Cetuximab (Erbitux)

Number: 0684

Policy

Aetna considers cetuximab (Erbitux) medically necessary for the treatment of members with the following diseases (see Appendix for selection criteria):

  • Anal adenocarcinoma - (as per selection criteria for rectal cancer) 
  • Appendiceal cancer - (as per selection criteria for colon cancer) 
  • Colon adenocarcinoma
  • Head and neck cancers - squamous cell carcinoma
  • Menetrier's disease
  • Non-small cell lung cancer 
  • Penile cancer 
  • Rectal adenocarcinoma
  • Small bowel adenocarcinoma (as per selection criteria for colon cancer)
  • Occult primary head and neck cancers
  • Squamous cell skin cancer.

Aetna considers continued use of cetuximab not medically necessary for persons whose disease has progressed with cetuximab or who have developed intolerance to this drug.

Aetna considers cetuximab experimental and investigational for use in conjunction with Vectibix (panitumumab), Tarceva (erlotinib), Gilotrif (afatinib), or Iressa (gefitinib) (all are EGFR inhibitors) because the safety and effectiveness of these combinations has not been established.

Aetna considers cetuximab experimental and investigational for use in conjunction with Avastin (bevacizumab) because the safety and effectiveness of this combination has not been established.

Aetna considers cetuximab experimental and investigational when used in combination with other monoclonal antibodies, and for use in persons who have previously been treated with panitumumab (Vectibix) because its effectiveness for these indications has not been established.

Aetna considers cetuximab experimental and investigational for metastatic colon adenocarcinoma, anal adenocarcinoma, appendiceal cancer, rectal adenocarcinoma and small bowel adenocarcinoma in members with KRAS mutations due to known lack of response and possible worse outcomes in this population. Erbitux (cetuximab) and Vectibix (panitumumab) are only indicated for members with tumors that express the wild type (normal) KRAS gene for these indications.

Aetna considers cetuximab experimental and investigational for the treatment of members with the following types of cancers (not an all-inclusive list) since its effectiveness for these indications has not been established.

  • Anal squamous cell carcinoma
  • Anaplastic astrocytoma
  • Bile duct cancer (cholangiocarcinoma)
  • Bladder cancer/urachal carcinoma
  • Breast cancer
  • Carcinoid tumor
  • Cholangiocarcinoma
  • Chordoma
  • Dendritic cell neoplasms
  • Esophageal adenocarcinoma
  • Gallbladder cancer
  • Gastric cancer
  • Glioma
  • Hepatic spindle cell sarcoma
  • Hepatocellular carcinoma
  • Non-melanoma skin cancer
  • Pancreatic cancer
  • Pheochromocytoma
  • Prostate cancer
  • Salivary duct carcinoma
  • Thyroid cancer
  • Urothelial carcinoma
  • Vaginal cancer.

Aetna considers K-ras (KRAS) and N-ras (NRAS) gene (or genetics) analysis medically necessary for predicting non-response to cetuximab in the treatment of metastatic colorectal cancer, anal cancer, and small bowel adenocarcinoma (see CPB 0352 - Tumor Markers).

Aetna consiers combination of cetuximab and encorafenib for the treatment of colorectal cancer experimental and investigational because the effectiveness of this approach has not been established.

Aetna considers combination of cetuximab and natural killer cells therapy for the treatment of non-small cell lung cancer, and liver metastases of gastro-intestinal carcinoma experimental and investigational because the effectiveness of this approach has not been established.

Background

Erbitux (cetuximab) is a recombinant, human/mouse chimeric monoclonal antibody that binds specifically to the human epidermal growth factor receptor (EGFR). EGFR is a transmembrane glycoprotein that is constitutively expressed in many normal epithelial tissues, including the skin and hair follicle. Over expression of EGFR is also detected in many human cancers, including those of colorectal and head and neck origin. Interaction of EGFR with normal ligands leads to phosphorylation and activation of a series of intracellular tyrosine kinases, which in turn regulate transcription of molecules involved with cellular growth and survival, motility, proliferation, and transformation.

Erbitux (cetuximab) has been approved by the U.S. Food and Drug Administration (FDA) for:

  • Head and neck cancer: Locally or regionally advanced squamous cell, in combination with radiation therapy
  • Head and neck cancer: Metastatic or recurrent squamous cell; as monotherapy in patients who failed prior platinum‐based therapy
  • Head and neck cancer: Recurrent locoregional disease or metastatic squamous cell carcinoma in combination with platinum‐based therapy with 5‐FU.
  • Metastatic colorectal cancer: EGFR‐expressing, as monotherapy, in patients who failed both irinotecan‐ and oxaliplatin‐based regimens or in patients intolerant to irinotecan‐based chemotherapy
  • Metastatic colorectal cancer: EGFR‐expressing, in combination with irinotecan, in patients refractory to irinotecan‐based chemotherapy. Approval is based on objective response rate; no data are available demonstrating an improvement in increased survival.
  • Metastatic colorectal cancer: In combination with FOLFIRI for first‐line treatment of K‐Ras mutation negative (wild‐type), EGFR expressing, metastatic colorectal cancer as determined by an FDA‐approved test.

Limitations of Use: Erbitux is not indicated for treatment of Ras‐mutant colorectal cancer or when the results of the Ras mutation are unknown.

Dosage Adjustments

  • Dermatologic toxicities (severe, Grade 3 or 4 acneiform rash): delay for one to two weeks; if improved, restart at 250 mg/m2 after the first occurrence, 200 mg/m2 after the second occurrence, and 150 mg/m2 after the third occurrence; cetuximab should be discontinued if a patient does not improve from a previous episode or has a fourth occurrence.
  • Infusion‐related toxicities: decrease infusion rate by 50% for Grade 1 or 2 (mild to moderate) infusion‐related reactions and non‐serious Grade 3 or 4 infusion reactions; permanently discontinue cetuximab in patients experiencing a serious reaction that requires medical intervention and/or hospitalization.
  • Pulmonary toxicities: interrupt for acute onset or worsening of pulmonary symptoms; permanently discontinue cetuximab in patients if interstitial pulmonary lung disease (ILD) is confirmed.

Black Box Warnings

  • Infusion Reactions: Serious infusion reactions occurred with the administration of Erbitux (cetuximab) in approximately 3% of patients in clinical trials, with fatal outcome reported in less than one‐in‐1000.Immediately interrupt and permanently discontinue Erbitux (cetuximab) infusion for serious infusion reactions.
  • Cardiopulmonary Arrest: Cardiopulmonary arrest and/or sudden death occurred in 2% of 208 patients with squamous cell carcinoma of the head and neck treated with radiation therapy and Erbitux (cetuximab). Closely monitor serum electrolytes, including serum magnesium, potassium, and calcium, during and after Erbitux (cetuximab) treatment.

KRAS: KRAS testing is recommended prior to initiating cetuximab or panitumumab therapy in metastatic colorectal cancer (mCRC) patients. KRAS is highly predictive of response to cetuximab or panitumumab in metastatic colorectal cancer setting. Due to lack of response seen in mCRC tumors with KRAS mutations—coverage will not be extended to this setting.

Crystal and Everest trials showed that cetuximab was beneficial in wild‐type mCRC tumors, but patients with KRAS mutations did not benefit from the addition of the EGFR targeted therapy. Cairo2 and Opus trials also demonstrated a lack of clinical benefit by adding the EGFR antibody, but also demonstrated a compelling decrease in progression-free survival (PFS) when EGFR targeted therapy was added. It is possible that this data reflects mCRC actually doing worse because they received EGFR targeted therapy. Amado demonstrated that KRAS wild‐type verification was also necessary prior to panitumumab therapy due to lack of response seen in tumors with KRAS mutations.

All NCI sponsored clinical trials analyzing these agents have been reevaluated to take KRAS testing into account. The EMEA already requires KRAS testing and wild‐type verification prior to initiation of cetuximab or panitumumab therapy.

Erbitux (cetuximab) should not be utilized in the following:

  • Members with hypersensitivity to Erbitux (cetuximab) or any component of the product
  • Safety and effectiveness of Erbitux (cetuximab) in pediatric and adolescent patients has not yet been established
  • Risk vs. benefit must be discussed with members that are pregnant or breast feeding.

Colorectal Cancer

Colorectal cancer is the second-leading cause of cancer death in the United States.  It is the nation's third most common cancer accounting for approximately 15 % of all new cancer cases.  Metastatic disease is present at diagnosis in 30 % of the patients, and about 50 % of early-stage patients will eventually present with metastatic disease.  For many years, standard treatment of colorectal cancer was 5-fluorouracil (5-FU)-based therapy.  Recent availability of newer agents, including capecitabine, irinotecan and oxaliplatin, has significantly expanded the options available for the management of patients with advanced colorectal cancer, with consequent improvements in survival. 

The expression of various growth factors, growth inhibitors, and their receptors contributes to the development of colorectal cancer as well as to the proliferation and survival of cancerous cells.  About 65 to 70 % of human colon carcinomas have been demonstrated to express the epidermal growth factor receptor (EGFR).  It has been reported that expression of EGFR correlates with tumor progression, resistance to chemotherapy and a poorer prognosis.  Epidermal growth factor receptor plays an important role in initiating signal transduction, and therapeutic approaches directed towards interrupting this pathway have been shown to impair tumor cell proliferation.  These strategies include anti-EGFR monoclonal antibodies, immunotoxin conjugates, and EGFR tyrosine kinase inhibitors.  Cetuximab is a genetically engineered mouse monoclonal antibody that works by inhibiting the EGFR.  Additionally, cetuximab has the potential to partially reverse resistance to a chemotherapy drug. 

On February 12, 2004, the Food and Drug Administration (FDA) approved cetuximab (Erbitux) under its accelerated approval program as a combination treatment with irinotecan for the treatment of patients with metastatic colorectal cancer; or alone if patients cannot tolerate irinotecan.  The approval of cetuximab by the FDA was largely based on the findings of a randomized, controlled study with 329 patients -- 218 for cetuximab plus irinotecan combination therapy and 111 for cetuximab monotherapy.  Furthermore, cetuximab was examined as a single agent in a third clinical study with 57 patients.  Safety data from the 111 patients treated only with cetuximab was also assessed.  All of the studies included patients with EGFR-expressing metastatic colorectal cancer, whose disease had progressed after receiving irinotecan.  Results of these trials showed that the combination treatment of cetuximab and irinotecan shrank tumors in 22.9 % of patients and delayed tumor growth by 4.1 months.  For patients who received cetuximab alone, the tumor response rate was 10.8 % and tumor growth was delayed by 1.5 months.  However, it should be noted that although cetuximab has been reported to shrink tumors in some patients and delay tumor growth, especially when used as a combination treatment, it has not been shown to increase survival. According to guidelines from the National Comprehensive Cancer Network (NCCN, 2009), cetuximab is not recommended for use as first-line therapy as a single agent unless the patient is unable to tolerate irinotecan.  NCCN guidelines and the FDA-approved labeling of Erbitux also stated that cetuximab should not be used in combination with other monoclonal antibodies.

Adverse effects associated with the use of cetuximab include difficulty in breathing and low blood pressure that usually occurs during the administration of the first treatment.  Infrequent interstitial lung disease has also been reported.  Other more common side effects of cetuximab treatment include acne-like rash, dry skin, tiredness or weakness, fever, constipation, and abdominal pain.

Cetuximab has also been shown to improve outcomes when used as first line therapy in combination with irinotecan-based regimens in patients with metastatic colorectal cancer.  Van Cutsem et al (2007) investigated the effectiveness of cetuximab in combination with standard folinic acid (leucovorin), 5-fluorouracil and irinotecan (FOLFIRI) compared with FOLFIRI alone in the first-line treatment of patients with metastatic colorectal cancer.  Patients were randomized to receive either cetuximab plus FOLFIRI (n = 608) or FOLFIRI alone (n = 609). Median progression free survival (the primary study endpoint) was significantly longer for the cetuximab plus FOLFIRI arm (8.9 months) compared to the FOLFIRI alone arm (8 months) (p = 0.036). Response rate was also significantly increased by cetuximab (46.9 % versus 38.7 %, p = 0.005).  The investigators reported that treatment was generally well-tolerated with neutropenia (26.7 % in cetuximab plus FOLFIRI versus 23.3 % in FOLFIRI alone), diarrhea (15.2 % and 10.5 %, respectively) and skin reactions (18.7 % and 0.2 %, respectively) being the most common grade 3/4 adverse events.  The investigators concluded that cetuximab in combination with FOLFIRI significantly increases response rate and significantly prolongs progression-free survival in the first-line treatment of patients with metastatic colorectal cancer, reducing the relative risk of progression by approximately 15 %.  Treatment-related side effects of cetuximab in combination with FOLFIRI were as expected, with diarrhea being moderately and skin reactions significantly more frequent as compared to FOLFIRI alone.

Neyns et al (2008) noted that both hepatic arterial infusion (HAI) of chemotherapy and cetuximab (CET) have interesting activity for the treatment of colorectal cancer liver metastases (CRC-LM).  Intravenous CET with HAI oxaliplatin (OXA) or intravenous irinotecan (IRI) followed by HAI of infusion of folic acid modulated 5-fluorouracil 5-FU/l-FA was administered to patients with CRC-LM who had failed at least 1 line of prior chemotherapy.  A total of 8 patients received intravenous CET with HAI-OXA (5 patients) and intravenousIRI (3 patients) and HAI-5-FU/l-FA. Adverse events included repeated grade 3 skin toxicity (1 patient), abdominal pain with elevated liver enzymes and asthenia (2 patients), duodenal ulcer (2 patients) with catheter migration and intestinal bleeding (1 patient), reversible interstitial pneumonitis (1 patient), and cystic bile duct dilatation (2 patients) with arterio-biliary fistulization (1 patient).  A partial response was documented in 5 patients (62 %).  The median time to progression was 8.7 months (95 % CI: 8 to 14 months).  The authors concluded that intravenous administration of CET with HAI of chemotherapy is feasible and has promising activity but is associated with specific toxicity.

