Panitumumab (Vectibix)
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Latest Research Publications

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Latest Research Publications

Tahara M, Onozawa Y, Fujii H, et al.
Feasibility of cisplatin/5-fluorouracil and panitumumab in Japanese patients with squamous cell carcinoma of the head and neck.
Jpn J Clin Oncol. 2014; 44(7):661-9 [PubMed] Free Access to Full Article Related Publications
OBJECTIVE: In Japan, cisplatin/5-fluorouracil 80/800 (cisplatin 80 mg/m2, 5-fluorouracil 800 mg/m2) is widely used to treat recurrent/metastatic squamous cell carcinoma of the head and neck, whereas cisplatin/5-fluorouracil 100/1000 (1000 mg/m2/24 h by continuous intravenous infusion on Days 1-4 plus cisplatin 100 mg/m2 on Day 1 in 3-week cycles) is the standard treatment in Europe and North America.
METHODS: We prospectively evaluated the feasibility of cisplatin/5-fluorouracil 100/1000 in Japanese patients enrolled in the global Phase 3 study of panitumumab 9 mg/kg combined with cisplatin/5-fluorouracil 100/1000 (Arm 1) versus cisplatin/5-fluorouracil 100/1000 alone (Arm 2).
RESULTS: Twenty Japanese patients were enrolled and received treatment (Arm 1, n=13; Arm 2, n=7). Grade 3/4 adverse events included neutropenia, hypomagnesemia, stomatitis, hyponatremia, paronychia, febrile neutropenia, decreased appetite and hypokalemia. There were no fatal adverse events. Median overall survival was not estimable in Arm 1 and 15.4 months in Arm 2. Median progression-free survival was 6.9 months in Arm 1 and 5.7 months in Arm 2. The median number of infusions (cycles) of cisplatin was 5 in Arm 1 and 4 in Arm 2; the median number of infusions (cycles) of 5-fluorouracil was 6 in both arms. The mean administered dose for cisplatin was 93.6 mg/m2 in Arm 1 and 97.2 mg/m2 in Arm 2, and 3732.6 and 3880 mg/m2 in Arm 1 and Arm 2, respectively, for 5-fluorouracil.
CONCLUSIONS: These results suggested that cisplatin/5-fluorouracil 100/1000 was feasible for recurrent/metastatic squamous cell carcinoma of the head and neck in Japanese patients.

Related: Monoclonal Antibodies Cisplatin Fluorouracil Head and Neck Cancers Head and Neck Cancers - Molecular Biology Panitumumab (Vectibix)


