People over age 50 are diagnosed more often than younger people.  Head and neck cancer usually originates in the squamous cells that line the moist, mucosal surfaces within the head and neck.  Cancers that are included in the head and neck category include tongue, mouth, pharynx, larynx, nasal cavity, sinus, salivary glands, and other sites located in the head and neck area.

About 90% of head and neck cancers are of the squamous cell variety and almost 100% of these express EGFR, which is critical for tumor growth.  Therefore, as noted in the cetuximab product information (2015), and based on the entry criteria for individuals enrolled in the head and neck cancer clinical trials, pretreatment assessment for evidence of EGFR expression was not required for individuals with squamous cell carcinoma of the head and neck.

Non-melanoma skin cancer is the most common type of cancer in the United States.  Subtypes of non-melanoma skin cancer include basal cell and squamous cell skin cancer.  According to the American Cancer Society (ACS), approximately 5.4 million non-melanoma cell skin cancers are diagnosed annually, and about 80% of the cases are basal cell cancers.  The precise incidence is unclear as skin cancers are not reported to cancer registries.  Risk factors for skin cancer include exposure to ultraviolet (UV) radiation; fair skin complexion; exposure to chemicals or radiation therapy; reduced immunity; human papilloma virus (HPV) infection and smoking.  Primary treatment for squamous cell carcinoma typically involves surgery or radiation.  Individuals with increased risk of the cancer spreading or recurring may be treated with radiation or chemotherapy (ACS, 2018; NCI, 2018).

Cetuximab and panitumumab are currently two intravenous anti-EGFR therapies approved by the U.S. Food and Drug Administration (FDA) to treat malignancies.  Cetuximab is thought to interfere with the growth of cancer cells by blocking the activation of receptor-associated kinases, inducing apoptosis and decreasing the production of vascular endothelial growth factor.  Antibody-dependent cellular cytotoxicity (ADCC) against specific human tumor types may also be mediated by cetuximab.  The binding of cetuximab to EGFR inhibits cell growth, induces apoptosis and decreases vascular endothelial growth factor production (Product Information Label, 2015). 

Colorectal Adenocarcinoma
Treatment of Metastatic Disease
Cetuximab is currently FDA approved for treatment of EGFR-expressing, metastatic colorectal carcinoma used in combination with irinotecan, in individuals who are refractory to both oxaliplatin- and irinotecan-based regimens and as a single agent for the treatment of EGFR-expressing, metastatic colorectal carcinoma in individuals who are intolerant to irinotecan-based chemotherapy; in combination with radiation therapy (Product information Label, 2015).  The prescribing information notes that cetuximab is not indicated in Ras-mutant colorectal cancer or in those cases in which the Ras mutation status is unknown.  KRAS testing is discussed further below.

The criteria in the Position Statement are based on the selection criteria in the pivotal trial as well as the expert view of medical practitioners practicing in the clinical area of oncology, who have familiarity with the available evidence at this time.  While both cetuximab and panitumumab are used in the treatment of metastatic colorectal cancer, there are no published head-to-head comparisons between the drugs.  In addition, there is no published peer-reviewed literature to support use of cetuximab in second or subsequent lines of therapy when cetuximab was used as initial therapy.

In 2018, the NCCN Clinical Practice Guidelines (CPGs) in Oncology® for advanced stage IV colon and rectal adenocarcinoma include off-label recommendations for cetuximab as a single agent and in combination therapy based on 2A category of evidence and uniform consensus.  These guidelines do not recognize the use of cetuximab for treatment of squamous cell anal cancer. 

Small bowel or appendix adenocarcinomas are rare and there is little to no high-level data regarding these conditions.  The 2018 NCCN Colon Cancer CPG recommends that systemic chemotherapy of these conditions follow the NCCN colon cancer guidelines.

There are several recommended off-label uses of cetuximab in combination therapy for metastatic colorectal carcinoma.  These regimens include the use of agents such as fluorouracil (5-FU), irinotecan and oxaliplatin.  In some situations, the oral formulation of 5-FU, capecitabine, is recommended as equivalent to infused 5-FU (NCCN, 2018).

Primary Tumor Sidedness
Evidence exists that supports that the location of the primary tumor is an integral factor in predicting whether cetuximab will be effective. Little to no benefit was found in those tumors treated with cetuximab which originated on the right side (cecum to hepatic flexure). Conversely, cetuximab appears to offer benefit when used to treat tumors originating on the left side (splenic flexure to rectum). The 2018 NCCN CPG for colon cancer recommends that cetuximab be limited as a first-line treatment of metastatic disease to those with left-sided tumors. While the evidence suggests that sidedness might also be predictive of response on subsequent lines of therapy, further definitive studies are needed.