Lv and colleagues (2015) estimated the safety and effectiveness of adding bevacizumab to cetuximab- or panitumumab-based therapy in the treatment of patients with mCRC, using a meta-analysis of randomized controlled trials (RCTs).  These researchers performed a literature search for RCTs through PubMed, Embase, and Web of Science (up to May 22, 2014).  The outcome measures were PFS, overall survival (OS), objective response rate (ORR), and adverse events (AEs).  Two investigators identified eligible studies and extracted data independently.  The quality of the included studies was assessed by the Jadad score.  Hazard ratios (HR), RR, and 95 % Cls were calculated and pooled.  A total of 4 RCTs with 2,069 patients were included in this meta-analysis.  The addition of bevacizumab to cetuximab- or panitumumab-based therapy did not significantly prolonged PFS, when compared with antibody alone.  The subgroup analysis of adding bevacizumab to cetuximab-based therapy also suggested no significant benefit in PFS or in OS.  Patients who received the combined therapy did not have a higher ORR (RR = 0.98, 95 % CI: 0.89 to 1.07; p = 0.608).  The incidence of grade 3/4 AEs was not significantly higher in the bevacizumab and cetuximab/panitumumab group.  The authors concluded that the addition of bevacizumab to cetuximab- or panitumumab-based therapy did not improve PFS and OS resulting in better ORR.  Thus, the combined therapy of bevacizumab with cetuximab or panitumumab is not recommended for the treatment of mCRC.  However, larger-scale RCTs are needed to confirm these findings.

Moosmann et al (2011) noted that the AIO KRK-0104 randomized phase II trial investigated the safety and effectiveness of cetuximab combined with capecitabine and irinotecan (CAPIRI) or capecitabine and oxaliplatin (CAPOX) in the 1st-line treatment of metastatic colorectal cancer (mCRC).  A total of 185 patients with mCRC were randomly assigned to cetuximab (400 mg/m(2) day 1, followed by 250 mg/m(2) weekly) plus CAPIRI (irinotecan 200 mg/m(2), day 1; capecitabine 800 mg/m(2) twice-daily days 1 through 14, every 3 weeks; or cetuximab plus CAPOX (oxaliplatin 130 mg/m(2) day 1; capecitabine 1,000 mg/m(2) twice-daily day 1 through 14, every 3 weeks).  The primary study end-point was ORR.  In the intention-to-treat patient population (n = 177), ORR was 46 % (95 % confidence interval [CI]: 35 to 57) for CAPIRI plus cetuximab versus 48 % (95 % CI: 37 to 59) for CAPOX plus cetuximab.  Analysis of the KRAS gene mutation status was performed in 81.4 % of the intention-to-treat population.  Patients with KRAS wild-type in the CAPIRI plus cetuximab arm showed an ORR of 50.0 %, a PFS of 6.2 months and an OS of 21.1 months.  In the CAPOX plus cetuximab arm, an ORR of 44.9 %, a PFS of 7.1 months and an OS of 23.5 months were observed.  While ORR and PFS were comparable in KRAS wild-type and mutant subgroups, a trend toward longer survival was associated with KRAS wild-type.  Both regimens had manageable toxicity profiles and were safe.  The authors concluded that this randomized trial demonstrated that the addition of cetuximab to CAPIRI or CAPOX is safe and effective in 1st-line treatment of mCRC.  In the analyzed regimens, ORR and PFS did not differ according to KRAS gene mutation status.  The findings of this phase II study were confounded by the concomitant use of irinotecan/oxaliplatin.

The Scottish Intercollegiate Guidelines Network (SIGN)’s clinical guideline on “Diagnosis and management of colorectal cancer” (2011) stated that “Cetuximab should be considered in combination with 5-FU/leucovorin/oxaliplatin or 5-FU/leucovorin/irinotecan chemotherapy for patients with unresectable liver metastases if patients fulfil the Scottish Medicines Consortium (SMC) criteria.  The use of cetuximab in combination with oxaliplatin and capecitabine cannot currently be recommended”.

de Souza and colleagues (2012) noted that newer systemic therapies have the potential to decrease morbidity and mortality from mCRC, yet such therapies are costly and have side effects.  Little is known about their non-evidence-based use.  These investigators conducted a retrospective cohort study using commercial insurance claims from UnitedHealthcare, and identified incident cases of metastatic colon cancer (mCC) from July 2007 through April 2010.  They evaluated the use of 3 regimens with recommendations against their use in the NCCN’s guidelines:
  1. bevacizumab beyond progression;
  2. single agent capecitabine as a salvage therapy after failure on a fluoropyridimidine-containing regimen; and
  3. panitumumab or cetuximab after progression on a prior epidermal growth factor receptor antibody. 

They performed sensitivity analyses of key assumptions regarding cohort selection.  Costs from a payer perspective were estimated using the average sales price for the entire duration and based on the number of claims.  A total of 7,642 patients with incident colon cancer were identified, of which 1041 (14 %) had mCC.  Of those, 139 (13 %) potentially received at least 1 of the 3 unsupported off-label (UOL) therapies; capecitabine was administered to 121 patients and 49 (40 %) likely received it outside of clinical guidelines, at an estimated cost of $718,000 for 218 claims.  Thirty-eight patients received panitumumab and 6 patients (16 %) received it after being on cetuximab at least 2 months, at an estimated cost of $69,500 for 19 claims.  Bevacizumab was administered to 884 patients.  Of those, 90 (10 %) patients received it outside of clinical guidelines, at an estimated cost of $1.34 million for 636 claims.  The authors concluded that in a large privately insured mCC cohort, a substantial number of patients potentially received UOL treatment.  The economic costs and treatment toxicities of these therapies warrant increased efforts to stem their use in settings lacking sufficient scientific evidence.

Modest et al (2013) examined the impact of early tumor shrinkage (ETS) on PFS and OS in patients with mCRC treated within the AIO KRK 0104 trial as 1st-line therapy.  Moreover, correlations of ETS with clinical characteristics and prognostic markers were evaluated.  In total, 121 patients were included into this analysis.  Patients were treated with cetuximab combined with either CAPIRI or CAPOX.  ETS at 6 weeks was defined as a relative change of greater than or equal to 20 % in the sum of the longest diameters of target lesions compared to baseline.  Survival times were compared between patients with ETS greater than or equal to 20 % versus no-ETS.  ETS greater than or equal to 20 % was observed in 59 % of all patients with KRAS wild-type tumors.  In these patients ETS greater than or equal to 20 % was associated with higher overall response rate (ORR) (82 % versus 19 %, p < 0.001).  Also, PFS (8.9 versus 4.7 months, p < 0.001) and OS (31.6 versus 15.8 months, p = 0.005) were significantly superior in ETS greater than or equal to 20 % of patients compared to no-ETS.  In patients with KRAS mutant mCRC ETS greater than or equal to 20 % neither had an effect on PFS nor OS.  Cetuximab-induced skin toxicity correlated with the occurrence of ETS greater than or equal to 20 % (p = 0.002).  The authors concluded that in patients with KRAS wild-type tumors treated with cetuximab plus capecitabine-based chemotherapy ETS greater than or equal to 20 % is an important predictor of favorable outcome.  (This appeared to be a sub-analysis on the data of the AIO KRK-0104 study discussed above).

Hoyle et al (2013) stated that colorectal cancer is the third most commonly diagnosed cancer in the UK after breast and lung cancer.  People with metastatic disease who are sufficiently fit are usually treated with active chemotherapy as 1st- or 2nd-line therapy.  Recently, targeted agents have become available including anti- EGFR agents (e.g., cetuximab and panitumumab) and anti- VEGF receptor agents (e.g., bevacizumab).  These researchers investigated the clinical effectiveness and cost-effectiveness of panitumumab monotherapy and cetuximab (mono- or combination chemotherapy) for Kirsten rat sarcoma (KRAS) wild-type (WT) patients, and bevacizumab in combination with non-oxaliplatin chemotherapy, for the treatment of metastatic colorectal cancer after 1st-line chemotherapy.  The assessment comprised a systematic review of clinical effectiveness and cost-effectiveness studies, a review and critique of manufacturer submissions and a de-novo cohort-based economic analysis.  For the assessment of effectiveness, a literature search was conducted in a range of electronic databases, including MEDLINE, EMBASE and The Cochrane Library, from 2005 to November 2010.  Studies were included if they were RCTs or systematic reviews of RCTs of cetuximab, bevacizumab or panitumumab in participants with EGFR-expressing metastatic colorectal cancer with KRAS WT status that has progressed after 1st-line chemotherapy (for cetuximab and panitumumab) or participants with metastatic colorectal cancer that has progressed after 1st-line chemotherapy (bevacizumab).  All steps in the review were performed by 1 reviewer and checked independently by a second.  Synthesis was mainly narrative.  An economic model was developed focusing on 3rd-line and subsequent lines of treatment.  Costs and benefits were discounted at 3.5 % per annum.  Probabilistic and uni-variate deterministic sensitivity analyses were performed.  The searches identified 7,745 titles and abstracts.  Two clinical trials (reported in 12 papers) were included.  No data were available for bevacizumab in combination with non-oxaliplatin-based chemotherapy in previously treated patients.  Neither of the included studies had KRAS status performed prospectively, but the studies did report retrospective analyses of the results for the KRAS WT subgroups.  Third-line treatment with cetuximab plus best supportive care (BSC) or panitumumab plus BSC appeared to have statistically significant advantages over treatment with BSC alone in patients with KRAS WT status.  For the economic evaluation, 5 studies met the inclusion criteria.  The base-case incremental cost-effectiveness ratio (ICER) for KRAS WT patients for cetuximab compared with BSC is £98,000 per quality-adjusted life-year (QALY), for panitumumab compared with BSC is £150,000 per QALY and for cetuximab plus irinotecan compared with BSC is £88,000 per QALY.  All ICERs are sensitive to treatment duration.  The authors concluded that although cetuximab and panitumumab appeared to be clinically beneficial for KRAS WT patients compared with BSC, they are likely to represent poor value for money when judged by cost-effectiveness criteria currently used in the UK.  It would be useful to conduct a RCT for patients with KRAS WT status receiving cetuximab plus irinotecan.

Furthermore, an UpToDate review on “Treatment protocols for small and large bowel cancer” (Brenner et al, 2015) does not mention the combinational use of cetuximab and capecitabine as a therapeutic option.

NCCN guidelines (2014) stated that all patients with metastatic colorectal cancer should have tumor tissue genotyped for RAS mutations (KRAS and NRAS). The guidelines stated that, at the very least, exon 2 KRAS mutation status should be determined. Whenever possible, non-exon 2 KRAS mutation status and NRAS mutation status should also be determined. Patients with any known KRAS mutation (exon 2 or non-exon 2) or NRAS mutation should not be treated with either cetuximab or panitumumab. Mutations in codons 12 and 13 in exon 2 of the coding region of the KRAS gene predict lack of response to therapy with antibodies targeted to the EGFR.The guidelines stated that testing for KRAS and NRAS mutations in codons 12 and 13 should be performed only in laboratories that are certified under the clinical laboratory improvement amendments of 1988 (CLIA-88) as qualified to perform high complexity clinical laboratory (molecular pathology) testing. No specific methodology was recommended (eg, sequencing, hybridization). The guidelines noted that testing can be performed on formalin-fixed paraffin-embedded tissue. The testing can be performed on the primary colorectal cancers and/or the metastasis, as literature has shown that the KRAS and NRAS mutations are similar in both specimen types. 

There was no data to support the use of cetuximab or panitunumab (Vectibix) after failure of the other drug.  Colorectal cancer guidelines from the NCCN (2009) stated: "If cetuximab is used as initial therapy, then neither the cetuximab nor panitunumab should be used in second or subsequent lines of therapy.  There are no data, nor is there compelling rationale, to support the use of panitumumab after clinical failure on cetuximab, or cetuximab after clinical failure on panitumumab.  As such, the use of one of these agents after therapeutic failure on the other is not recommended."  NCCN colorectal cancer guidelines (2009) also stated that routine use of bevacizumab (Avastin) and cetuximab is not recommended in patients with prior disease progression on bevacizumab.

Guidelines on colorectal cancer from the NCCN (2009) cited evidence that the effectiveness of cetuximab cannot be predicted on the base of the presence or absence of EGFR receptors (see Cunningham et al, 2004; Hecht et al. 2006).  The NCCN guidelines recommended use of cetuximab for colorectal cancer without regard to EGFR receptor status.

A provisional clinical opinion by the American Society for Clinical Oncology (ASCO, 2009) recommended that patients with metastatic colorectal cancer receive testing for mutations in the KRAS gene to predict whether patients will benefit from treatment with cetuximab and other EGFR inhibitors.  Colorectal cancer guidelines from the NCCN (2009) stated that the EGFR inhibitors cetuximab and panitumumab  were recommended only for patients with tumors characterized by the wild-type KRAS gene.