Price TJ, Peeters M, Kim TW, et al.
Panitumumab versus cetuximab in patients with chemotherapy-refractory wild-type KRAS exon 2 metastatic colorectal cancer (ASPECCT): a randomised, multicentre, open-label, non-inferiority phase 3 study.
Lancet Oncol. 2014; 15(6):569-79 [PubMed] Related Publications
BACKGROUND: The anti-EGFR monoclonal antibodies panitumumab and cetuximab are effective in patients with chemotherapy-refractory wild-type KRAS exon 2 metastatic colorectal cancer. We assessed the efficacy and toxicity of panitumumab versus cetuximab in these patients.
METHODS: For this randomised, open-label, phase 3 head-to-head study, we enrolled patients (from centres in North America, South America, Europe, Asia, Africa, and Australia) aged 18 years or older with chemotherapy-refractory metastatic colorectal cancer, an Eastern Cooperative Oncology Group (ECOG) performance status of 2 or less, and wild-type KRAS exon 2 status. Using a computer-generated randomisation sequence, we assigned patients (1:1; stratified by geographical region and ECOG performance status, with a permuted block method) to receive panitumumab (6 mg/kg once every 2 weeks) or cetuximab (initial dose 400 mg/m(2); 250 mg/m(2) once a week thereafter). The primary endpoint was overall survival assessed for non-inferiority (retention of ≥ 50% of the cetuximab treatment effect; historical hazard ratio [HR] for cetuximab plus best supportive care vs best supportive care alone of 0.55). The primary analysis included patients who received one or more dose of panitumumab or cetuximab, analysed per allocated treatment. Recruitment for this trial is closed. The trial is registered with ClinicalTrials.gov, number NCT01001377.
FINDINGS: Between Feb 2, 2010, and July 19, 2012, we enrolled and randomly allocated 1010 patients, 999 of whom began study treatment: 499 received panitumumab and 500 received cetuximab. For the primary analysis of overall survival, panitumumab was non-inferior to cetuximab (Z score -3.19; p=0.0007). Median overall survival was 10.4 months (95% CI 9.4-11.6) with panitumumab and 10.0 months (9.3-11.0) with cetuximab (HR 0.97; 95% CI 0.84-1.11). Panitumumab retained 105.7% (81.9-129.5) of the effect of cetuximab on overall survival seen in this study. The incidence of adverse events of any grade and grade 3-4 was similar across treatment groups. Grade 3-4 skin toxicity occurred in 62 (13%) patients given panitumumab and 48 (10%) patients given cetuximab. The occurrence of grade 3-4 infusion reactions was lower with panitumumab than with cetuximab (one [<0.5%] patient vs nine [2%] patients), and the occurrence of grade 3-4 hypomagnesaemia was higher in the panitumumab group (35 [7%] vs 13 [3%]). We recorded one treatment-related fatal adverse event: a lung infection in a patient given cetuximab.
INTERPRETATION: Our findings show that panitumumab is non-inferior to cetuximab and that these agents provide similar overall survival benefit in this population of patients. Both agents had toxicity profiles that were to be expected. In view of the consistency in efficacy and toxicity seen, small but meaningful differences in the rate of grade 3-4 infusion reactions and differences in dose scheduling can guide physician choice of anti-EGFR treatment.

Related: Monoclonal Antibodies Colorectal (Bowel) Cancer KRAS gene Panitumumab (Vectibix) Cetuximab (Erbitux)


Schwartzberg LS, Rivera F, Karthaus M, et al.
PEAK: a randomized, multicenter phase II study of panitumumab plus modified fluorouracil, leucovorin, and oxaliplatin (mFOLFOX6) or bevacizumab plus mFOLFOX6 in patients with previously untreated, unresectable, wild-type KRAS exon 2 metastatic colorectal cancer.
J Clin Oncol. 2014; 32(21):2240-7 [PubMed] Related Publications
PURPOSE: To evaluate panitumumab plus modified fluorouracil, leucovorin, and oxaliplatin (mFOLFOX6) or bevacizumab plus mFOLFOX6 in patients with previously untreated wild-type (WT) KRAS exon 2 (codons 12 and 13) metastatic colorectal cancer (mCRC). A prespecified secondary objective was to assess treatment effects in an extended RAS analysis that included exons 2, 3, and 4 of KRAS and NRAS.
PATIENTS AND METHODS: Patients with WT KRAS exon 2 tumors were randomly assigned at a one-to-one ratio to panitumumab plus mFOLFOX6 or bevacizumab plus mFOLFOX6. The primary end point was progression-free survival (PFS); secondary end points included overall survival (OS) and safety.
RESULTS: Of 285 randomly assigned patients, 278 received treatment. In the WT KRAS exon 2 intent-to-treat group, PFS was similar between arms (hazard ratio [HR], 0.87; 95% CI, 0.65 to 1.17; P = .353). Median OS was 34.2 and 24.3 months in the panitumumab and bevacizumab arms, respectively (HR, 0.62; 95% CI, 0.44 to 0.89; P = .009). In the WT RAS subgroup (WT exons 2, 3, and 4 of KRAS and NRAS), PFS favored the panitumumab arm (HR, 0.65; 95% CI, 0.44 to 0.96; P = .029). Median OS was 41.3 and 28.9 months (HR, 0.63; 95% CI, 0.39 to 1.02; P = .058) in the panitumumab and bevacizumab arms, respectively. Treatment discontinuation rates because of adverse events were similar between arms.
CONCLUSION: PFS was similar and OS was improved with panitumumab relative to bevacizumab when combined with mFOLFOX6 in patients with WT KRAS exon 2 tumors. Patients with WT RAS tumors seemed to experience more clinical benefit with anti-epidermal growth factor receptor therapy.