Cetuximab in Combination with Other Monoclonal Antibodies
In a phase III open-label trial, 732 individuals with metastatic, unresectable colon or rectal carcinoma were randomized to receive treatment with capecitabine-bevacizumab (CB) and oxaliplatin, or capecitabine-bevacizumab-cetuximab (CBC) with oxaliplatin (Tol, 2009).  The CBC cohort had a significantly decreased median progression-free survival (PFS), quality of life and health status compared to the CB group.  The authors concluded that the addition of cetuximab to capecitabine, oxaliplatin and bevacizumab “resulted in a significant decrease in progression-free survival and a poorer quality of life.”  This was supported by a second phase III study (Hecht, 2009).

The 2018 NCCN CPG® notes that the panel “strongly recommends against the use of therapy involving concurrent combination of an anti-EGFR agent (cetuximab or panitumumab) and an anti-VEGF agent (bevacizumab).

Adjuvant Therapy
Alberts and colleagues (2012) reported results from a phase III randomized trial investigating the addition of cetuximab to adjuvant chemotherapy for individuals with stage III disease.  The trial was halted when data from the second interim analysis did not demonstrate improved disease-free survival (DFS) probabilities in comparison to the control group (74.6% compared to 71.5%) respectively.  The investigators noted although cetuximab has demonstrated improved outcomes in the metastatic colorectal setting, additional studies are needed to determine the efficacy of cetuximab in the adjuvant setting. The 2018 NCCN CPG notes that cetuximab “has no role in the adjuvant treatment of colon cancer.”

KRAS Mutations
Studies of metastatic colorectal carcinoma treatment have shown there are subsets of individuals who are not as responsive to anti-EGFR monoclonal antibodies.  Research into the KRAS gene has demonstrated that the absence of mutations in the KRAS gene (i.e. KRAS wild-type) is a predictive factor for a positive response to cetuximab therapy.  Therefore the mutation status of the KRAS has emerged as an important selection criterion and is included in the FDA label.  For example, in a systematic review and meta-analysis, Adelstein and colleagues (2011) analyzed data from 11 studies that included 8924 individuals treated with anti-EGFR therapy.  Individuals with KRAS wild-type had a hazard ratio (HR) for progressive disease of 0.80 (4436 individuals 95% confidence interval [CI], 0.64, 0.99) compared to 1.11 (3119 individuals, 95% CI, 0.97, 1.27) in those with the mutant KRAS.  The authors concluded the status of KRAS mutation modified the treatment effect of anti-EGFR therapy in the treatment of metastatic CRC.  Van Cutsem (2011) reported updated results from a phase III randomized controlled trial (CRYSTAL) of cetuximab combined with irinotecan in first-line therapy for metastatic CRC.  The KRAS status was determined in 1063 (89%) individuals of a total 1198 participants.  In individuals with KRAS wild-type metastatic CRC treated with the cetuximab regimen, there were significant improvements in overall survival (OS) with a median survival of 23.5 months compared to 20.0 months, and improved response rates of 57.3% compared to 39.7% (p<0.001) in the control group.  The authors concluded KRAS mutation status was a predictive biomarker for efficacy of cetuximab.  Other studies have offered similar conclusions (De Roock, 2008; Karapetis, 2008; Messersmith, 2008).

The updated NCCN guidelines (2018) note “The panel believes that patients with any known KRAS mutation, including G13D, should not be treated with cetuximab or panitumumab”.  Use of cetuximab is indicated for individuals with tumors that express the wild-type KRAS gene.  The American Society of Clinical Oncology (ASCO) (Allegra, 2009) issued a provisional, consensus clinical opinion based on systematic reviews of literature primarily from phase II and III clinical trials involving individuals with metastatic colorectal cancer:

All individuals with metastatic colorectal carcinoma who are candidates for anti-EGFR antibody therapy should have their tumor tested for KRAS mutations in a CLIA-accredited laboratory.  If KRAS mutation in codon 12 or 13 is detected, then individuals with metastatic colorectal carcinoma should not receive anti-EGFR antibody therapy as part of their treatment.

EGFR
Unlike KRAS testing, EGFR testing of colorectal tumor cells has not demonstrated predictive value in determining the likelihood of a response to either cetuximab or panitumumab.  Thus, this testing is not required to establish medical necessity for this indication for cetuximab. However, in 2015, the product label was updated to note the following for colorectal cancer “Determine EGFR-expression status using FDA-approved tests prior to initiating treatment.”

BRAF V600E Mutations
The NCCN CPG was revised in 2017 to note that the presence of BRAF V600E mutation makes a response to cetuximab or panitumumab highly unlikely.  However, the guideline does not explicitly state that individuals with a BRAF V600E should not be treated with these drugs.  The guideline does include a 2A recommendation that the workup of a suspected or proven metastatic synchronous adenocarcinoma should include determination of tumor gene status for both RAS and BRAF.