The NCCN guidelines on colon cancer (2011) stated that "[i]nterestingly, a recent publication from de Roock et al raises the possibility that codon 13 mutations may not be absolutely predictive of non-response.  However, as stated in that manuscript, these findings are hypothesis-generating only, and prospective studies will be needed to determien if patients with codon 13 mutations can, in fact, benefit from anti-EGFR therapy.  At present, use of anti-EGFR agents in patients whose tumors have codon 13 mutations remains investigational, and is not endorsed by the panel for routine practice".

The FDA-approved labeling of Erbitux has the following recommendations regarding dosing in colorectal cancer:

  • Premedicate with an H1 antagonist.
  • Administer 400 mg/m2 initial dose as a 120-minute intravenous infusion followed by 250 mg/m2 weekly infused over 60 minutes.
  • Initiate Erbitux one week prior to initiation of radiation therapy. Complete Erbitux administration 1 hour prior to platinum-based therapy with 5-FU and FOLFIRI.
  • Reduce the infusion rate by 50% for NCI CTC Grade 1 or 2 infusion reactions and non-serious NCI CTC Grade 3 infusion reaction.
  • Permanently discontinue for serious infusion reactions.
  • Withhold infusion for severe, persistent acneiform rash. Reduce dose for recurrent, severe rash.

The NCCN Guidelines (v4.2018) on "Colon cancer" states that for small bowel adenocarcinoma or appendiceal adenocarcinoma, to consider systemic therapy as per NCCN guidelines for colon cancer.

See Appendix for the 2018 NCCN Drugs & Biologics Compendium recommendations and selection criteria for cetuximab on colon and rectal cancer.

Head and Neck Cancer

The majority of head and neck cancers over-express the epidermal growth factor receptor (EGFR), which is associated with aggressive tumor behavior and poor clinical outcome.  In a recent review, Caponigro et al (2004) noted that 3 phase II studies have evaluated the combination of cetuximab with platinum-based chemotherapy in pre-treated patients with recurrent/metastatic head and neck cancer, with a control rate ranging from 29 to 66 %.  However, the authors noted that a phase III placebo-controlled trial has shown that the addition of cetuximab to cisplatin does not significantly improve median progression-free survival, despite a difference in the response rate between the two arms.

Bonner et al (2004, 2006) reported on the results of a phase III trial to examine the impact of combining cetuximab with high dose radiation on locoregional disease control and survival in patients with locally advanced squamous cell carcinoma of the head and neck.  The investigators randomized 424 patients with locoregionally advanced squamous cell carcinoma of the oropharynx, hypopharynx or larynx to either radiation alone for 6-7 weeks, or radiation plus weekly cetuximab.  Following completion of treatment, patients were followed by physical examination and radiographic imaging every 4 months for 2 years, and then every 6 months up to 5 years.  Median survival was 54 months in subjects receiving cetuximab plus radiation therapy compared to 28 months in subjects receiving radiation therapy alone.  The investigators noted that the overall toxicity profile was dominated by classic known effects of high dose head and neck radiation, although some additional toxicity was attributed to cetuximab. Significantly more subjects receiving combination therapy had grade 3/4 skin reactions (34 %) than subjects receiving radiation therapy alone (18 %).  Grade 3/4 infusion reactions were seen in 3 % of subjects receiving cetuximab.  The investigators concluded that the addition of cetuximab to high dose radiation in patients with locoregionally advanced squamous cell carcinoma of the head and neck demonstrated a statistically significant prolongation in overall survival.  This clinical benefit was achieved with minimal enhancement in the overall toxicity profile associated with curative-intent radiation therapy.  In an editorial that accompanied the 2006 article by Bonner et al, Posner and Wirth (2006) stated that "[a]t present, for patients who can tolerate it, chemoradiotherapy with cisplatin remains the standard of care.  Patients who cannot tolerate platinum-based chemotherapy for any of a variety of reasons should be expected to benefit from the addition of cetuximab to radiotherapy".

Cetuximab has also been shown to be effective when combined with standard chemotherapy for locally advanced squamous cell carcinoma of the head and neck. Vermorken et al (2007) reported on the results of a multi-center phase III study to assess the efficacy and safety of cetuximab in combination with standard chemotherapy for persons with stage III/IV recurrent and/or metastatic squamous cell carcinoma of the head and neck, not suitable for local therapy.  Patients from 35 European sites were randomized either to 2 groups.  The chemotherapy plus cituximab arm (n = 222) received cetuximab plus cisplatin or carboplatin and 5-fluorouracil (FU).  The chemotherapy arm (n = 220) received cisplatin or carboplatin with 5-FU.  Median survival (the primary study endpoint) was 7.4 months in the chemotherapy alone arm compared to 10.1 months for chemotherapy plus cetuximab arm (p = 0.036).  The investigators concluded that the addition of cetuximab to standard chemotherapy resulted in a clinically meaningful survival benefit.  The investigators noted that the observed median survival time of 10.1 months is among the longest ever reported in a phase III trial for these patients.

In a phase 1b clinical trial, Saba et al (2014) examined the effects of everolimus in combination with cetuximab and carboplatin for recurrent/metastatic squamous cell carcinoma of the head and neck (RMSCCHN).  Patients received carboplatin (area under the curve = 2 mg/ml/min; 3 weeks on, 1 week off), cetuximab (with a loading dose of 400 mg/m(2) and then 250 mg/m(2) weekly), and dose-escalating everolimus (2.5, 5.0, 7.5, and 10 mg/day) with a 3+3 design.  After 4 cycles, patients without progression continued cetuximab/everolimus until progression or intolerable toxicity.  Patients (age greater than or equal to 18 years) had previously untreated, unresectable RMSCCHN not amenable to radiotherapy and an ECOG performance status of 0 to 2.  The study enrolled 20 patients (male/female = 18/2) with RMSCCHN; the median age was 65 years (44 to 75 years).  Thirteen patients received everolimus (male/female = 92 %); 2 of 6 patients receiving 2.5 mg/day experienced dose-limiting toxicity (DLT) with grade 3 hyponatremia and nausea.  In 7 patients receiving de-escalated everolimus (2.5 mg every other day), grade 3 hyperglycemia produced DLT in 1 of 6 patients.  The ORR was 61.5 % (all partial responses); PFS was 8.15 months.  The pharmacokinetics of everolimus was described with a 2-compartment mixed-effects model.  There was a significant correlation between tumor p-p44/42 staining and response (p = 0.044) and a marginally significant correlation between phosphorylated mammalian target of rapamycin and OS.  The maximum tolerated dose (MTD) of everolimus with cetuximab and carboplatin was 2.5 mg every other day.  The authors concluded that this regimen was associated with an encouraging RR and PFS, and this suggested possible clinical efficacy in a select group of patients with SCCHN.

Non-Small Cell Lung Cancer

Ciardiello et al (2004) stated that 3 drugs are currently in phase II and phase III development as single agents or in combination with other anti-cancer therapies in non-small cell lung cancer (NSCLC) patients: cetuximab (Erbitux), a chimeric human-mouse monoclonal IgG1 antibody that blocks ligand binding and functional EGFR activation; and erlotinib (Tarceva) and gefitinib (Iressa), 2 orally bioavailable, small-molecule EGFR inhibitors of tyrosine kinase enzymatic activity that prevent EGFR autophosphorylation and activation.  The authors concluded that anti-EGFR has shown promising anti-tumor activity in NSCLC patients with a mild toxicity profile.  However, a series of important clinical issues such as selection of potentially responsive patients and optimal combination with conventional anti-cancer treatments needs to be addressed to use these drugs better in lung cancer.  This is in agreement with the observation by Langer (2004) who noted that EGFR inhibitors currently under investigation for the treatment of NSCLC include gefitinib and erlotinib, as well as cetuximab.  Pre-clinical models have demonstrated synergy for all these agents in combination with either chemotherapy or radiotherapy, leading to great enthusiasm regarding their ultimate contribution to lung cancer therapy.  However, serious clinical challenges persist.  These include the identification of the optimal dose(s); the proper integration of these agents into popular, established cytotoxic regimens; and the selection of the optimal setting(s) in which to test these compounds.  

Hanna et al (2006) examined the effectiveness of cetuximab in patients with recurrent or progressive NSCLC after receiving at least one prior chemotherapy regimen.  This was an open-label, phase II study of patients with EGFR-positive and EGFR-negative advanced NSCLC with Eastern Cooperative Oncology Group performance status 0 to 1.  Patients received cetuximab 400 mg/m2 intravenously (IV) during 120 mins on week 1 followed by weekly doses of cetuximab 250 mg/m2 IV during 60 mins.  A cycle was considered as 4 weeks of treatment and therapy was continued until disease progression or intolerable toxicities.  The primary end point was to evaluate response rate.  Secondary end points included an estimation of time to progression and survival.  Patient and disease characteristics (n = 66) included EGFR-positive status (n = 60); EGFR-negative status (n = 6); number of prior regimens (one, n = 28; two, n = 27; greater than or equal to three, n = 11); male (n = 41); female (n = 25); adenocarcinoma (n = 36); and smoking status (never, n = 13; former, n = 45; current, n = 8).  Grade 3/4 toxicities included acne-like rash (6.1 %), anaphylactic reactions (1.5 %), and diarrhea (1.5 %).  The response rate for all patients (n = 66) was 4.5 % (95 % confidence interval [CI]: 0.9 % to 12.7 %) and the stable disease rate was 30.3 % (95 % CI: 19.6 % to 42.9 %).  The response rate for patients with EGFR-positive tumors (n = 60) was 5 % (95 % CI: 1.0 % to 13.9 %).  The median time to progression for all patients was 2.3 months (95 % CI: 2.1 to 2.6 months) and median survival time was 8.9 months (95 % CI: 6.2 to 12.6 months).  The authors concluded that although the response rate with single-agent cetuximab in this heavily pretreated patient population with advanced NSCLC was only 4.5 %, the disease control rates and overall survival seem comparable to that of pemetrexed, docetaxel, and erlotinib in similar groups of patients.

Azim and Ganti (2006) stated that cytotoxic chemotherapy has helped improve the outcomes in patients with advanced NSCLC) but seemed to have reached a plateau with respect to the benefit obtained.  Also, a large subset of elderly patients and those with a poor performance status cannot tolerate these drugs at recommended doses.  There is a growing need to incorporate newer drugs with different mechanisms of action and better safety profile.  The EGFR and vascular endothelial growth factor (VEGF) have been identified as potential targets and agents acting specifically against these targets have been developed with the hope of improving outcomes.  Although recent data with the small molecule EGFR tyrosine kinase inhibitors have been disappointing, there have been instances of dramatic responses, thus raising questions regarding the ideal patient to whom these drugs should be administered.  Cetuximab, the anti-EGFR antibody has shown promising results.  Bevacizumab, the anti-VEGF antibody was the first drug to demonstrate a survival benefit in first line treatment when added to chemotherapy.

Butts et al (2007) reported on a randomized phase II study to evaluate the efficacy of cetuximab added to first-line gemcitabine/platinum in chemotherapy-naïve patients with advanced NSCLC.  Chemotherapy-naïve patients with recurrent/metastatic NSCLC (stage IV or stage IIIB with malignant pleural effusion) received cisplatin or carboplatin, and gemcitabine plus cetuximab in arm A, or chemotherapy alone, in arm B.  A total of 65 patients were randomly assigned to arm A and 66 to arm B.  The investigators observed partial responses in 18 patients (27.7 %) in arm A and 12 (18.2 %) in arm B.  Median progression-free survival was 5.09 months for arm A and 4.21 months in arm B.  Median overall survival was 11.99 months and 9.26 months in arms A and B, respectively.  The investigators noted that overall toxicity was acceptable and consistent with the profiles of the individual agents.  The investigators concluded that first-line treatment with cetuximab plus gemcitabine/platinum is well-tolerated and can be administered safely in patients with advanced NSCLC.  The investigators stated that differences in response rate, progression-free survival, and overall survival suggest that the addition of cetuximab to platinum/gemcitabine may improve clinical outcomes.

Rosell et al (2008) reported on the Lung Cancer Cetuximab Study, an open-label, randomized phase II pilot study of cisplatin and vinorelbine combined with cetuximab versus cisplatin and vinorelbine alone, in 83 patients with advanced EGFR-positive NSCLC.  Following randomization, for a maximum of eight cycles, patients received 3-weekly cycles of cisplatin and vinorelbine alone or following cetuximab treatment.  The investigators reported that response rates were 28 % in the cisplatin/vinorelbine arm (A) and 35 % in the cetuximab plus cisplatin/vinorelbine arm (B).  Median PFS was 4.6 months in arm A and 5.0 months in arm B, with PFS rates at 12 months of 0 % and 15 %, respectively.  Median survival was 7.3 months in arm A and 8.3 months in arm B.  The 24-month survival rates were 0 % and 16 %, respectively.  The investigators reported that the cetuximab combination was well-tolerated.  The investigators concluded that, in the first-line treatment of advanced NSCLC, the combination of cetuximab plus cisplatin/vinorelbine demonstrated an acceptable safety profile and the potential to improve activity over cisplatin/vinorelbine alone.