Related: Angiogenesis Inhibitors Monoclonal Antibodies Colorectal (Bowel) Cancer Fluorouracil Leucovorin KRAS gene Panitumumab (Vectibix) Bevacizumab (Avastin)


Boku N, Sugihara K, Kitagawa Y, et al.
Panitumumab in Japanese patients with unresectable colorectal cancer: a post-marketing surveillance study of 3085 patients.
Jpn J Clin Oncol. 2014; 44(3):214-23 [PubMed] Free Access to Full Article Related Publications
OBJECTIVE: Panitumumab was approved in Japan in April 2010 for the treatment of Kirsten rat sarcoma-2 virus oncogene wild-type unresectable and recurrent colorectal cancer. We conducted a post-marketing surveillance study to evaluate the safety and effectiveness of panitumumab.
METHODS: After panitumumab was commercially available in Japan, all patients to be treated with panitumumab were enrolled. Data on baseline characteristics, treatment outcome, and incidence and severity of adverse drug reactions were collected.
RESULTS: In total, 3091 patients were registered. In the safety analysis set (n = 3085), panitumumab was administered as monotherapy (40.7%) or combination therapy (59.4%). The median treatment duration was 113 days (range: 1-559 days), and 451 (14.6%) patients received panitumumab for ≥10 months. The overall incidence rate of adverse drug reactions was 84.1%, and the most common adverse drug reaction was skin disorders (78.4%). The incidence rates (all grades) of interstitial lung disease, infusion reaction, electrolyte abnormalities and cardiac disorders were 1.3% (mortality rate: 0.6%), 1.5, 19.3 and 0.2%, respectively. The median survival time of patients treated with panitumumab monotherapy as the third-line, or later, therapy was 10.3 months.
CONCLUSION: This post-marketing survey in clinical practice confirmed the safety and effectiveness of panitumumab. The benefit/risk balance for panitumumab in Japanese patients with unresectable colorectal cancer remains favorable.

Related: Monoclonal Antibodies Colorectal (Bowel) Cancer Panitumumab (Vectibix) Cetuximab (Erbitux)


Abrams TA, Meyer G, Schrag D, et al.
Chemotherapy usage patterns in a US-wide cohort of patients with metastatic colorectal cancer.
J Natl Cancer Inst. 2014; 106(2):djt371 [PubMed] Related Publications
BACKGROUND: Since the introduction of biologic therapies for the treatment of metastatic colorectal cancer (mCRC), few studies have examined patterns of care or predictors of specific treatment approaches.
METHODS: We assessed 4877 mCRC patients who received chemotherapy between January 2004 and March 2011 at academic, private, and community-based oncology practices subscribing to a US-wide chemotherapy order entry (system capturing disease, patient, provider, and treatment data. Multivariable analyses of these prospectively recorded characteristics were used to identify independent predictors of specific therapeutic choices. All statistical tests were two-sided.
RESULTS: Throughout the study period, fluoropyrimidine/oxaliplatin combination was the most commonly used first-line chemotherapy regimen, representing 71% of first-line therapy by 2007. First-line bevacizumab use averaged 51%, peaking at 55% in 2006. Of those who received first-line bevacizumab, 34% continued to receive bevacizumab in the second-line. Only 26% of patients in our cohort ever received an anti-EGFR monoclonal antibody (cetuximab = 22%; panitumumab = 6%) at some point in their treatment course. Patients treated at academic centers, with longer duration of first-line therapy, and at sites in the western United States were statistically more likely to receive an anti-EGFR antibody. Anti-EGFR antibody use fell by 18% after the US Food and Drug Administration limited its use to patients with KRAS wild-type tumors in June 2009.
CONCLUSIONS: Analysis of this US-wide mCRC cohort demonstrates that bevacizumab has been more consistently integrated into treatment regimens than anti-EGFR antibody therapies, particularly in first-line therapy. However, treatment choices vary substantially according to specific patient, practice, and provider characteristics.