Anal Carcinoma
Squamous cell anal cancer is the most common histologic form of anal cancer.  Adenocarcinoma and melanoma of the anal canal represent infrequently occurring subtypes of anal carcinoma.  The management of anal adenocarcinoma generally follows management strategies for rectal cancer according to the NCCN Anal Carcinoma CPG (NCCN, 2018).  Specialty consensus opinion also supports the recommendations to treat stage IV anal adenocarcinoma similar to stage IV colorectal adenocarcinoma.

Head and Neck Carcinoma
In 2006, the FDA approved cetuximab in combination with radiation therapy, as treatment of locally or regionally advanced squamous cell carcinoma of the head and neck (SCCHN).  An additional approval was given for use as a single agent for the treatment of individuals with recurrent or metastatic SCCHN for whom prior platinum-based therapy has failed.  In 2011, the FDA approved cetuximab in combination with platinum-based therapy with 5-FU for the first-line treatment of individuals with recurrent locoregional disease or metastatic squamous cell carcinoma of the head and neck (Product Information Label, 2015).  The FDA based their approval, in part, on the results of randomized Phase III trials reporting that the addition of cetuximab to standard chemotherapy regimens improved response rates and survival (Burtness, 2005; Vermorken, 2008).

Since expression of EGFR has been detected in nearly all individuals with head and neck cancer, individuals enrolled in the head and neck cancer clinical studies were not required to have immunohistochemical evidence of EGFR expression prior to study entry (Product Information Label, 2015).

Additional recommended off-label uses for cetuximab include single-agent, combination with chemotherapy, with or without radiation therapy for the treatment of recurrent, unresectable or metastatic squamous cell carcinoma of the head and neck (American Hospital Formulary Service® [AHFS®], 2018).  The 2018 NCCN CPG for Head and Neck Cancers includes the same recommendation when there is no surgery or radiotherapy option.

Squamous Cell Carcinoma of the Skin (SCCS)
The 2018 NCCN guidelines note the rarity of cutaneous squamous cell cancer with distant metastases, and the lack of systemic therapy information.  Retrospective case reports have described responses to cetuximab treatment in individuals with metastatic, unresectable SCCS.  In a phase II, multicenter, open-label study, cetuximab was used as first-line chemotherapy to treat individuals with metastatic, unresectable SCCS.  The initial dose of cetuximab infusion was 400 mg/m2, with subsequent weekly doses of 250 mg/m2.  The primary endpoint was disease control rate (DCR) after 6 weeks of treatment.  Thirty-one participants were evaluable out of 36 enrolled individuals.  Based on intent to treat analysis, the DCR was 69% (95% CI, 52% to 84%).  The best overall response rate was 28% (95% CI, 14% to 45%) which included 2 individuals with complete response (CR) and 6 participants with partial response (PR).  The most frequently occurring adverse event was grade 1 to grade 2 acne-like rash. 

The efficacy of cetuximab as a treatment for squamous cell carcinoma was noted in limited but supportive published case series and specialty consensus opinion, including the NCCN Clinical Practice Guideline (2018) category 2A recommendation.

Other Indications

Glioblastoma Multiforme
A phase II trial by Hasselbach and colleagues (2010) investigated the combination of cetuximab, bevacizumab and irinotecan to treat individuals with progressive primary glioblastoma multiforme (GBM) within 6 months of initial radiation and temozolomide therapy.  The overall response rate based on intent to treat was 26% (95% CI: 14%-41%).  When compared to data from other studies utilizing bevacizumab with or without irinotecan, the authors concluded the addition of cetuximab to the bevacizumab regimen was not supported as “the response rate does not appear to be superior with the addition of cetuximab.”

Ménétrier's Disease
Ménétrier's disease is a rare disorder characterized by a premalignant hyperproliferative disorder of epithelial cells and diffusely enlarged gastric folds (Fiske, 2009).  The presenting signs and symptoms include abdominal pain, nausea, vomiting, anemia, hypochlorhydria and peripheral edema.  Due to severe symptoms, lack of effective medical therapy and concern of transformation into gastric cancer, individuals with intractable symptoms require partial or total gastrectomy.  A single-arm study of cetuximab treatment reported that in 7 of the 9 enrolled participants who completed the 4-week trial period, there was improvement in the predominant presenting symptoms; improved quality of life; and reduced Ki-67, a marker of cellular proliferation.  The investigators noted due to the rarity of Ménétrier's disease, a randomized controlled study was not feasible, and this case series demonstrates resolution of severe predominant symptoms in some individuals is possible.  However, further data is needed to determine the long-term efficacy of cetuximab treatment for Ménétrier's disease. 

Non-Small Cell Lung Cancer (NSCLC)
The role of cetuximab in NSCLC has been controversial.  The key pieces of data are the results of two randomized trials, the open-label FLEX trial and the BMS099 trial, both of which compared cetuximab with and without chemotherapy in individuals with advanced NSCLC.  

