Aetna considers cetuximab (Erbitux) medically necessary for the treatment of members with the following diseases:
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 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 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.
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).
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 state 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, OS, 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 objective response rate (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: (i) bevacizumab beyond progression; (ii) single agent capecitabine as a salvage therapy after failure on a fluoropyridimidine-containing regimen; and (iii) 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) state that all patients with metastatic colorectal cancer should have tumor tissue genotyped for RAS mutations (KRAS and NRAS). The guidelines state 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 state 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 is recommended (eg, sequencing, hybridization). The guidelines note 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 are no data to support the use of cetuximab or panitunumab (Vectibix) after failure of the other drug. Colorectal cancer guidelines from the NCCN (2009) state: "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 state 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) cite 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 recommend 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) recommends 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) state that the EGFR inhibitors cetuximab and panitumumab are now 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:
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
Guidelines from the NCCN (2015) no longer indicate cetuximab for non-small cell lung cancer (NSCLC). The guidelines explain that the benefits of the cetuximab/cisplatin/vinorelbine regimen are very slight, it is a difficult regimen to administer, and patients have poorer tolerance for this regimen when compared with other regimens. For example, almost 40 percent of patients have grade 4 neutropenia. Patients may also have comorbid conditions that prevent them from receiving cisplatin such as poor kidney function. The cetuximab/cisplatin/vinorelbine regimen is generally not used in the United States because of concerns about toxicity. Some feel that although the FLEX trial results were statistically significant they were not clinically significant.
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. Per NCCN’s Drugs & Biologics Compendium (2013), cetuximab is indicated for various malignancies/cancers when prior platinum-based therapy has failed.
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 progression-free survival (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 overall survival [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.
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.
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.
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 Squamous Cell Cancer
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 (i) RT alone, (ii) RT with 5-FU, and (iii) 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.
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.
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)").
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.
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.
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 (2011) lists treatment of squamous cell skin cancer with regional recurrence or distant metastases as one of the indications of cetuximab.
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, 2014a) and "Adjuvant treatment for localized, potentially resectable gallbladder cancer" (Mehrotra, 2014b) do not mention the use of cetuximab. Also, the 2014 NCCN Drugs and Biologics Compendium does not list gall bladder cancer as an indication of cetuximab.
UpToDate reviews on “Treatment of localized cholangiocarcinoma: Surgical management and adjuvant therapy” (Anderson and Stuart, 2014a), and “Treatment options for locally advanced cholangiocarcinoma” (Anderson and Stuart, 2014b) do not mention the use of cetuximab as a therapeutic option.
An UpToDate review on “Systemic therapy for advanced cholangiocarcinoma” (Stuart, 2014) states that “GEMOX plus cetuximab -- Two phase II trials have addressed the efficacy of combined therapy with GEMOX plus cetuximab, a monoclonal antibody targeting the epidermal growth factor receptor: In an initial phase II study of 30 patients with previously untreated locally advanced or unresectable biliary tract cancer (27 cholangiocarcinoma, 3 gallbladder), 19 had objective responses (63 %), 3 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 %), gallbladder, or ampullary cancer were randomly assigned to GEMOX with or without cetuximab (500 mg/m2 every 2 weeks). Median PFS 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 % of the cetuximab-treated patients compared to 35 % of the control group”. Furthermore, according to 2014 NCCN’s Drugs and Biologics Compendium, bile duct cancer/cholangiocarcinoma is not a listed indication of cetuximab (Erbitux).
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 prostate cancer” (Dawson, 2014) and “Treatment protocols for castration-resistant prostate cancer” (Brenner et al, 2014) 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.
National Comprehensive Cancer Network guidelines on penile cancer (NCCN, 2015) recommends consideration of cetuximab as single agent therapy for second-line treatment of metastatic disease in select patients.
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.
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.
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.
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.
|CPT Codes / HCPCS Codes / ICD-10 Codes|
|Information in the [brackets] below has been added for clarification purposes.  Codes requiring a 7th character are represented by "+":|
|ICD-10 codes will become effective as of October 1, 2015:|
|CPT codes covered if selection criteria are met:|
|81275||KRAS (v-Ki-ras2 Kirsten rat sarcoma viral oncogene) (eg, carcinoma) gene analysis, variants in codons 12 and 13|
|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)]|
|Other HCPCS codes related to the CPB:|
|J9206||Injection, irinotecan, 20 mg|
|J9303||Injection, panitumumab, 10 mg|
|Q0083 - Q0085||Chemotherapy administration|
|ICD-10 codes covered if selection criteria are met:|
|C00.0 - 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 [covered for advanced or metastatic adenocarcinoma of the small bowel or appendiceal cancer expressing the wild type KRAS and NRAS mutation only] [not covered for anal squamous cell carcinoma]|
|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, C44.92||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|
|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):|
|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|
|C34.00 - C34.92||Malignant neoplasm of bronchus and lung [non-small cell lung cancer]|
|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]|
|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]|
|C7A.00 - C7A.098||Malignant carcinoid tumors|
|C7B.00 - C7B.09||Secondary carcinoid tumors|
|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]|