Related: Monoclonal Antibodies Colorectal (Bowel) Cancer Fluorouracil USA KRAS gene Panitumumab (Vectibix) Bevacizumab (Avastin) Oxaliplatin Irinotecan EGFR Cetuximab (Erbitux)


Kishiki T, Ohnishi H, Masaki T, et al.
Overexpression of MET is a new predictive marker for anti-EGFR therapy in metastatic colorectal cancer with wild-type KRAS.
Cancer Chemother Pharmacol. 2014; 73(4):749-57 [PubMed] Free Access to Full Article Related Publications
PURPOSE: Since the KRAS mutation is not responsible for all metastatic colorectal cancer (mCRC) patients with resistance to anti-epidermal growth factor receptor (EGFR) monoclonal antibody (MoAb) therapy, new predictive and prognostic factors are actively being sought.
METHODS: We retrospectively evaluated the efficacy of anti-EGFR MoAb-based therapies in 91 patients with mCRC according to KRAS, BRAF, and PIK3CA mutational status as well as PTEN and MET expression.
RESULTS: In the patient group with wild-type KRAS, the presence of BRAF mutation or PIK3CA mutations was associated with lower disease control rate (DCR), shorter progression-free survival (PFS), and shorter overall survival. Patients with MET overexpression also showed lower DCR and shorter PFS when compared with patients with normal MET expression. In a separate analysis, 44 patients harboring wild-type KRAS tumors were sorted into subgroups of 25 patients without abnormality in three molecules (BRAF, PIK3CA and MET) and 19 patients with abnormality in at least one of these three molecules. The former group showed significantly higher DCR and longer PFS following anti-EGFR therapy than the latter group.
CONCLUSIONS: Our data point to the usefulness of MET overexpression, in addition to BRAF and PIK3CA mutations, as a new predictive marker for responsiveness to anti-EGFR MoAbs in mCRC patients with wild-type KRAS. This study also suggests that application of multiple biomarkers is more effective than the use of a single marker in selecting patients who might benefit from anti-EGFR therapy.

Related: Monoclonal Antibodies Colorectal (Bowel) Cancer KRAS gene Panitumumab (Vectibix) Irinotecan EGFR Cetuximab (Erbitux)


Bonetti A, Giuliani J, Muggia F
Targeted agents and oxaliplatin-containing regimens for the treatment of colon cancer.
Anticancer Res. 2014; 34(1):423-34 [PubMed] Related Publications
Oxaliplatin and fluoropyrimidines are synergic combinations very active for the treatment of advanced colorectal cancer and for the adjuvant treatment of stage III colon cancer. Oxaliplatin-based regimens can be further strengthened by the addition of a third component, either a traditional drug such as irinotecan or targeted agents such as anti-vascular endothelial growth factor (VEGF) drugs, bevacizumab and aflibercept, or the anti-epidermal growth factor receptor (EGFR), cetuximab and panitumumab. The availabilty of all these active agents prompted several clinical trials on different lines of treatment of advanced colorectal cancer patients and in the adjuvant setting. Clinical studies involving the administration of anti-EGFR drugs also helped identify mutations in KRAS as a negative marker for the activity of these agents. However, positive selection criteria for targeted agents have not been identified. The results of oxaliplatin-containing regimens are critically presented and discussed in this review.