The FLEX trial randomized 1125 participants to receive chemotherapy (cisplatin, vinorelbine) alone (n=568) or chemotherapy plus cetuximab (n=557).  With a median follow-up of 23.8 months, there was a significantly prolonged OS in the chemotherapy plus cetuximab group versus chemotherapy alone (HR 0.871, 0.762-0.996; p=0.044).  The median OS in the chemotherapy plus cetuximab group was 11.3 months (9.4-12.4) versus 10.1 months (9.1-10.9) in the group treated with chemotherapy (Pirker, 2009).

The BMS099 trial randomized 676 participants to receive chemotherapy (taxane/carboplatin [TC]) alone (n=338) or chemotherapy plus cetuximab (n=338).  There was no significant difference in median progression-free survival (4.40 months for cetuximab/TC, 4.24 months for TC alone, p=0.236).  The cetuximab/TC group had a slightly longer OS of 9.69 months, but it was not statistically significant versus 8.38 months for the TC group (HR=0.890; 95% CI, 0.754-1.051; p=0.169) (Lynch, 2010).

The clinical significance of these results has been questioned.  In 2009, the American Society of Clinical Oncology (ASCO) clinical guideline update on chemotherapy for stage IV NSCLC, recommendations for first-line chemotherapy included cetuximab with cisplatin and vinorelbine for individuals with EGFR-positive tumors.  This guideline was updated in 2011, without any change to the recommendation for use of cetuximab (Azzoli, 2011). 

Janjigian and colleagues (2014) evaluated the use of afatinib and cetuximab in individuals with advanced EGFR-mutant lung cancer who had been heavily pre-treated and had acquired resistance to erlotinib/gefitinib (n=126). Treatment continued until disease progression, intolerable adverse events withdrawal or death. Efficacy endpoints included objective response (OR) and progression-free survival (PFS). Within the treated population, 29% (37/126) had confirmed OR and of those, 18% (22/126) had at least a 50% shrinkage of the tumor size. The median duration of response lasted 5.7 months. None of the subjects showed a complete response to treatment. An additional 41% (52/126) were reported as having stable disease. The median PFS was 4.7 months (95% CI, 4.3–6.4). Treatment related adverse events (AEs) were reported in 99% of subjects. Grade 3 and 4 AEs were reported in 44% and 2% of the treated population respectively. Serious treatment related events were reported in 14% of individuals and 13% of individuals discontinued treatment due to treatment related AEs.

The 2017 NCCN CPG for NSCLC includes a 2A recommendation for the use of afatinib/cetuximab for those with sensitizing EGFR mutations who have progressed following EGFR tyrosine kinase inhibitors (TKIs) and chemotherapy. This was based on one phase Ib, open-label, uncontrolled, multicenter study (Janjigian 2014). Confirmatory trials are underway. In 2015, NCCN assigned a category 3 recommendation (i.e., denoting significant disagreement that the intervention is appropriate) for the use of cetuximab in the treatment of advanced NSCLC citing concerns of toxicity with the regimen containing cetuximab, cisplatin and vinorelbine.  This regimen was removed from the treatment algorithms and recommended chemotherapy lists.  The guidelines concluded, “Some clinicians feel that although the FLEX trial results were statistically significant they were not clinically significant.”

In 2013, the American College of Chest Physicians (ACCP) published guidelines regarding the treatment of Stage IV NSCLC (Socinski, 2013) which assigned a 2B recommendation to cetuximab regimens and suggested that the drug should not be used outside of a clinical trial.  The document summarizes the data as follows:

In summary, the data are conflicting with regard to the impact of adding cetuximab to platinum-based chemotherapy in the first-line setting of advanced NSCLC.  There appears to be an improvement in response rates as a result of adding cetuximab, but no effect on PFS and no consistent effect on overall survival.  In the trials in which there has been a survival benefit, the magnitude of the benefit is very modest and not felt to be clinically robust, particularly relative to the toxicity….     

Pancreatic Cancer
Casino and colleagues (2008) reported results from a phase II trial that randomized 84 individuals with advanced pancreatic carcinoma to receive either chemotherapy with gemcitabine and cisplatin with and without cetuximab.  At a median follow-up of 11.8 months, there was no significant difference for the primary endpoint of objective response.  The investigators concluded that the addition of cetuximab did not have a significantly positive effect and therefore, “should not be further assessed in phase III trials.” 

The NCCN CPG (2018) for pancreatic cancer does not recommend the addition of cetuximab to chemotherapy as an off-label indication to treat pancreatic adenocarcinoma.  The guidelines note a phase III trial reported a lack of improvement in OS with the addition of cetuximab.