In a 3-arm, randomized, phase II clinical trial, Hanna et al (2015) examined the effects of carboplatin and paclitaxel in combination with cetuximab, cixutumumab, or both for advanced NSCLC patients who will not receive bevacizumab-based therapy.  Patients with chemotherapy-naive, advanced NSCLC who had an ECOG performance status of 0 or 1 were eligible.  Patients were randomized to receive carboplatin intravenously at an area under the plasma drug concentration-time curve of 6.0 plus paclitaxel 200 mg/m2 intravenously on day 1 every 3 weeks combined with either intravenous cetuximab weekly (arm A), intravenous cixutumumab every 2 weeks (arm B), or both (arm C).  Patients who had non-progressing disease after 12 weeks of therapy were permitted to continue on maintenance antibody therapy until they developed progressive disease.  The primary end-point was PFS.  The study design required 180 eligible patients and had 88 % power to detect a 60 % increase in median PFS for either comparison (arm A versus arm C or arm B versus arm C) using the log-rank test.  From September 2009 to December 2010, a total of 140 patients were accrued.  The study was closed to accrual early because of an excessive number of grade 5 AEs reported on arms A and C; 13 patients died during treatment (6 patients on arm A, 2 patients on arm B, and 5 patients on arm C), including 9 within approximately 1 month of starting therapy.  The estimated median PFS for arms A, B, and C were similar at 3.4 months, 4.2 months, and 4 months, respectively.  The authors concluded that on the basis of the apparent lack of efficacy and excessive premature deaths, the current results do not support the continued investigation of carboplatin, paclitaxel, and cixutumumab either alone or in combination with cetuximab for patients with advanced NSCLC.

In a single-arm phase II trial in NSCLC combining cetuximab with carboplatin and paclitaxel, 31 patients had EGFR IHC performed; 4 patients who tested negative for EGFR IHC had a worse survival than those who tested positive for EGFR IHC (median OS 6 versus 14 months) (Borghaei et al, 2008).  Also, in the pivotal phase III FLEX trial (Pirker et al, 2009; O'Byrne et al, 2009), patients were required to express EGFR IHC in at least 1 tumor cell, whereas in another pivotal phase III trial (BMS-099) (Lynch et al, 2008), there was no biomarker requirement for enrollment.  This is one suggested theory as to why the FLEX trial was statistically significant for a survival benefit and the BMS-099 trial was negative.  However, a retrospective analysis of the BMS-099 trial found that neither KRAS or EGFR mutations were predictive of response to treatment with cetuximab.

EGFR FISH analysis was evaluated in the SWOG 0342 trial, a phase II trial comparing concurrent cetuximab with chemotherapy versus sequential treatment (Hirsch et al, 2008).  Although there was no difference in clinical efficacy between the SWOG 0342 concurrent and sequential arms, the biomarker analyses suggested that EGFR FISH positive or gene amplification may have predictive value for cetuximab treatment, as patients with higher gene copy numbers had better survival outcomes.  Patients scored as 1 to 4 or low FISH (n = 18) had a median PFS of 3 months, whereas those patients with a score of 5 to 6 or high FISH (n = 26) had a median PFS of 6 months.

The National Comprehensive Cancer Network (NCCN) Drugs & Biologics Compendium (2018) states that cetuximab may be considered in combination with afatinib as subsequent therapy for recurrent, advanced or metastatic disease in patients with a known sensitizing EGFR mutation in non-small cell lung cancer (adenocarcinoma, large cell carcinoma, squamous cell carcinoma) (Category 2A-2B recommendation). See appendix for selection criteria.

Pancreatic Adenocarcinoma

Cetuximab has been shown in a phase III study to lack efficacy in the treatment of pancreatic adenocarcinoma.  Philip et al (2007) tested the efficacy of cetuximab and gemcitabine combination in the phase III setting in 735 patients with locally advanced unresectable or metastatic pancreatic cancer.  Patients were stratified by performance status, stage and prior pancreatectomy, and randomized to either gemcitabine alone or gemcitibine plus cetuximab.  The median survival was 6 months in the gemcitabine arm and 6.5 months in the gemcitabine plus cetuximab arm for an overall hazard ratio of 1.09 (95 % CI: 0.93 to 1.27, p= 0.14).  The corresponding progression free survival (the primary study endpoint) was 3 months and 3.5 months, for gemcitabine and gemcitabine plus cetuximab arms, respectively (hazard ratio = 1.13, 95 % CI: 0.97 to 1.3, p = 0.058).  The confirmed response probabilities were 7 % in each arm, and inclusion of unconfirmed responses yielded 14 % in the gemcitabine arm and 12 % in the gemcitabine plus cetuximab arm.  The investigators reported that 90 patients experienced at least one grade 4 toxicity; 14 % on the gemcitabine plus cetuximab, 11 % on gemcitabine alone.  The investigators concluded that the study failed to demonstrate a clinically significant advantage of the addition of cetuximab to gemcitabine for overall survival, progression free survival and response in advanced pancreas cancer.

Thyroid Cancer

Wiseman et al (2007) noted that anaplastic thyroid cancer is an endocrine malignancy. Its rare and rapidly lethal disease course has made it challenging to study.  Little is known regarding the expression by anaplastic tumors of molecular targets for new human anti-cancer agents that have been studied in the pre-clinical or clinical setting.  These investigators  evaluated the expression profile of anaplastic thyroid tumors for molecular targets for treatment.  Of the 94 cases of anaplastic thyroid cancers diagnosed and treated in British Columbia, Canada over a 20-year period (1984 to 2004), 32 cases (34 %) had adequate archival tissue available for evaluation.  A tissue microarray was constructed from these anaplastic thyroid tumors and immuno-histochemistry was utilized to evaluate expression of 31 molecular markers.  The markers evaluated were: EGFR, HER2, HER3, HER4, ER, PR, uPA-R, clusterin, E-cadherin, beta-catenin, AMF-R, c-kit, VEGF, ILK, aurora A, aurora B, aurora C, RET, CA-IX, IGF1-R, p53, MDM2, p21, Bcl-2, cyclin D1, cyclin E, p27, calcitonin, MIB-1, TTF-1, and thyroglobulin.  A single tumor with strong calcitonin expression was identified as a poorly differentiated medullary carcinoma and excluded from the study cohort.  The mean age of the anaplastic cohort was 66 years; 16 patients (51 %) were females, and the median patient survival was 23 weeks.  A wide range in molecular marker expression was observed by the anaplastic thyroid cancer tumors (0 to 100 %).  The therapeutic targets most frequently and most strongly over-expressed by the anaplastic tumors were: beta-catenin (41 %), aurora A (41 %), cyclin E (67 %), cyclin D1 (77 %), and EGFR (84 %).  The authors concluded that anaplastic thyroid tumors exhibit considerable derangement of their cell cycle and multiple signal transduction pathways that leads to uncontrolled cellular proliferation and the development of genomic instability.  This report was the first to comprehensively evaluate a panel of molecular targets for therapy of anaplastic thyroid cancer and supported the development of clinical trials with agents such as cetuximab, small-molecule tyrosine kinase inhibitors, and aurora kinase inhibitors, which may offer new hope for individuals diagnosed with this fatal thyroid malignancy.

Hepatocellular Carcinoma

Zhu et al (2007) performed a phase 2 study with cetuximab in patients with advanced hepato-cellular carcinoma (HCC).  Eligibility criteria included unresectable or metastatic measurable HCC, an Eastern Cooperative Oncology Group performance status les than or equal to 2, Cancer of the Liver Italian Program (CLIP) score less than or equal to 3, and adequate organ functions.  The initial dose of cetuximab was 400 mg/m(2) given intravenously followed by weekly intravenous infusions at 250 mg/m(2).  Each cycle was defined as 6 consecutive weekly treatments.  Expression of EGFR was assayed by immuno-histochemistry and trough serum concentrations of cetuximab were determined during the first cycle.  A total of 30 patients were enrolled and assessable for efficacy and toxicity.  No responses were seen; 5 patients had stable disease (median time of 4.2 months; range of 2.8 to 4.2 months).  The median overall survival (OS) was 9.6 months (95 % CI: 4.3 to 12.1 months) and the median PFS was 1.4 months (95 % CI: 1.2 to 2.6 months).  The treatment was generally well-tolerated.  No treatment-related grade 4 to 5 toxicities occurred.  Grade 3 (according to the National Cancer Institute's Common Terminology Criteria for Adverse Events [version 3.0]) aspartate aminotransferase, hypo-magnesemia, and fever without neutropenia were noted in 1 patient (3.3 %) each.  On week 6 of cycle 1, arithmetic mean serum cetuximab concentrations for patients with Child-Turcotte-Pugh (CTP) A and CTP B disease were 47.6 mcg/ml and 66.9 mcg/ml, respectively.  The authors concluded that although cetuximab could be safely administered with tolerable toxicity profiles, it demonstrated no anti-tumor activity in HCC in this phase 2 study.  Cetuximab trough concentrations were not notably altered in patients with mild-to-moderate hepatic dysfunction.

Asnacios and associates (2008) conducted a phase 2 trial of cetuximab in combination with the gemcitabine plus oxaliplatin (GEMOX) regimen in patients with documented progressive HCC.  A total of 45 untreated patients with advanced-stage progressive HCC were prospectively enrolled.  Treatment consisted of cetuximab at a dose of 400 mg/m2 initially then 250 mg/m2 weekly, plus gemcitabine at a dose of 1000 mg/m2 on day 1 and oxaliplatin at a dose of 100 mg/m2 on day 2, every 2 weeks.  Treatment was continued until disease progression, unacceptable toxicity, or patient refusal.  Overall, 306 cycles were administered.  Grade 3 to 4 hematologic toxicity consisted of thrombocytopenia (24 %), neutropenia (20 %), and anemia (4 %).  Grade 3 oxaliplatin-induced neurotoxicity occurred in 5 patients (11 %) and grade 3 cutaneous toxicity in 7 patients (16 %).  There were no treatment-related deaths.  The confirmed response rate was 20 % and disease stabilization was obtained in 40 % of patients.  The median PFS and OS times were 4.7 months and 9.5 months, respectively.  The 1-year survival rate was 40 %.  The authors concluded that in poor-prognosis patients with progressive advanced-stage HCC, the GEMOX-cetuximab combination appears to be active and to have manageable toxicity. A comparative randomized trial is now being planned.

Anal Cancer (Squamous Cell and Adenocarcinoma)

Czito and Willett (2009) stated that squamous cell carcinoma of the anal canal has been treated with abdomino-perineal resection, resulting in high rates of morbidity and local recurrence.  Pioneering work led to the finding that radiation therapy (RT) combined with 5-FU and mitomycin results in high rates of local control as well as disease-free and colostomy-free survival without surgery.  Prospective, randomized trials from Europe and the United States have shown the superiority of RT, 5-FU, and mitomycin over
  1. RT alone,
  2. RT with 5-FU, and
  3. neoadjuvant cisplatin/5-FU with concurrent radiation, cisplatin, and 5-FU. 

At present, RT with 5-FU and mitomycin is the standard of care for anal cancer patients.  Recent advances include the integration of positron emission tomography into staging, radiation treatment planning and monitoring, and the use of intensity modulated RT.  European randomized trials are further evaluating the role of cisplatin in the neoadjuvant, concurrent, and adjuvant settings, as well as radiation dose escalation.  Other studies are evaluating the use of capecitabine, oxaliplatin, and cetuximab with RT in this malignancy.

An UpToDate review on "Clinical features, staging, and treatment of anal cancer" (Ryan and Willett, 2018) state that the management of adenocarcinomas arising in the anal canal should follow the same principles as those applied to the treatment of rectal cancer.

The National Comprehensive Cancer Network (NCCN) Drugs and Biologics Compendium (2018) does not list anal squamous cell cancer as an indication for cetuximab.

The NCCN Guidelines (v.2.2018) for "Anal carcinoma" states that cetuximab's anti-tumor activity is dependent on the presence of wild-type KRAS, and that "because KRAS mutations appear to be very rare in anal cancer, the use of an EGFR inhibor such as cetuximab has been considered to be a promising avenue of investigation."; however, for treatment of anal adenocarcinoma, NCCN recommends following the guidelines for rectal cancer.

Bladder Cancer

Agarwal and Hussain (2009) stated that cancer of the urinary bladder is the 5th most prevalent solid tumor in the United States.  Urothelial carcinoma is the most common form of bladder cancer, accounting for about 90 % of cases.  About 25 % of patients with bladder cancer have advanced disease (muscle-invasive or metastatic disease) at presentation and are candidates for systemic chemotherapy.  Urothelial carcinoma is a chemo-sensitive disease, with a high overall and complete response rate to combinational chemotherapy.  In the setting of muscle-invasive urothelial carcinoma, use of neoadjuvant chemotherapy is associated with overall survival benefit.  The role of adjuvant chemotherapy in this setting is yet to be validated.  In the setting of metastatic disease, use of cisplatin-based regimens improves survival.  However, despite initial high response rates, the responses are typically not durable leading to recurrence and death in the vast majority of these patients.  Currently, there is no standard second-line therapy for patients in whom first-line chemotherapy for metastatic disease has failed.  Many newer chemotherapeutic agents have shown modest activity in urothelial carcinoma.  Improved understanding of molecular biology and pathogenesis of urothelial carcinoma has opened avenues for the use of molecularly targeted therapies, several of which are being tested in clinical trials.  Currently, several novel drugs seem particularly promising including inhibitors of the EGFR pathway, such as cetuximab, and inhibitors of tumor angiogenesis, such as bevacizumab and sunitinib.  Development of reliable molecular predictive markers is expected to improve treatment decisions, therapy development and outcomes in urothelial carcinoma.  Funding of and participation in clinical trials are key to advancing the care of urothelial cancer patients.