Related: Monoclonal Antibodies Panitumumab (Vectibix) Bevacizumab (Avastin) Oxaliplatin Cetuximab (Erbitux)


Saridaki Z, Tzardi M, Sfakianaki M, et al.
BRAFV600E mutation analysis in patients with metastatic colorectal cancer (mCRC) in daily clinical practice: correlations with clinical characteristics, and its impact on patients' outcome.
PLoS One. 2013; 8(12):e84604 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: To prospectively evaluate the usefulness of the BRAFV600E mutation detection in daily clinical practice in patients with metastatic Colorectal Cancer (mCRC).
PATIENTS AND METHODS: 504 mCRC patients treated with systemic chemotherapy ± biologics were analyzed.
RESULTS: A statistically significant higher incidence of the BRAF mutation was observed in patients with ECOG-PS 2 (p=0.001), multiple metastatic sites (p=0.002),> 65 years old (p=0.004), primary tumors located in the colon (p<0.001), high-grade tumors (p=0.001) and in those with mucinous features (p=0.037). Patients with BRAFV600E mutated tumors had a statistically significantly reduced progression-free survival (PFS) compared to wild-type (wt) ones (4.1 and 11.6 months, respectively; p<0.001) and overall survival (OS) (14.0 vs. 34.6 months, respectively; p<0.001). In the multivariate analysis the BRAFV600E mutation emerged as an independent factor associated with reduced PFS (HR: 4.1, 95% CI 2.7-6.2; p<0.001) and OS (HR: 5.9, 95% CI 3.7-9.5; p<0.001). Among the 273 patients treated with salvage cetuximab or panitumumab, the BRAFV600E mutation was correlated with reduced PFS (2.2 vs. 6.0 months; p<0.0001) and OS (4.3 vs. 17.4 months; p<0.0001).
CONCLUSIONS: The presence of BRAFV600E-mutation in mCRC characterizes a subgroup of patients with distinct biologic, clinical and pathological features and is associated with very poor patients' prognosis.

Related: BRAF gene KRAS gene


Korb ML, Hartman YE, Kovar J, et al.
Use of monoclonal antibody-IRDye800CW bioconjugates in the resection of breast cancer.
J Surg Res. 2014; 188(1):119-28 [PubMed] Related Publications
BACKGROUND: Complete surgical resection of breast cancer is a powerful determinant of patient outcome, and failure to achieve negative margins results in reoperation in between 30% and 60% of patients. We hypothesize that repurposing Food and Drug Administration-approved antibodies as tumor-targeting diagnostic molecules can function as optical contrast agents to identify the boundaries of malignant tissue intraoperatively.
MATERIALS AND METHODS: The monoclonal antibodies bevacizumab, cetuximab, panitumumab, trastuzumab, and tocilizumab were covalently linked to a near-infrared fluorescence probe (IRDye800CW) and in vitro binding assays were performed to confirm ligand-specific binding. Nude mice bearing human breast cancer flank tumors were intravenously injected with the antibody-IRDye800 bioconjugates and imaged over time. Tumor resections were performed using the SPY and Pearl Impulse systems, and the presence or absence of tumor was confirmed by conventional and fluorescence histology.
RESULTS: Tumor was distinguishable from normal tissue using both SPY and Pearl systems, with both platforms being able to detect tumor as small as 0.5 mg. Serial surgical resections demonstrated that real-time fluorescence can differentiate subclinical segments of disease. Pathologic examination of samples by conventional and optical histology using the Odyssey scanner confirmed that the bioconjugates were specific for tumor cells and allowed accurate differentiation of malignant areas from normal tissue.
CONCLUSIONS: Human breast cancer tumors can be imaged in vivo with multiple optical imaging platforms using near-infrared fluorescently labeled antibodies. These data support additional preclinical investigations for improving the surgical resection of malignancies with the goal of eventual clinical translation.