Penile Squamous Cell Cancer
Carthon and colleagues (2014) reported results from a retrospective analysis of 23 men with metastatic penile squamous cell cancer and 1 individual with metastatic scrotal cancer.  All men received an EGFR-targeted agent after a prior line of therapy in a majority (22/24) of the men and after 2 lines of therapy in a third (8/24).  Three men in this cohort were treated with EGFR-targeted therapy other than cetuximab.  PR was observed in 1/5 men treated with cetuximab alone.  PR was reported in 5/15 individuals who received cetuximab in combination with other chemotherapy.  The most common (71%) adverse event was grade I/II skin rash.  With a median follow-up of 207 days (14-1441 days), the median overall time to progression (TTP) for the cohort was 79 days (range, 11-281 days).  The median overall survival (OS) was 207 days (range 14-1441 days).  The authors reported OS and TTP were worse in men with visceral, soft tissue or bone metastases.  The authors noted limitations to this study include the retrospective nature and the non-standardized chemotherapy regimens used to treat the men.  The authors concluded the study demonstrated tolerable therapy with EGFR-targeted agents and recommended further prospective studies are needed.

The 2018 NCCN CPG for penile cancer recommends cetuximab as a 2A off-label indication as a second line of therapy, particularly if not previously treated with a similar class or agent.  However, the literature is based primarily on case reports and retrospective non-randomized studies.  Data from prospective studies are recommended.

Other Cancers
There are ongoing trials studying additional indications such as multiple myeloma, solid tumors (including breast cancer, ovarian, esophageal, GBM, urothelial and pancreatic cancers), and at different stages of various diseases (e.g., early stage colorectal cancer).  The use of cetuximab in combination with a variety of chemotherapy or other biologic agents is also under investigation.  However, further data is needed to determine the efficacy and safety of cetuximab therapy for these indications

Adverse Events and Warnings:
Black box warnings from the FDA Product Information Label (2015) include the following serious infusion reactions and cardiopulmonary arrest:

Additional Warnings from the FDA Product Information Label (2015) include:

Pulmonary toxicity as evidenced by interstitial lung disease (ILD) has been reported in individuals with squamous cell carcinoma of the head and neck treated with cetuximab.  ILD, including 1 fatality, occurred in 4 of 1570 (<0.5%) individuals receiving cetuximab in Studies 1, 3, and 6, as well as other studies, in colorectal cancer and head and neck cancer.  Interrupt cetuximab for acute onset or worsening of pulmonary symptoms.  Permanently discontinue cetuximab for confirmed ILD.

Dermatologic toxicities, including acneiform rash, skin drying and fissuring, paronychial inflammation, infectious sequelae (for example, S. aureus sepsis, abscess formation, cellulitis, blepharitis, conjunctivitis, keratitis/ulcerative keratitis with decreased visual acuity, cheilitis), and hypertrichosis occurred in patients receiving cetuximab therapy.  Acneiform rash occurred in 76–88% of 1373 individuals receiving cetuximab in Studies 1, 3, 5, and 6.  Severe acneiform rash occurred in 1–17% of patients.  

Acneiform rash usually developed within the first two weeks of therapy and resolved in a majority of the patients after cessation of treatment, although in nearly half, the event continued beyond 28 days. Life-threatening and fatal bullous mucocutaneous disease with blisters, erosions, and skin sloughing has also been observed in patients treated with Erbitux. It could not be determined whether these mucocutaneous adverse reactions were directly related to EGFR inhibition or to idiosyncratic immune-related effects (eg, Stevens-Johnson syndrome or toxic epidermal necrolysis). Monitor individuals receiving cetuximab for dermatologic toxicities and infectious sequelae.  Individuals should limit sun exposure during cetuximab therapy.

In individuals evaluated during clinical trials, hypomagnesemia occurred in 55% of 365 participants receiving cetuximab in Study 5 and two other clinical trials in colorectal cancer and head and neck cancer, respectively, and was severe (NCI Common Toxicity Criteria Grades 3 and 4) in 6–17%.  The onset of hypomagnesemia and accompanying electrolyte abnormalities occurred days to months after initiation of cetuximab.  Periodically monitor individuals for hypomagnesemia, hypocalcemia, and hypokalemia, during and for at least 8 weeks following the completion of cetuximab.  Replete electrolytes as necessary.

Definitions

Adenocarcinoma: Cancer originating in cells that line specific internal organs and that have gland-like (secretory) properties.

Anal cancer: Cancer originating in the tissues of the anus; the anus is the opening of the rectum (last part of the large intestine) to the outside of the body.

Apoptosis: A series of molecular steps resulting in a type of cell death. The body’s normal way of getting rid of unneeded or abnormal cells; programmed cell death.

Colon cancer: Cancer originating in the tissues of the colon (the longest part of the large intestine).  Most colon cancers are adenocarcinomas that begin in cells that make and release mucus and other fluids.

Colorectal cancer: Cancer originating in the colon (the longest part of the large intestine) or the rectum (the last several inches of the large intestine before the anus).

Head and neck cancer: Cancer that arises in the head or neck region (in the nasal cavity, sinuses, lips, mouth, salivary glands, throat, or larynx [voice box]).