Chordoma

Guidelines on bone cancer from the NCCN (2012) no longer indicate the use of cetuximab for the treatment of chordoma.  Previously, cetuximab in combination with erlotinib for chordoma received an NCCN Category 2B recommendation ("based on lower level evidence and there is nonuniform NCCN consensus (but no major disagreement)").

Menetrier's Disease

Fiske et al (2009) stated that Menetrier's disease is a rare pre-malignant disorder of the stomach with no proven effective medical therapy.  Increased EGFR signaling has been implicated in the pathogenesis of Menetrier's disease.  These investigators conducted a single-arm clinical trial with cetuximab in 9 patients (aged 29 to 79 years) with clinically and histologically documented severe Menetrier's disease that impaired quality of life to the extent that gastrectomy was being considered.  Patients were treated with a loading dose of intravenous cetuximab (400 mg/m2 of body surface area), followed by 3 weekly intravenous infusions of 250 mg/m2.  Of the 7 patients who completed the 1-month course of treatment, all showed statistically significant improvement both clinically (quality-of-life indices) and biochemically (increased parietal cell mass and gastric acidity).  Furthermore, all 7 patients who completed the 1-month trial elected to continue treatment (follow-up of 8 to 40 months), and 4 subsequently showed near-complete histological remission.  The authors concluded that cetuximab should be considered as first-line therapy for Menetrier's disease.

An UpToDate review on "Large gastric folds: Hyperplastic and nonhyperplastic gastropathies" (Feldman and Jensen, 2018) state that Menetrier's disease is a rare acquired condition of the stomach that is characterized by giant mucosal fold in the gastric fundus and body, diminished acid secretory capactiy, and a protein losing state with hypoabluminemia. The pathogenesis is thought to be due to increased signaling of the epidermal growth factor (EGFR) which results in proliferation of epithelial cells of the mucous cell compartment. Treatment option includes cetuximab; however, controlled trials are lacking. "In small case series, cetuximab was found to be successful in treating patients with disease-related refractory symptoms. In another uncontrolled study, cetuximab was used to treat nine patients with Ménétrier's disease. Of the seven patients treated, four had almost complete reversal of foveolar hyperplasia; however, four of the seven required total gastrectomy. All seven patients demonstrated statistically significant improvement in quality-of-life indices as well as in biochemical measures (gastric acidity). The FDA has allowed cetuximab to be used on a compassionate need basis in some patients with Ménétrier's disease."

Gliomas

In a phase II study, Neyns et al (2009) evaluated the anti-tumor activity and toxicity of single-agent cetuximab in patients with recurrent high-grade glioma (HGG) after failure of surgery, radiation therapy, and chemotherapy.  In this 2-arm, open-label study patients were stratified according to their EGFR gene amplification status.  Cetuximab was administered intravenously at a dose of 400 mg/m(2) on week 1 followed by weekly dose of 250 mg/m(2).  The primary end point for this study was the response rate in both study arms separately.  A total of 55 eligible patients (28 with and 27 without EGFR amplification) tolerated cetuximab well.  Three patients (5.5 %) had a partial response and 16 patients (29.6 %) had stable disease.  The median time to progression was 1.9 months [95 % CI: 1.6 to 2.2 months].  Whereas the PFS was less than 6 months in the majority (n = 50/55) of patients, 5 patients (9.2 %) had a PFS on cetuximab of greater than 9 months.  Median OS was 5.0 months (95 % CI: 4.2 to 5.9 months).  No significant correlation was found between response, survival and EGFR amplification.  The authors concluded that cetuximab was well-tolerated but had limited activity in this patient population with progressive HGG.  A minority of patients may derive a more durable benefit but were not prospectively identified by EGFR gene copy number.

Loew et al (2009) stated that the EGFR is dysregulated in various tumor types such as glioblastoma multiforme (GBM), breast cancer, ovarian carcinoma, non-small cell lung cancer and other cancers.  As the intracellular tyrosine kinase of the EGFR activates signaling cascades leading to cell proliferation, angiogenesis and inhibition of apoptosis, the EGFR represents an attractive target in cancer therapy.  In GBM which is the most common primary central nervous system tumor in adults, the EGFR is over-expressed in about 40 to 50 % of cases, and almost half of these co-express the mutant receptor subtype EGFRvIII.  This EGFR variant is constitutively activated, and thereby may contribute to the aggressive and refractory course of GBM which is associated with a median survival of only 40 to 60 weeks from diagnosis.  Various trials are ongoing focusing on EGFR and EGFRvIII as new therapeutic targets in GBM.  Anti-EGFR monoclonal antibodies (MAbs), e.g., cetuximab, and tyrosine kinase inhibitors (TKIs), e.g., erlotinib and gefitinib, are the most advanced in clinical development.  Several trials are investigating MAbs or TKIs in combination with other agents such as inhibitors of the mammalian target of rapamycin.  Other still preliminary approaches targeting the EGFR are small interfering RNA, antisense RNA and ribozymes, which lead to degradation of EGFR mRNA.  The authors concluded that further studies are needed to define their clinical potential, to identify biological predictors of response and thus to characterize subgroups of patients who will benefit from treatment with these new agents.

In a phase II study, Hasselbalch et al (2010) examined the safety and effectiveness when combining cetuximab with bevacizumab and irinotecan in patients with recurrent primary GBM.  Patients were included with recurrent primary GBM and progression within 6 months of ending standard treatment (radiotherapy and temozolomide).  Bevacizumab and irinotecan were administered IV every 2 weeks.  The first 10 patients received bevacizumab 5 mg/kg, but this was increased to 10 mg/kg after interim safety analysis.  Irinotecan dose was based on whether patients were taking enzyme-inducing anti-epileptic drugs or not: 340 and 125 mg/m(2), respectively.  Cetuximab 400 mg/m(2) as loading dose followed by 250 mg/m(2) weekly was administered IV.  Forty-three patients were enrolled in the trial, of which 32 were available for response.  Radiographical responses were noted in 34 %, of which 2 patients had complete responses and 9 patients had partial responses.  The 6-month PFS probability was 30 % and median OS was 29 weeks (95 % CI: 23 to 37 weeks).  One patient had lacunar infarction, 1 patient had multiple pulmonary embolisms, and 3 patients had grade 3 skin toxicity, for which 1 patient needed plastic surgery.  One patient was excluded due to suspicion of interstitial lung disease.  Three patients had deep-vein thrombosis; all continued on study after adequate treatment.  Cetuximab in combination with bevacizumab and irinotecan in recurrent GBM is well-tolerated except for skin toxicity, with an encouraging response rate.  However, the efficacy data do not seem to be superior compared with results with bevacizumab and irinotecan alone.

Bronchioloalveolar Carcinoma

In an Eastern Cooperative Oncology Group (ECOG) phase II study, Ramalingam et al (2011) evaluated cetuximab for the treatment of advanced bronchiolo-alveolar carcinoma (BAC).  Patients with advanced-stage pure BAC or adenocarcinoma with BAC features, fewer than 2 prior chemotherapy regimens, and ECOG performance status of 0 to 2 were eligible.  Those with prior EGFR inhibitor therapy were excluded.  Cetuximab was given as a weekly intravenous infusion at 250 mg/m(2) after an initial loading dose of 400 mg/m(2) in week 1.  The primary end point was determination of response rate.  EGFR and KRAS mutations were evaluated by pyro-sequencing.  A total of 72 patients were enrolled and 68 met eligibility requirements.  Characteristics of patients included median age, 71 years; sex, 57 % females; PS 0 or 1, 88 % of patients; and smoking status, 19 % never-smokers.  Central pathology review confirmed the diagnosis in 45 of 49 available specimens.  Approximately 50 % of patients received more than 2 cycles of therapy (greater than 8 weeks).  Skin rash was the most common toxicity (grade 3, 15 %).  The confirmed response rate was 7 %, and stable disease was observed in 35 %.  The median survival and PFS were 13 and 3.3 months, respectively.  Only 1 of the 6 patients with an EGFR mutation and 1 of the 7 patients with a KRAS mutation had a partial response.  The authors concluded that cetuximab was associated with modest effectiveness in patients with advanced BAC, despite a low response rate.  They noted that EGFR and KRAS mutations were not predictive of response to cetuximab.

Squamous Cell Carcinoma of Skin

The NCCN's Drugs and Biologics Compendium (2018) lists treatment of squamous cell skin cancer with inoperable positive regional lymph nodes, regional recurrence or distant metastases as one of the indications of cetuximab. See Appendix for selection criteria.

Jalili and colleagues (2008) stated that cutaneous squamous cell carcinoma (SCC) is one of the most common cancers worldwide.  Epidermal growth factor receptor is expressed at the cell surface by more than 90 % of SCCs and its activation is responsible for cell cycle progression, proliferation, survival, angiogenesis and metastasis.  Cyclooxygenase-2 (COX-2) is an enzyme up-regulated through EGFR signaling and responsible for some of the EGFR-dependent biological effects.  These researchers presented the case of an 88-year old man with a recurrent, locoregionally meta-static SCC of the right parietal region, which was resistant to radiotherapy.  With a combination therapy of cetuximab and celecoxib, the tumor regressed partially and the patient's Karnofsky index improved.  These investigators speculated that the combined use of cetuximab and COX-2 inhibitors can be a new and effective therapy for advanced and recurrent cutaneous SCCs.

Maubec et al (2011) evaluated the safety and effectiveness of cetuximab as a first-line monotherapy in patients with unresectable squamous cell carcinoma of the skin (SCCS).  A total of 36 patients received cetuximab (initial dose of 400 mg/m(2) followed by subsequent weekly doses of 250 mg/m(2)) for at least 6 weeks with a 48-week follow-up.  The primary end point was the disease control rate (DCR) at 6 weeks (according to Response Evaluation Criteria in Solid Tumors [RECIST] criteria).  Secondary end points included best response rate, OS, PFS, and toxicity assessment.  Association of treatment efficacy with RAS mutations or FcγR genotypes was investigated.  Median age of the study population was 79 years.  Disease control rate at 6 weeks was obtained in 25 of 36 patients (69 %; 95 % CI: 52 % to 84 %) of the intention-to-treat population.  The best responses were 8 partial responses and 2 complete responses.  There were no cetuximab-related deaths.  There were 3 related serious adverse events: 2 grade 4 infusion reactions and 1 grade 3 interstitial pneumopathy.  Grade 1 to 2 acne-like rash occurred in 78 % of patients and was associated with prolonged PFS.  One HRAS mutation was identified.  Combined FcγRIIa-131H/H and/or FcγRIIIa-158V/V polymorphisms were not associated with the clinical outcomes.  The authors concluded that as a first-line treatment in patients with unresectable SCCS, cetuximab achieved 69 % DCR.

Gallbladder Cancer and Cholangiocarcinoma

UpToDate reviews on "Treatment of advanced, unresectable gallbladder cancer" (Mehrotra and Bekaii-Saab, 2018a) and "Adjuvant treatment for localized, resectable gallbladder cancer" (Mehrotra and Bekaii-Saab, 2018b) does not mention the use of cetuximab.  Also, the 2018 NCCN Drugs and Biologics Compendium does not list gall bladder cancer as an indication of cetuximab.

UpToDate reviews on “Treatment of localized cholangiocarcinoma: Adjuvant and neoadjuvant therapy and prognosis" (Angerson and Stuart, 2018) and “Treatment options for locally advanced unersectable but nonmetastatic cholangiocarcinoma" (Anderson et al., 2018) do not mention the use of cetuximab as a therapeutic option. 

An UpToDate review on "Systemic therapy for advanced cholangiocarcinoma" (Stuart, 2018) state that, "phase II trials addressing the efficacy of combined therapy with GEMOX plus either cetuximab or panitumumab have come to differing conclusions, and the role of these agents in advanced biliary tract cancer remains uncertain: In an initial phase II study of 30 patients with previously untreated locally advanced or unresectable biliary tract cancer (27 cholangiocarcinoma, 3 gallbladder cancer), 19 had objective responses to GEMOX plus cetuximab (63 percent, three complete). Nine patients with locally advanced previously unresectable disease had sufficient tumor shrinkage to permit a later potentially curative resection, although long-term outcomes were not reported. Unfortunately, benefit for the addition of cetuximab to GEMOX could not be confirmed in a randomized phase II trial in which 150 patients with advanced cholangiocarcinoma (82 percent), gallbladder cancer, or ampullary cancer were randomly assigned to GEMOX with or without cetuximab (500 mg/m2 every two weeks). Median progression-free survival was modestly (but not significantly) higher with cetuximab (6.1 versus 5.5 months), but median overall survival was shorter (11 versus 12.4 months). Serious adverse events were reported in 51 percent of the cetuximab-treated patients compared with 35 percent of the control group."  Furthermore, according to 2018 NCCN’s Drugs and Biologics Compendium, bile duct cancer/cholangiocarcinoma is not a listed indication of cetuximab (Erbitux).