Related: Breast Cancer


Peeters M, Price TJ, Cervantes A, et al.
Final results from a randomized phase 3 study of FOLFIRI {+/-} panitumumab for second-line treatment of metastatic colorectal cancer.
Ann Oncol. 2014; 25(1):107-16 [PubMed] Related Publications
BACKGROUND: The study 20050181 demonstrated significant improvements in progression-free survival (PFS), objective response, and a nonsignificant trend toward increased overall survival (OS) with panitumumab-FOLFIRI versus FOLFIRI alone for second-line wild-type (WT) KRAS metastatic colorectal cancer (mCRC). Updated long-term data from a prespecified descriptive analysis are reported.
PATIENTS AND METHODS: Patients receiving one prior mCRC treatment were randomly assigned (1:1) to panitumumab (6.0 mg/kg)-FOLFIRI versus FOLFIRI every 2 weeks. Co-primary end points (PFS and OS) were prospectively analyzed by tumor KRAS status.
RESULTS: One thousand one hundred and eighty-six patients were randomly assigned. In patients with WT KRAS tumors, panitumumab-FOLFIRI significantly improved PFS versus FOLFIRI [median 6.7 versus 4.9 months; hazard ratio (HR) 0.82 [95% confidence interval (CI) 0.69, 0.97]; P = 0.023]. A trend toward longer OS was observed (median 14.5 versus 12.5 months; HR 0.92 [95% CI 0.78, 1.10]; P = 0.37). Response rates improved from 10% to 36% (P < 0.0001). From post hoc analyses in patients receiving prior oxaliplatin-bevacizumab, panitumumab-FOLFIRI improved PFS (median 6.4 versus 3.7 months; HR 0.58 [95% CI 0.37, 0.90]; P = 0.014). PFS and OS appeared longer for worst-grade skin toxicity of 2-4, versus 0-1 or FOLFIRI. Safety results were as previously reported and consistent with the known toxicities with anti-epidermal growth factor receptor therapy.
CONCLUSIONS: These data confirm the primary efficacy and safety findings of this trial and support panitumumab-FOLFIRI as a second-line treatment of WT KRAS mCRC.

Related: Monoclonal Antibodies Colorectal (Bowel) Cancer Fluorouracil Leucovorin Panitumumab (Vectibix)


Li X, Shan BE, Wang J, et al.
Incidence and risk of treatment-related mortality with anti-epidermal growth factor receptor monoclonal antibody in cancer patients: a meta-analysis of 21 randomized controlled trials.
PLoS One. 2013; 8(11):e81897 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Anti-epidermal growth factor receptor (EGFR) monoclonal antibodies (MoAbs) cetuximab and panitumumab have emerged as an effective targeted therapy in the treatment of cancer patients, but the overall incidence and risk of fatal adverse events (FAEs) associated with these agents is still unclear.
METHODS: Databases from PubMed, Web of Science and abstracts presented at ASCO meeting up to May 31, 2013 were searched to identify relevant studies. Eligible studies included prospective randomized controlled trials evaluating MoAbs in cancer patients with adequate data on FAEs. Statistical analyses were conducted to calculate the summary incidence, odds ratio and 95% confidence intervals (CIs) by using either random effects or fixed effect models according to the heterogeneity of included studies.
RESULTS: A total of 14,776 patients with a variety of solid tumors from 21 clinical trials were included in our analysis. The overall incidence of MoAbs associated FAEs was 1.7% (95%CI: 1.1-2.5%), and the incidence of cetuximab-related FAEs was higher than that of panitumumab (2.0% versus 0.9%). Compared with the controls, the use of MoAbs was associated with a significantly increased risk of FAEs, with an OR of 1.37 (95%CI: 1.04-1.81, p=0.024). Subgroup analysis based on EGFR-MoAbs drugs, phase of trials and tumor types demonstrated a tendency to increase the risk of FAEs, but the risk did not increase in breast cancer, esophagus cancer and phase II trials.
CONCLUSIONS: With present evidence, the use of EGFR-MoAbs is associated with an increased risk of FAEs in patients with advanced solid tumors.