KRAS wild-type: The normal or typical form of the KRAS gene, as distinguished from any mutant forms of KRAS; KRAS lacking mutation.

Line of therapy:

Metastasis: The spread of cancer from one part of the body to another; a metastatic tumor contains cells that are like those in the original (primary) tumor and have spread.

Monoclonal antibody: A protein developed in the laboratory that can locate and bind to a specific substance in the body.

Non-small cell lung cancer: A group of lung cancers that are named for the kinds of cells found in the cancer and how the cells look under a microscope. The three main types of non-small cell lung cancer are squamous cell carcinoma, large cell carcinoma, and adenocarcinoma. Non-small cell lung cancer is the most common kind of lung cancer.

Off-label: Utilization of a United States Food and Drug Administration (FDA) approved drug for uses other than those listed in the FDA approved labeling.

Partial response: A decrease in the size of a tumor, or in the amount of cancer in the body, resulting from treatment; also called partial remission.

Rectal cancer: Cancer originating in tissues of the rectum (the last several inches of the large intestine closest to the anus).

Vascular endothelial growth factor (VEGF): A substance made by cells that stimulates new blood vessel formation.

References

Peer Reviewed Publications:

  1. Alberts SR, Sargent DJ, Nair S, et al. Effect of oxaliplatin, fluorouracil, and leucovorin with or without cetuximab on survival among patients with resected stage III colon cancer. JAMA. 2012; 307(13):1383-1393.
  2. Bokemeyer C, Bondarenko I, Hartmann JT, et al. Efficacy according to biomarker status of cetuximab plus FOLFOX-4 as first-line treatment for metastatic colorectal cancer: the OPUS study. Ann Oncol. 2011; 22(7):1535-1546.
  3. Bonner J, Harari P, Giralt J, et al. Radiotherapy plus cetuximab for squamous cell carcinoma of the head and neck. N Engl J Med. 2006; 354(6):567-578.
  4. Bonner JA, Harari PM, Giralt J, et al. Radiotherapy plus cetuximab for locoregionally advanced head and neck cancer: 5-year survival data from a phase 3 randomised trial, and relation between cetuximab-induced rash and survival. Lancet Oncol. 2010; 11(1):21-28.
  5. Brown A, Ma Y, Danenberg K, et al. Epidermal growth factor receptor-targeted therapy in squamous cell carcinoma of the penis: a report of 3 cases. Urology. 2014; 83(1):159-165.
  6. Burtness B, Goldwasser MA, Flood W, et al. Phase III randomized trial of cisplatin plus placebo compared with cisplatin plus cetuximab in metastatic/recurrent head and neck cancer: an Eastern Cooperative Oncology Group Study. J Clin Oncol. 2005; 23(34):8646-8654.
  7. Carthon BC, Ng CS, Pettaway CA, Pagliaro LC. Epidermal growth factor receptor-targeted therapy in locally advanced or metastatic squamous cell carcinoma of the penis. BJU Int. 2014; 113(6):871-877.
  8. Cascinu S, Berardi R, Labianca R, et al.; Italian Group for the Study of Digestive Tract Cancer (GISCAD).  Cetuximab plus gemcitabine and cisplatin compared with gemcitabine and cisplatin alone in patients with advanced pancreatic cancer: a randomised, multicentre, phase II trial. Lancet Oncol. 2008; 9(1):39-44.
  9. Coffey RJ, Washington MK, Corless CL, Heinrich MC. Ménétrier disease and gastrointestinal stromal tumors: hyperproliferative disorders of the stomach. J Clin Invest. 2007; 117(1):70-80.
  10. Crosby T, Hurt CN, Falk S, et al. Chemoradiotherapy with or without cetuximab in patients with oesophageal cancer (SCOPE1): a multicenter, phase 2/3 randomised trial. Lancet Oncol. 2013; 14(7):627-637.
  11. Cunningham D, Humblet Y, Siena S et al. Cetuximab monotherapy and cetuximab plus irinotecan in irinotecan-refractory metastatic colorectal cancer. N Engl J Med. 2004; 351(4):337-345.
  12. 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):508-515.
  13. Fiske WH, Tanksley J, Nam KT, et al. Efficacy of cetuximab in the treatment of Menetrier's disease. Sci Transl Med. 2009; 1(8):8ra18.
  14. Hasselbalch B, Lassen U, larysen S, et al. Cetuximab, bevacizumab, and irinotecan for patients with primary glioblastoma and progression after radiation therapy and temozolomide: a phase II trial. Neuro Oncol. 2010; 12(5):508-516.
  15. Hecht JR, Mitchell E, Chidiac T, et al. A randomized phase IIIB trial of chemotherapy, bevacizumab, and panitumumab compared with chemotherapy and bevacizumab alone for metastatic colorectal cancer. J Clin Oncol. 2009; 27(5):672-680.