Prostate Cancer

Cathomas et al (2012) stated that the EGFR is over-expressed in the majority of metastatic castration-resistant prostate cancers (mCRPC) and might represent a valid therapeutic target.  The combination of docetaxel and cetuximab, the monoclonal antibody against EGFR, has not been tested in patients with prostate cancer.  Patients with mCRPC progressing during or within 90 days after at least 12 weeks of docetaxel were included in this phase II clinical trial.  Treatment consisted of docetaxel (75 mg/m(2) every 3 weeks or 35 mg/m(2) on days 1, 8, 15 every 4 weeks) in combination with cetuximab (400 mg/m(2) on day 1 and then 250 mg/m(2) weekly).  The primary endpoint was PFS at 12 weeks defined as the absence of prostate-specific antigen (PSA), radiographic, or clinical progression.  Evaluation of known biomarkers of response and resistance to cetuximab (EGFR, PTEN, amphiregulin, epiregulin) was conducted.  A total of 38 patients were enrolled at 15 Swiss centers.  Median age was 68 years and median PSA was 212 ng/ml.  Progression-free survival at 12 weeks was 34 % [95 % CI: 19 % to 52 %], PFS at 24 weeks was 20 %, and median OS was 13.3 months (95 % CI: 7.3 to 15.4).  Seven patients (20 %) had a confirmed greater than or equal to 50 % and 11 patients (31%) a confirmed greater than or equal to 30 % PSA decline.  About 47 % of enrolled patients experienced grade 3 and 8 % grade 4 toxicities.  A significantly improved PFS was found in patients with over-expression of EGFR and persistent activity of PTEN.  The authors concluded that EGFR inhibition with cetuximab might improve the outcome of patients with mCRPC.  They stated that a potential correlation between EGFR over-expression, persistent expression of PTEN, and EGFR inhibition should be investigated further. 

UpToDate reviews on "Overview of the treatment of disseminated castration-sensitive prostate cancer" (Dawson, 2018a) and "Overview of the treatment of castration-resistant prostate cancer (CRPC)" (Dawson, 2018b) do not mention the use of cetuximab as a therapeutic option.  Also, the 2014 NCCN’s Drugs and biologics Compendium does not list prostate cancer as a recommended indication of cetuximab.

Penile Cancer

National Comprehensive Cancer Network guidelines on penile cancer (NCCN, 2018) recommends consideration of cetuximab as single agent therapy for subsequent-line systemic therapy for metastatic disease in select patients. See Appendix for selection criteria.

Rescigno et al (2012) stated that guidelines on the treatment of metastatic squamous cell carcinoma of the penis are limited to a few prospective trials.  Cisplatin-based regimens represent the standard of treatment with promising activity of taxanes.  Recently, EGFR over-expression has been shown in these patients.  These researchers treated an elderly man with a docetaxel-cetuximab combination after failure of the cisplatin regimen.  They observed a necrosis of the inguinal lymph nodes and a reduction of (18)F-fluorodeoxyglucose uptake at PET/CT scan.  Only mild mucositis and skin toxicity had been detected.  The authors concluded that this case report, the first in the literature, showed that this combination is active and well-tolerated in penile squamous cell carcinoma.  These preliminary findings need to be validated by well-designed studies.

Brown et al (2014) described 3 cases of advanced refractory penile cancer treated with targeted therapy against the EGFR.  These researchers identified 3 patients with advanced penile cancer who had disease progression after platinum chemotherapy refractory and who subsequently received EGFR-targeted therapy.  Their tumor tissue was evaluated for expression of EGFR by immunohistochemistry and messenger RNA quantitation and was also tested for the presence of human papillomavirus DNA by line hybridization.  K-ras mutation was evaluated by polymerase chain reaction for 6 mutations in codon 12 and 1 mutation in codon 13.  One patient responded to cetuximab and remained disease-free 42 months after presentation.  One patient responded to panitumumab, then suffered relapse.  One other progressed through EGFR-targeted therapy; EGFR expression by immunohistochemistry was 1-2+ in all cases, and messenger RNA expression ranged from 4.08 to 7.33.  No K-ras mutations or human papillomavirus DNA was detected.  The authors reported 3 cases in which EGFR-targeted therapy was used to treat platinum-refractory penile cancer patients.  The authors concluded that because 2 of the 3 had clinical benefit, future prospective trials of EGFR-targeted therapy in penile cancer are warranted.

Carthon et al (2014) evaluated the safety and effectiveness of EGFR-targeted therapy in patients with advanced penile or scrotal cancer.  These investigators retrospectively reviewed the charts of patients with penile or scrotal squamous cell carcinoma who had visited their tertiary cancer center between 2002 and 2009, including their subsequent treatment and follow-up.  These researchers collected details of EGFR-targeted therapy and clinical outcomes.  Treatment-associated time-to-disease-progression (TTP), OS, responses to therapy and toxicity were evaluated.  A total of 24 patients had received EGFR-targeted therapies, including cetuximab, erlotinib and gefitinib.  The most common treatment given (to 67 % of patients) was cetuximab combined with 1 or more cytotoxic drugs.  The most common adverse effect was skin rash (71 %). The median (range) TTP and OS were 11.3 (1 to 40) and 29.6 (2 to 205) weeks, respectively.  The OS time for patients with visceral or bone metastases was significantly shorter than it was for those without (24.7 versus 49.9 weeks, p = 0.013).  Among 17 patients treated with cetuximab alone or in combination with cisplatin, there were 4 partial responses (23.5 %) including 2 patients with apparently chemotherapy-resistant tumors.  The authors concluded the findings of this study suggested that cetuximab has anti-tumor activity in metastatic penile cancer, and may enhance the effect of cisplatin-based chemotherapy.  Moreover, they stated that prospective studies of EGFR-targeted therapies in men with these tumors are needed.

Esophageal Cancer

Tian et al (2015) stated that esophageal cancer is one cause of the most common cancer death and diagnosed in approximately half a million people annually worldwide, as well as has resulted in worse status, which is responsible for an estimated 482,300 new cases and 406,800 deaths in 2008, and is the 5th highest in the mortality rate among tumor sites.  Esophageal cancer mainly occurred in southern and eastern Africa, eastern Asia and some areas of China.  The results of meta-analysis suggested that survival rate can be improved [relative risk (RR) 1.6; 95 % CI: 1.17 to 2.18]; objective response rate (ORR) (RR 1.47; 95 % CI: 1.05 to 2.06) and disease control rate (RR 1.21; 95 % CI: 1.03 to 1.43) in combination group are superior to that of the control group; however, the higher incidence of acne-like rash was caused (RR 9.03; 95 % CI: 1.64 to 49.63).  Moreover, collated differences in OS rate and PFS remained the most common grade 3/4/5 toxicities, and quality of life after intervention revealed no evidence of a difference between the 2 groups.  The authors concluded that with the present evidence, there is no role for cetuximab combined with standard approaches for esophageal cancer.

Urothelial Carcinoma

In a randomized phase II clinical trial, Hussain and colleagues (2014) examined the effectiveness of gemcitabine/cisplatin (GC) with or without cetuximab (CTX) in patients with advanced urothelial carcinoma (UC). Patients with advanced UC, measurable disease, and adequate organ function were randomized 1:2 to cisplatin (70 mg/m(2) ) on day 1 plus gemcitabine (1,000 mg/m(2) ) on days 1, 8, and 15 (arm A) or GC plus CTX (500 mg/m(2) ) on days 1 and 15 (arm B). The primary end-point was the ORR. The secondary end-points were the response duration, safety, PFS, OS, determination of whether or not CTX sensitized non-responders to GC, and exploratory biomarker analysis. The accrual targets were 27 and 54 patients for the 2 arms, respectively. The ORR was reported by arm with binomial CIs. Kaplan-Meier methods were used for time-to-event end-points. A total of 88 eligible patients were randomized; 87 were toxicity-evaluable, and 85 were response-evaluable. The ORRs were 57.1 % for arm A (95 % CI: 37 % to 76 %) and 61.4 % for arm B (95 % CI: 48 % to 74 %). The median PFS times were 8.5 months for arm A (95 % CI: 5.7 to 10.4 months) and 7.6 months for arm B (95 % CI: 6.1 to 8.7 months). The median OS times were 17.4 months for arm A (95 % CI: 12.8 months to unreached) and 14.3 months for arm B (95 % CI: 11.6 to 22.2 months). The most common grade 3/grade 4 AEs in both arms were myelosuppression and nausea. Thromboembolism, acneiform rash, fatigue, pain, hypersensitivity reactions, elevated transaminases, hyponatremia, and hypomagnesemia were more common in arm B; 3 grade 5 AEs occurred in arm B. The presence of primary disease significantly correlated with thromboembolism. An increased soluble E-cadherin level after cycle 2 correlated with a higher risk of death. The authors concluded that GC plus CTX was feasible but was associated with more AEs and no improvements in outcomes.

Other Tumors

In a phase I clinical trial, Deeken et al (2015) evaluated the safety, DLTs, and MTDs of cetuximab and lapatinib in patients with solid tumors.  Patients received standard weekly cetuximab with escalating lapatinib doses of 750 mg, 1,000 mg, or 1,250 mg daily in 3-week cycles; DLTs were monitored through the end of cycle 2.  Pre-treatment and post-treatment tumor biopsies and germline DNA samples were obtained for correlative studies.  A total of 22 patients were enrolled, and 18 patients each were evaluable for toxicity and response; 59 % of patients had received prior anti-EGFR therapy.  Common toxicities included rash and diarrhea.  No patient experienced a DLT at the highest dose level, and no grade 4 toxicity was observed.  Response included no complete responses, 3 partial responses, 9 patients with stable disease, and 6 patients with disease progression, for an ORR of 17 % and a clinical benefit rate of 67 %.  The clinical benefit rate in patients who had previously received anti-EGFR therapy was 70 %.  The mean treatment duration was 4.7 cycles (range of 1 to 14 cycles).  Decreased expression of EGFR/ErbB2 pathway components after treatment was correlated with response, whereas increased expression in the PI3K, Jak/Stat, and MAPK pathways occurred in non-responders.  The authors concluded that the combination of cetuximab and lapatinib was well-tolerated, had the expected toxicities, and exhibited notable clinical activity, including in patients who had received previous anti-EGFR therapy.  Moreover, they stated that further clinical study of this combination is needed.

Anaplastic Astrocytoma

National Comprehensive Cancer Network’s clinical practice guideline on “Central nervous system cancers” (Version 1.2016) does not list cetuximab as a therapeutic option; NCCN’s Drugs & Biologics Compendium (2018) does not list astrocytoma as a recommended indication of cetuximab.

Furthermore, an UpToDate review on “Initial postoperative therapy for glioblastoma and anaplastic astrocytoma” (Batchelor, 2017) does not mention cetuximab as a therapeutic option.

Salivary Duct Carcinoma

Kawahara and colleagues (2017) noted that salivary duct carcinoma is a highly aggressive disease with a poor prognosis.  Surgical resection is currently the only curative treatment, as there is no effective systemic therapy for this malignancy.  Recently, trastuzumab has been shown to be effective in the treatment of salivary duct carcinoma; similarly, molecularly targeted agents, such as cetuximab, are expected to be useful for salivary duct carcinoma treatment.  These researchers described the case of a 56-year old man diagnosed with salivary duct carcinoma in the left submandibular region, with ipsilateral multiple metastases to the neck lymph nodes.  Radical resection of the tumor and submandibular gland with neck dissection were performed.  One month after radical surgery, computed tomography (CT) scans indicated metastasis in the lower lobe of the left lung.  CT-guided transthoracic fine-needle aspiration biopsy revealed a single metastasis and lung metastasectomy was immediately performed.  The tumor cells of the primary lesion and those of the lung metastasis were immunohistochemically positive for EGFR.  One month later, multiple right lung metastases appeared, and the patient was treated with cisplatin/5-FU chemotherapy plus cetuximab, achieving a complete radiographic response.  However, multiple lung metastases developed during adjuvant weekly cetuximab monotherapy.  Subsequently, treatment with S-1 and weekly cetuximab was initiated, and the multiple lung metastases have been maintained as stable disease for 5 months.  The authors concluded that this was the first report of cetuximab use for the treatment of salivary duct carcinoma.  They noted that although cisplatin/5-FU chemotherapy plus cetuximab was effective in treating the lung metastasis, cetuximab monotherapy was insufficient for controlling tumor growth.  Moreover, they stated that prospective and larger randomized studies with longer follow-up periods are needed to confirm these findings.

Furthermore, an UpToDate review on “Malignant salivary gland tumors: Treatment of recurrent and metastatic disease” (Laurie and Schiff, 2017) states that “Molecularly targeted therapy -- The increasing understanding of the underlying molecular changes in malignant salivary gland tumors has led to the identification of several potential therapeutic targets.  There are few objective responses to these agents in phase II trials, but several demonstrate high rates and long duration of disease stabilization.  However, whether this reflects antitumor activity or the indolent natural history of many malignant salivary gland tumors is unclear, particularly since many trials did not require clear evidence of disease progression prior to enrollment.  The data are too preliminary or demonstrate insufficient evidence of activity to recommend the routine use of any of these agents, with the possible exception of trastuzumab in human epidermal growth factor receptor 2 (HER2)-overexpressing or amplified subtypes … Another method to target the EGFR is with anti-EGFR monoclonal antibodies, such as cetuximab.  No objective responses were observed in 30 patients (23 with adenoid cystic carcinoma), although 12 of the patients with adenoid cystic carcinoma had disease stabilization for a median of 6 months, as did 3 of those with non-adenoid cystic carcinoma histology.  The addition of cetuximab to combination chemotherapy with standard doses of cisplatin and fluorouracil in patients with adenoid cystic carcinoma over-expressing EGFR by immunohistochemistry resulted in objective responses in 5 of 12 patients; however 2 of 12 patients experienced febrile neutropenia, and the added role of cetuximab to cisplatin-based chemotherapy cannot be determined from a single-arm trial”.