  16. Janjigian YY, Smit EF, Groen HJ, et al. Dual inhibition of EGFR with afatinib and cetuximab in kinase inhibitor-resistant EGFR-mutant lung cancer with and without T790M mutations. Cancer Discov. 2014; 4(9):1036-1045.
  17. Jonker DJ, O'Callaghan CJ, Karapetis CS, et al. Cetuximab for the treatment of colorectal cancer. N Engl J Med. 2007; 357(20):2040-2048.
  18. Karpetis 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):1757-1765.
  19. Ku GY, Haaland BA, de Lima Lopes G Jr. Cetuximab in the first-line treatment of K-ras wild-type metastatic colorectal cancer: the choice and schedule of fluoropyrimidine matters. Cancer Chemother Pharmacol. 2012; 70(2):231-238.
  20. Lenz HJ, Van Cutsem E, Khambata-Ford S, et al. Multicenter phase II and translational study of cetuximab in metastatic colorectal carcinoma refractory to irinotecan, oxaliplatin and fluoropyrimidines. J Clin Oncol.  2006; 24(30):4914-4921.
  21. Lynch TJ, Patel T, Dreisbach L, et al. Cetuximab and first-line taxane/carboplatin chemotherapy in advanced non-small-cell lung cancer: results of the randomized multicenter phase III trial BMS099. J Clin Oncol.  2010; 28(6):911-917.
  22. Maubec E, Petrow P, Scheer-Senyarich I, et al. Phase II study of cetuximab as first-line single-drug therapy in patients with unresectable squamous cell carcinoma of the skin. J Clin Oncol. 2011; 29(25):3419-3426.
  23. Maughan TS, Adams RA, Smith CG, et al.; MRC COIN Trial Investigators. Addition of cetuximab to oxaliplatin-based first-line combination chemotherapy for treatment of advanced colorectal cancer: results of the randomised phase 3 MRC COIN trial. Lancet. 2011; 377(9783):2103-2114.
  24. Messersmith WA, Ahnen DJ. Targeting EGFR in colorectal cancer. N Engl J Med. 2008; 359(17):1834-1836.
  25. Philip PA, Benedetti J, Corless CL, et al. Phase III study comparing gemcitabine plus cetuximab versus gemcitabine in patients with advanced pancreatic adenocarcinoma: Southwest Oncology Group-directed intergroup trial S0205. J Clin Oncol. 2010; 28:3605-3610.
  26. Pirker R, Pereira JR, Szczesna A, et al.; FLEX Study Team. Cetuximab plus chemotherapy in patients with advanced non-small-cell lung cancer (FLEX): an open-label randomized phase III trial. Lancet. 2009; 373(9674):1525-1531.
  27. Pirker R, Pereira JR, von Pawel J, et al. EGFR expression as a predictor of survival for first-line chemotherapy plus cetuximab in patients with advanced non-small-cell lung cancer: analysis of data from the phase 3 FLEX study. Lancet Oncol. 2012; 13(1):33-42.
  28. Rich A, Toro TZ, Tanksley J, et al. Distinguishing Ménétrier's disease from its mimics. Gut. 2010; 59(12):1617-1624.
  29. Saltz LB, Lenz HJ, Kindler L, et al. Randomized phase II trial of cetuximab, bevacizumab, and irinotecan compared with cetuximab and bevacizumab alone in irinotecan-refractory colorectal cancer: the BOND-2 study. J Clin Oncol. 2007; 25(29):4557-4561.
  30. Sorich MJ, Wiese MD, Rowland A, et al. Extended RAS mutations and anti-EGFR monoclonal antibody survival benefit in metastatic colorectal cancer: a meta-analysis of randomized, controlled trials. Ann Oncol. 2015; 26(1):13-21.
  31. Tol J, Koopman M, Cats A, et al. Chemotherapy, bevacizumab, and cetuximab in metastatic colorectal cancer. N Engl J Med. 2009; 360(6):563-572.
  32. Van Cutsem E, Köhne CH, Hitre E, et al. Cetuximab and chemotherapy as initial treatment for metastatic colorectal cancer. N Engl J Med. 2009; 360(14):1408-1417.
  33. 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):2011-2019.
  34. Vermorken JB, Mesia R, Rivera F, et al.  Platinum-based chemotherapy plus cetuximab in head and neck cancer. N Engl J Med. 2008; 359(11):1116-1127.
  35. Vermorken JB, Trigo J, Hitt R, et al. Open-label, uncontrolled, multicenter phase II study to evaluate the efficacy and toxicity of cetuximab as a single agent in patients with recurrent and/or metastatic squamous cell carcinoma of the head and neck who failed to respond to platinum-based therapy. J Clin Oncol. 2007; 25(16):2171-2177.
  36. Xiong HQ, Rosenberg A, LoBuglio A, et al. Cetuximab, a monoclonal antibody targeting the epidermal growth factor receptor, in combination with gemcitabine for advanced pancreatic cancer: a multicenter phase II trial. J Clin Oncol. 2004; 22(13):2610-2616.
  37. Zhu Z. Targeted cancer therapies based on antibodies directed against epidermal growth factor receptor: status and perspectives. Acta Pharmacol Sin. 2007; 28(9):1476-1493.

Government Agency, Medical Society, and Other Authoritative Publications:

  1. 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):2091-2096.
  2. Azzoli C, Baker S, Temin S, Aliff T, et al. 2011 Focused update of 2009 American Society of Clinical Oncology Clinical Practice Guideline update on chemotherapy for stage IV non–small-cell lung cancer. J Clin Oncol. 2011; 29(28):3825-3831.
  3. Cetuximab. In: DrugPoints® System (electronic version). Truven Health Analytics, Greenwood Village, CO.  Updated February 2, 2018. Available at: http://www.micromedexsolutions.com. Accessed on April 10, 2018.
  4. Cetuximab Monograph. Lexicomp® Online, American Hospital Formulary Service® (AHFS®) Online, Hudson, Ohio, Lexi-Comp., Inc. Last revised February 27, 2018. Accessed on April 10, 2018.
  5. Erbitux (cetuximab) [Product Information].  Branchburg, NJ. ImClone Systems Incorporated. April 2015. Available at: http://www.accessdata.fda.gov/drugsatfda_docs/label/2015/125084s262lbl.pdf . Accessed on April 10, 2018.
  6. National Cancer Institute (NCI). Available at: http://www.cancer.gov/cancertopics. Accessed on April 10, 2018.
    • Anal cancer treatment (PDQ®).  Last modified February 1, 2018.
    • Colon cancer treatment (PDQ).  Last modified February 16, 2018.
    • Laryngeal cancer Treatment (PDQ): Last modified February 8, 2018.
    • Oropharyngeal cancer treatment (PDQ). Last modified March 28, 2018.
    • Rectal cancer treatment (PDQ).  Last modified February 16, 2018.
    • Skin cancer treatment (PDQ).  Last modified February 1, 2018.
  7. National Cancer Institute (NCI) - Head and Neck Cancer. Reviewed March 29, 2017. Available at: http://www.cancer.gov/cancertopics/factsheet/Sites-Types/head-and-neck. Accessed on April 10, 2018.
  8. National Comprehensive Cancer Network®. NCCN Drugs & Biologic Compendium® (electronic version). For additional information visit the NCCN website: http://www.nccn.org. Accessed on April 10, 2018.
  9. NCCN Clinical Practice Guidelines in Oncology™. © 2018. National Comprehensive Cancer Network, Inc. For additional information visit the NCCN website: http://www.nccn.org/index.asp. Accessed on April 9, 2018.
    • Anal carcinoma (V.1.2018). Revised February 6, 2018.
    • Colon cancer (V.2.2018). Revised March 14, 2018.
    • Head and neck cancers (V.1.2018). Revised February 15, 2018.
    • Non-small cell lung cancer (V.3.2018). Revised February 21, 2018.
    • Pancreatic Adenocarcinoma (V.1.2017). Revised February 24, 2017.
    • Penile Cancer (V.2.2018). Revised March 26, 2018.
    • Rectal cancer (V.1.2018). Revised March 14, 2018.
    • Squamous Cell Skin Cancer (V.2.2018). Revised October 5, 2017.
  10. Socinski MA, Evans T, Gettinger S, et al. Treatment of stage IV non-small cell lung cancer: Diagnosis and management of lung cancer, 3rd ed: American College of Chest Physicians evidence-based clinical practice guidelines. Chest. 2013; 143(5 Suppl):e341S-e3468S.
Websites for Additional Information
  1. American Cancer Society. Available at: http://www.cancer.org/index. Accessed on April 11, 2018.
  2. National Cancer Institute. Available at: http://www.cancer.gov. Accessed on April 11, 2018.
  3. U.S. National Library of Medicine MedlinePlus. Cetuximab Injection. Last Revised on August 15, 2015. Available at: https://www.nlm.nih.gov/medlineplus/druginfo/meds/a607041.html. Accessed on April 11, 2018.
Index

Cetuximab
Epidermal Growth Factor Receptor (EGFR)
Erbitux
Monoclonal Antibody
Vectibix

The use of specific product names is illustrative only. It is not intended to be a recommendation of one product over another, and is not intended to represent a complete listing of all products available.

History

Status

Date

Action

New

05/03/2018

Medical Policy & Technology Assessment Committee (MPTAC) review.

New

05/02/2018

Hematology/Oncology Subcommittee review. Initial document development. Moved content of DRUG.0036 Cetuximab (Erbitux®) to new clinical utilization management guideline document with the same title.