Non-Melanoma Skin Cancer

Wollina and colleagues (2017) stated that non-melanoma skin cancer (NMSC) is the most common malignancy in humans.  These investigators discussed the use of cetuximab in NMSC searching PubMed from 2011 to 2017 using the following items: "Non-melanoma skin cancer and cetuximab", "cutaneous squamous cell carcinoma and cetuximab", and "basal cell carcinoma and cetuximab", and "cetuximab and skin toxicity".  Available data were analyzed including case reports.  Current evidence of cetuximab efficacy in NMSC was mainly obtained in cutaneous SCC and to a lesser extend in basal cell carcinoma (BCC).  Response rates varied for neoadjuvant, adjuvant, mono- and combined therapy with cetuximab.  Management of cutaneous toxicities is necessary.  The authors concluded that cetuximab is an option for recurrent or advanced NMSC of the skin.  It appeared to be justified particularly in very high-risk tumors.  Moreover, they stated that there is a need for phase-III clinical trials.

Combination of Cetuximab and Encorafenib for the Treatment of Colorectal Cancer

van Geel and colleagues (2017) performed a phase-Ib, dose-escalation study of encorafenib and cetuximab with or without alpelisib in patients with metastatic BRAF-mutant metastatic colorectal cancer (mCRC).  Patients with refractory BRAF-mutant mCRC were treated with encorafenib plus a cetuximab, with (n = 28) or without (n = 26) a PI3Kα inhibitor (alpelisib).  The primary objective was to determine the MTD or a recommended phase-II dose; DLT were reported in 3 patients receiving dual treatment and 2 patients receiving triple treatment.  The MTD was not reached for either group and the phase-II doses were selected as 200 mg encorafenib (both groups) and 300 mg alpelisib.  Combinations of cetuximab and encorafenib showed promising clinical activity and tolerability in patients with BRAF-mutant mCRC; confirmed overall response rates of 19 % and 18 % were observed and median PFS was 3.7 and 4.2 months for the dual- and triple-therapy groups, respectively.  The authors demonstrated that dual (encorafenib plus cetuximab) and triple (encorafenib plus cetuximab and alpelisib) combination treatments are tolerable and provide promising clinical activity in the difficult-to-treat patient population with BRAF-mutant mCRC.

Combination of Cetuximab and Natural Killer Cells Therapy for the Treatment of Non-Small Cell Lung Cancer

Liang and colleagues (2018) stated that natural killer (NK) cells therapy has the potential to prolong survival in patients with advanced NSCLC.  These researchers conducted a clinical trial to examine the safety and efficacy of cetuximab plus NK cells therapy in patients with advanced NSCLC.  Between June 2015 and August 2016, a total of 54 patients with advanced EGFR-expressing NSCLC were randomly assigned to the cetuximab plus NK cells therapy group (A; n = 27) or cetuximab alone group (B; n = 27).  Patients in group A received 2 courses of NK cells therapy continuously.  Cetuximab was administered intravenously and the weekly maintenance dose was continued until tumor progression.  All AEs were manageable and no significant difference was noted between the 2 groups (p > 0.05).  Levels of CEA, NSE and circulating tumor cells (CTCs) in group A were significantly lower than those before treatment (p < 0.05).  Patients in group A had a significant improvement in immune function and quality of life (QOL) (p < 0.05).  Patients in group A survived longer than those in group B (median PFS: 6 months versus 4.5 months; median OS: 9.5 months versus 7.5 months; p < 0.05).  The authors concluded that the findings of this study showed that combination therapy of cetuximab and NK cell therapy yielded better outcomes in patients with advanced EGFR-overexpressing NSCLC.  This was the first clinical trial to examine the safety and efficacy of a combination of cetuximab and NK cells therapy.  However, this study was not powered to adequately demonstrate its clinical benefit due to the small sample size.  These investigators noted that the encouraging survival results observed suggested that additional long-term follow-up on a larger cohort of patients merits consideration to further define the benefits of this combination therapy and to provide an alternative to chemo-radiotherapy for patients with advanced EGFR-overexpressing NSCLC.

Combination of Cetuximab and Natural Killer Cells Therapy for the Treatment of Liver Metastases of Gastro-Intestinal Carcinoma

In a phase-I clinical trial, Adotevi and associates (2018) examined the safety and efficacy of in-situ delivery of allogeneic NK cells combined with cetuximab in liver metastasis of gastro-intestinal (GI) origin. The conditioning chemotherapy was administrated before the allogeneic NK cells injection via hepatic artery.  Three escalating doses were tested (3.106, 8.106 and 12.106 NK cells/kg) following by a high-dose interleukin-2 (IL-2).  Cetuximab was administered intravenously every week for 7 weeks.  A total of 9 patients with liver metastases of CRC or pancreatic cancers were included, 3 per dose-level.  Hepatic artery injection was successfully performed in all patients with no report of DLT; 2 patients had febrile aplasia requiring a short-term anti-biotherapy.  Grade 3/4 anemia and thrombopenia were also observed related to the chemotherapy.  Objective clinical responses were documented in 3 patients and among them 2 occurred in patients injected with cell products harboring 2 KIR ligand mismatches and 1 in a patient with 1 KIR ligand mismatch.  Immune monitoring revealed that most patients presented an increase but transient of IL-15 and IL-7 cytokines levels 1 week after chemotherapy.  Furthermore, a high expansion of FoxP3+regulatory T cells and PD-1+ T cells was observed in all patients, related to IL-2 administration.  The authors concluded that these findings demonstrated that combining allogeneic NK cells transfer via intra-hepatic artery, cetuximab and a high-dose IL-2 was feasible, well-tolerated and may result in clinical responses.  These preliminary findings need to be validated by well-designed studies.

Appendix

Recommended dosing

Cetuximab is available as Erbitux Intravenous Solution: 2 mg/ml (100 mg and 200mg vials).

Dosing for colorectal cancer: Erbitux (Cetuximab) 400 mg/m2 initial IV loading dose over 120 min, followed by weekly doses of 250 mg/m2 IV over 60 min until disease progression or unacceptable toxicity.

Dosing for head and neck cancer: Erbitux (cetuximab) 400 mg/m2 initial IV loading dose over 120 min, followed by weekly doses of 250 mg/m2 IV over 60 min until disease progression or unacceptable toxicity.

Selection Criteria

The National Comprehensive Cancer Network Drugs and Biologics Compendium (NCCN, 2018) recommends cetuximab for the following indications:

  • Colon Cancer (adenocarcinoma) -
     
    • Therapy for left sided only tumors expressing KRAS/NRAS wild-type gene in combination with FOLFOX (fluorouracil, leucovorin, and oxaliplatin) or FOLFIRI (fluorouracil, leucovorin, and irinotecan) regimen, or as a single agent in persons not appropriate for intensive therapy
       
      • as primary treatment for locally unresectable or medically inoperable disease
      • for unresectable synchronous liver and/or lung metastases that remain unresectable after primary systemic therapy
      • as primary treatment for synchronous abdominal/peritoneal metastases that are nonobstructing, or following local therapy for persons with imminent or existing obstruction
      • for unresectable synchronous metastases of other sites
      • as primary treatment for unresectable metachronous metastases in persons who have not received previous adjuvant FOLFOX or CapeOX within the past 12 months
      • for unresectable metachronous metastases that remain unresectable after primary treatment
         
    • Primary treatment for left-sided only tumors expressing KRAS/NRAS wild-type gene for unresectable synchronous liver and/or lung metastases in combination with
       
      • FOLFOX (fluorouracil, leucovorin, and oxaliplatin) regimen
      • FOLFIRI (fluorouracil, leucovorin, and irinotecan) regimen
         
    • Therapy for left-sided only tumors expressing KRAS/NRAS wild-type gene in combination with FOLFOX (fluorouracil, leucovorin, and oxaliplatin) or FOLFIRI (fluorouracil, leucovorin, and irinotecan) regimen, or as a single agent in persons not appropriate for intensive therapy 
       
      • as adjuvant treatment following synchronized or staged resection for synchronous liver and/or lung metastases that converted from unresectable to resectable disease
      • as adjuvant treatment following resection and/or local therapy for resectable metachronous metastases in persons who have received previous chemotherapy or had growth on neoadjuvant chemotherapy
      • as adjuvant treatment for unresectable metachronous metastases that converted to resectable disease
         
    • Primary treatment for tumors expressing KRAS/NRAS wild-type gene for persons with unresectable metachronous metastases and previous adjuvant FOLFOX (fluorouracil, leucovorin, and oxaliplatin) or CapeOX (capecitabine and oxaliplatin) within the past 12 months
       
      • in combination with irinotecan
      • in combination with irinotecan or with FOLFIRI (fluorouracil, leucovorin, and irinotecan) regimen
         
    • Primary treatment in combination with irinotecan and vemurafenib for unresectable metachronous metastases (BRAF V600E mutation positive) and previous adjuvant FOLFOX (fluorouracil, leucovorin, and oxaliplatin) or CapeOX (capecitabine and oxaliplatin) within the past 12 months
    • Subsequent therapy for tumors expressing KRAS/NRAS wild-type gene for unresectable advanced or metastatic disease not previously treated with cetuximab or panitumumab
       
      • in combination with irinotecan or with FOLFIRI (fluorouracil, leucovorin, and irinotecan) regimen after first progression for disease previously treated with oxaliplatin-based therapy without irinotecan
      • in combination with irinotecan after first progression for disease previously treated with irinotecan-based therapy without oxaliplatin
      • in combination with irinotecan for disease previously treated with FOLFOXIRI (fluorouracil, leucovorin, oxaliplatin, and irinotecan) regimen
      • in combination with irinotecan if previously treated with a fluoropyrimidine without irinotecan or oxaliplatin followed by FOLFOX (fluorouracil, leucovorin, and oxaliplatin) or CapeOX (capecitabine and oxaliplatin) with or without bevacizumab
         
    • Subsequent therapy in combination with irinotecan and vemurafenib for progression of unresectable advanced or metastatic disease (BRAF V600E mutation positive) not previously treated with cetuximab or panitumumab, in persons prevously treated with
       
      • oxaliplatin-based therapy without irinotecan
      • irinotecan-based therapy without oxaliplatin
      • FOLFOXIRI (fluorouracil, leucovorin, oxaliplatin, and irinotecan) regimen
      • a fluoropyrimidine without irinotecan or oxaliplatin followed by FOLFOX (fluorouracil, leucovorin, and oxaliplatin) or CapeOX (capecitabine and oxaliplatin) with or without bevacizumab
         
  • Cancer of the Glottic Larynx
     
    • Primary concurrent chemoradiation as a single agent for
       
      • for T3, N0-3 disease requiring (amenable to) total laryngectomy
      • may be considered for selected T4a patients who decline surgery
         
    • Sequential chemoradiation as a single agent given weekly following partial response at the primary site to induction chemotherapy for
       
      • T3, N0-3 disease requiring (amenable to) total laryngectomy
      • selected T4a patients who decline surgery
         
  • Cancer of the Hypopharynx
     
    • Primary concurrent chemoradiation as a single agent for
       
      • T1, N+
      • T2-3, any N disease requiring (amenable to) pharyngectomy with partial or total laryngectomy
      • T4a, any N disease
         
    • Sequential chemoradiation as a single agent given weekly for T1, N+, for T2-3, any N requiring (amenable to) pharyngectomy with partial or total laryngectomy, or for T4a, any N disease
       
      • following a partial response at the primary site and stable or improved disease in the neck following induction chemotherapy
      • may be considered following a complete response at the primary site and stable or improved disease in the neck following induction chemotherapy
         
  • Cancer of the Lip - Primary concurrent chemoradiation as a single agent for persons with T3-4a, N0 or for any T, N1-3 disease who are candidates for but do not receive surgery
  • Cancer of the Nasopharynx - First-line platinum-based chemotherapy in combination with carboplatin for any T, any N, M1 diesease 
  • Cancer of the Oropharynx
     
    • Primary concurrent chemoradiation as a single agent for p16-negative
       
      • T1-2, N1 disease
      • T3-4a, N0-1 disease
      • any T, N2-3 disease
         
    • Primary concurrent chemoradiation as a single agent for p16 (HPV)-positive
       
      • T2, single node less than or equal to 3 cm disease
      • cT3-4, cN0-1 (single node less than or equal to 3 cm) disease
      • any T, cN1 (single node greater than 3 cm, or 2 or more ipsilateral nodes less than or equal to 6 cm), cN2-3 disease
         
    • Sequential chemoradiation as a single agent given weekly following induction chemotherapy for p16-negative
       
      • T3-4a, N0-1 disease
      • any T, N2-3 disease
         
    • Sequential chemoradiation as a single agent given weekly following induction chemotherapy for p16 (HPV)-positive
       
      • cT3-4, cN0-1 (single node less than or equal to 3 cm) disease
      • any T, cN1 (single node greater than 3 cm, or 2 or more ipsilateral nodes less than or equal to 6 cm), cN2-3 disease
         
  • Cancer of the Supraglottic Larynx
     
    • Primary concurrent chemoradiation as a single agent
       
      • for T3, N0 and most T3, N2-3 disease requiring (amenable to) total laryngectomy
      • for T1-2, N+ and selected T3, N1 disease amenable to larynx-preserving (conservation) surgery
      • may be considered for T4a, N0-3 disease for persons who decline surgery
         
    • Sequential chemoradiation as a single agent given weekly following a partial response at the primary site to induction chemotherapy for
       
      • T3, N0 and most T3, N2-3 disease requiring (amenable to) total laryngectomy
      • T1-2, N+ and selected T3, N1 disease amenable to larynx-preserving (conservation) surgery
      • T4a, N0-3 disease for persons who decline surgery
         
  • Ethmoid Sinus Tumors - (squamous cell carcinoma with mixed subtypes) - Primary concurrent chemoradiation as a single agent for
     
    • newly diagnosed T3-4b disease
    • patients who decline surgery
    • cancer diagnosed after incomplete resection and gross residual disease
       
  • Maxillary Sinus Tumors  - (squamous cell carcinoma with mixed subtypes) - Primary concurrent chemoradiation as a single agent for T4b, any N disease
  • Occult Primary Head and Neck Cancers - Initial definitive treatment as a single agent
     
    • for concurrent chemoradiation for ≥N2 disease
    • given weekly for sequential chemoradiation following induction chemotherapy for N2-3 disease
       
  • Very Advanced and Recurrent/Persistent Head and Neck Cancer
     
    • Primary concurrent chemoradiation for non-nasopharyngeal cancer as a single agent for
       
      • newly diagnosed T4b, any N, M0 disease, unresectable nodal disease with no metastases, or for persons who are unfit for surgery, or unresectable locoregional recurrence without prior radiation therapy (RT) and performance status (PS) 0-2
      • metastatic (M1) disease at initial presentation or recurrent/persistent disease with distant metastases and PS 0-1
      • resectable locoregional recurrence without prior RT
      • unresectable locoregional reccurence or second primary with prior RT
         
    • Sequential chemoradiation as a single agent given weekly following induction chemotherapy in persons with non-nasopharyngeal cancer for
       
      • newly diagnosed T4b, any N, M0 disease, unresectable nodal disease with no metastases, or persons who are unfit for surgery
      • unresectable locoregional recurrence in persons without prior radiation therapy and performance status (PS) 0-1 
      • resectable locoregional recurrence without prior RT
         
    • Systemic therapy as a first-line, second-line, or subsequent therapy option as
       
      • single agent for persons with non-nasopharyngeal cancer with newly diagnosed T4b, any N, M0 disease, unresectable nodal disease with no metastases, unresectable locoregional recurrence without prior radiation therapy (RT), or for persons who are unfit for surgery and performance status (PS) 3
      • single agent (non-nasopharyngeal cancer) in PS 0-2 persons or in combination (PS 0-1) with carboplatin (nasopharyngeal cancer) or cisplatin (non-nasopharyngeal cancer) alone, or in combination with cisplatin or carboplatin and fluorouracil , docetaxel, or paclitaxel (non-nasopharyngeal cancer) for metastatic (M1) disease at initial presentation, recurrent/persistent disease with distant metastases, or unresectable locoregional recurrence or second primary with prior RT
         
  • Non-Small Cell Lung Cancer (NSCLC) - May be considered in combination with afatinib as subsequent therapy for metastatic disease in persons with a known sensitizing EGFR mutation
     
    • who have progressed on EGFR tyrosine kinase inhibitor therapy for asymptomatic disease, symptomatic brain lesions, or isolated symptomatic systemic lesions
    • who are T790M negative, have progressed on EGFR tyrosine kinase inhibitor therapy, and have multiple symptomatic systemic lesions
       
  • Penile Cancer - Consider in select persons as a single agent as subsequent-line systemic chemotherapy for metastatic disease
  • Rectal Cancer (adenocarcinoma) -
     
    • Used for tumors expressing KRAS/NRAS wild-type gene in combination with FOLFOX (fluorouracil, leucovorin, and oxaliplatin) or FOLFIRI (fluorouracil, leucovorin, and irinotecan) regimen, or as a single agent in persons not appropriate for intensive therapy 
       
      • as primary treatment for T3, N any; T1-2, N1-2; T4, N any; or locally unresectable or medically inoperable disease if resection is contraindicated following neoadjuvant therapy
      • for synchronous liver only and/or lung only metastases that are unresectable or medically inoperable and remain unresectable (with no progression of primary tumor) after primary systemic therapy
      • following short-course radiation therapy (RT) or chemo/RT for synchronous liver only and/or lung only metastases that are unresectable or medically inoperable and remain unresectable (with progression of primary tumor) after primary systemic therapy
      • as primary treatment for synchronous abdominal/peritoneal metastases that are nonobstructing, or following local therapy for persons with existing or imminent obstruction
      • as primary treatment for synchronous unresectable metastases of other sites
      • as primary treatment for unresectable metachronous metastases in persons who have not received previous adjuvant FOLFOX or CapeOX within the past 12 months, who have received previous fluorouracil/leucovorin (5-FU/LV) or capecitabine therapy, or who have not received any previous chemotherapy 
      • for unresectable metachronous metastases that remain unresectable after primary treatment
         
    • Primary treatment for synchronous liver only and/or lung only metastases (KRAS/NRAS wild-type gene ony) that are unresectable or medically inoperable in combination with
       
      • FOLFIRI (fluorouracil, leucovorin, and irinotecan) regimen
      • FOLFOX (fluorouracil, leucovorin, and oxaliplatin) regimen
         
    • Therapy for KRAS/NRAS wild-type gene tumors in combination with FOLFOX (fluorouracil, leucovorin, and oxaliplatin) or FOLFIRI (fluorouracil, leucovorin, and irinotecan) regimen, or as a single agent in persons not appropriate for intensive therapy
       
      • as adjuvant treatment (following resection and/or local therapy) for resectable metachronous metastases in persons who have received previous chemotherapy or had growth on neoadjuvant chemotherapy 
      • as adjuvant treatment for unresectable metachronous metastases that converted to resectable disease after primary treatment
         
    • Primary treatment for tumors expressing KRAS/NRAS wild-type gene for persons with unresectable metachronous metastases and previous adjuvant FOLFOX (fluorouracil, leucovorin, and oxaliplatin) or CapeOX (capecitabine and oxaliplatin) within the past 12 months
       
      • in combination with irinotecan 
      • in combination with FOLFIRI (fluorouracil, leucovorin, and irinotecan) regimen
         
    • Primary treatment in combination with irinotecan and vemurafenib for persons with unresectable metachronous metastases (BRAF V600E mutation positive) and previous adjuvant FOLFOX (fluorouracil, leucovorin, and oxaliplatin) or CapeOX (capecitabine and oxaliplatin) within the past 12 months
    • Subsequent therapy for tumors expressing KRAS/NRAS wild-type gene for unresectable advanced or metastatic disease not previously treated with cetuximab or panitumumab
       
      • in combination with irinotecan or with FOLFIRI (fluorouracil, leucovorin, and irinotecan) regimen after first progression for disease previously treated with oxaliplatin-based therapy without irinotecan
      • in combination with irinotecan after first progression for disease previously treated with irinotecan-based therapy without oxaliplatin
      • in combination with irinotecan for disease previously treated with FOLFOXIRI (fluorouracil, leucovorin, oxaliplatin, and irinotecan) regimen
      • in combination with irinotecan if previously treated with a fluoropyrimidine without irinotecan or oxaliplatin followed by FOLFOX (fluorouracil, leucovorin, and oxaliplatin) or CapeOX (capecitabine and oxaliplatin) with or without bevacizumab
         
    • Subsequent therapy in combination with irinotecan and vemurafenib for progression of unresectable advanced or metastatic disease (BRAF V600E mutation positive) not previously treated with cetuximab or panitumumab, in persons previously treated with
       
      • oxaliplatin-based therapy without irinotecan
      • irinotecan-based therapy without oxaliplatin
      • FOLFOXIRI (fluorouracil, leucovorin, oxaliplatin, and irinotecan) regimen
      • a fluoropyrimidine without irinotecan or oxaliplatin followed by FOLFOX (fluorouracil, leucovorin, and oxaliplatin) or CapeOX (capecitabine and oxaliplatin) with or without bevacizumab
         
  • Squamous Cell Skin Cancer - Treatment for inoperabale positive regional lymph nodes, regional recurrence or distant metastases.
     
Table: CPT Codes / HCPCS Codes / ICD-10 Codes
Code Code Description

Information in the [brackets] below has been added for clarification purposes.   Codes requiring a 7th character are represented by "+":

CPT codes covered if selection criteria are met:

81275 KRAS (Kirsten rat sarcoma viral oncogene homolog) (eg, carcinoma) gene analysis; variants in exon 2 (eg, codons 12 and 13)
81276     additional variant(s) (eg, codon 61, codon 146)

CPT codes not covered for indications listed in the CPB:

Natural killer cells therapy - no specific code [not covered in combination with cetuximab]:

Other CPT codes related to the CPB:

88363 Examination and selection of retrieved archival (ie, previously diagnosed) tissue(s) for molecular analysis (eg, KRAS mutational analysis)
96401 - 96450 Chemotherapy administration

HCPCS codes covered if selection criteria are met:

J9055 Injection, cetuximab, 10 mg [not covered when used in combination with other monoclonal antibodies, and for use in persons who have previously been treated with panitumumab (Vectibix)]

HCPCS codes not covered for indications listed in the CPB:

Encorafenib - no specific code [NK Cell not covered in combination with cetuximab]:

Other HCPCS codes related to the CPB:

J0640 Injection, leucovorin calcium, per 50 mg
J8565 Gefitinib, oral, 250 mg
J9035 Injection, bevacizumab, 10 mg
J9190 Injection, fluorouracil, 500 mg [covered in combination with cetuximab]
J9206 Injection, irinotecan, 20 mg
J9263 Injection, oxaliplatin, 0.5 mg
J9303 Injection, panitumumab, 10 mg
Q0083 - Q0085 Chemotherapy administration
Q5107 Injection, bevacizumab-awwb, biosimilar, (mvasi), 10 mg

ICD-10 codes covered if selection criteria are met:

C00.0 - C08.1, C09.0 - C14.8 Malignant neoplasm of lip, oral cavity, and pharynx [covered for squamous cell carcinoma of the head and neck only]
C17.0 - C21.8 Malignant neoplasm of small intestine, colon, rectosigmoid junction, rectum, anus and anal canal [not covered for anal squamous cell carcinoma] [not covered in members with KRAS mutations] [not covered for combination of cetuximab and natural killer cells therapy]
C34.00 - C34.92 Malignant neoplasm of bronchus and lung [non-small cell lung cancer]
C44.02, C44.121 - C44.191, C44.221 - C44.229, C44.320, C44.42, C44.520 - C44.529, C44.621 - C44.629, C44.721 - C44.729, C44.82, C44.90-C44.99 Squamous cell carcinoma of skin of lip, eyelid including canthus, ear and external auditory canal, other and unspecified parts of face, or scalp and skin of neck, other and unspecified malignant neoplasm of skin, unspecified [not covered for non-squamous non-melanoma skin cancer]
C60.0 - C60.9 Malignant neoplasm of penis
C76.0 Malignant neoplasm of head, face and neck [squamous cell]
K29.60 - K29.61 Other gastritis [Menetrier's disease]
Z85.038, Z85.048 Personal history of malignant neoplasm of large intestine, rectum, rectosigmoid junction, and anus [covered for advanced or metastatic adenocarcinoma of the small bowel expressing the wild type KRAS mutation only]

ICD-10 codes not covered for indications listed in the CPB (not all-inclusive):

C08.9 Malignant neoplasm of major salivary gland, unspecified
C15.3 - C15.9 Malignant neoplasm of esophagus [esophageal adenocarcinoma]
C16.0 - C16.9 Malignant neoplasm of stomach [gastric cancer]
C22.0 Liver cell carcinoma [hepatocellular carcinoma]
C22.1 Intrahepatic bile duct carcinoma [cholangiocarcinoma]
C22.4 Other sarcomas of liver [hepatic spindle cell sarcoma]
C23 - C24.0 Malignant neoplasm of gallbladder and extrahepatic duct [including cholangiocarcinoma]
C25.0 - C25.9 Malignant neoplasm of pancreas
C41.0 Malignant neoplasm of bones of skull and face [chordoma]
C41.2 Malignant neoplasm of vertebral column [chordoma]
C41.4 Malignant neoplasm of pelvic bones, sacrum, and coccyx [chordoma]
C44.520 Squamous cell carcinoma of anal skin
C50.011 - C50.929 Malignant neoplasm of breast
C52 Malignant neoplasm of vagina
C61 Malignant neoplasm of prostate
C67.0 - C67.9 Malignant neoplasm of bladder [bladder cancer/urachal carcinoma]
C7A.00 - C7A.098 Malignant carcinoid tumors
C7B.00 - C7B.09 Secondary carcinoid tumors
C71.0 - C71.9 Malignant neoplasm of brain [glioma]
C72.0 Malignant neoplasm of spinal cord [glioma]
C73 Malignant neoplasm of thyroid gland
C74.00 - C74.92 Malignant neoplasm of adrenal gland [pheochromocytoma]
C78.7 Secondary malignant neoplasm of liver and intrahepatic bile duct [not covered in combination cetuximab]
C79.31 Secondary malignant neoplasm of brain [glioma]
C96.4 Sarcoma of dendritic cells (accessory cells) [dendritic cell neoplasms]
C96.6 Unifocal Langerhans-cell histiocytosis [dendritic cell neoplasms]
D02.20 - D02.22 Carcinoma in situ of bronchus and lung [non-small cell lung cancer only]
D33.0 - D33.2, D33.4 Benign neoplasm of brain or spinal cord [glioma]
D3A.00 - D3A.098 Benign carcinoid tumors
D43.0 - D43.2, D43.4 Neoplasm of uncertain behavior of brain or spinal cord [glioma]
D49.6 Neoplasm of unspecified behavior of brain [glioma]

The above policy is based on the following references:

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