Related: Monoclonal Antibodies Cancer Prevention and Risk Reduction Panitumumab (Vectibix) Cetuximab (Erbitux)


Krens LL, Baas JM, de Jong FA, et al.
Pharmacokinetics of panitumumab in a patient with liver dysfunction: a case report.
Cancer Chemother Pharmacol. 2014; 73(2):429-33 [PubMed] Related Publications
PURPOSE: Panitumumab is used for the treatment for metastatic RAS wild-type colorectal cancer (mCRC). It is likely that many of these patients will present with liver metastases and some with liver dysfunction. The pharmacokinetics in patients with hepatic impairment has not been investigated, and dosage adjustments are undetermined. Here, we present a case of a patient with progressive mCRC and liver dysfunction.
METHODS: A heavily pretreated KRAS wild-type mCRC patient with liver disease Child-Pugh class B was treated with 2-weekly intravenous panitumumab (6 mg/kg). The patient received 2 doses of 490 mg i.v. panitumumab after which progressive disease was documented. Toxicities were graded using CTCAEv4.0. Serum samples were collected, and panitumumab concentrations were determined using a validated immunoassay. Pharmacokinetic parameters after the first dose, including dose-normalized AUC from time zero-day 14, clearance (CL), and elimination half-life (T1/2), were estimated via trapezoidal noncompartmental methods. Data were compared to historical data from a population with adequate liver function, as reported by Stephenson (Clin Colorectal Cancer, 8:29-37, 2009). Values within the range of the mean ±1 standard deviation (SD) were considered not deviant.
RESULTS: Calculated AUC after the first dose of 6 mg/kg panitumumab in this patient with hepatic dysfunction was 877 μg day/mL (Stephenson's cohort 1: 744 ± 195 μg day/mL). Estimated T1/2 was 3.58 days (5.28 ± 1.90 days), and CL was 6.9 mL/day/kg (8.21 ± 3.79 mL/day/kg). Estimated PK parameters during the first cycle were inside reported mean ±1 SD of historical controls without liver dysfunction. No toxicity was reported during treatment; particularly, no diarrhea and skin toxicity were noticed.
CONCLUSIONS: The pharmacokinetics of panitumumab in this patient suffering from metastatic colorectal cancer with liver dysfunction Child-Pugh class B was similar compared to patients with adequate liver function. Moreover, no substantial toxicity was detected. The here-presented data may help clinical decision making in real-life practice. Two-weekly panitumumab monotherapy seems to be safely applicable in patients with KRAS wild-type mCRC and hepatic dysfunction, without the need for any dose adjustments.

Related: Monoclonal Antibodies Colorectal (Bowel) Cancer Panitumumab (Vectibix)


Brown A, Ma Y, Danenberg K, et al.
Epidermal growth factor receptor-targeted therapy in squamous cell carcinoma of the penis: a report of 3 cases.
Urology. 2014; 83(1):159-65 [PubMed] Related Publications
OBJECTIVE: To describe 3 cases of advanced refractory penile cancer treated with targeted therapy against the epidermal growth factor receptor (EGFR).
MATERIALS AND METHODS: We 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 ribonucleic acid quantitation and was also tested for the presence of human papillomavirus deoxyribonucleic acid by line hybridization. K-ras mutation was evaluated by polymerase chain reaction for 6 mutations in codon 12 and 1 mutation in codon 13.
RESULTS: One patient responded to cetuximab and remains 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 ribonucleic acid expression ranged from 4.08 to 7.33. No K-ras mutations or human papillomavirus deoxyribonucleic acid was detected.
CONCLUSION: We report 3 cases in which EGFR-targeted therapy was used to treat platinum-refractory penile cancer patients. Because 2 of the 3 had clinical benefit, future prospective trials of EGFR-targeted therapy in penile cancer are warranted.

Related: Monoclonal Antibodies Penile (Penis) Cancer Panitumumab (Vectibix) Cetuximab (Erbitux)


Misiukiewicz K, Posner M
The SPECTRUM of findings in treatment options for recurrent/metastatic head and neck cancer.
J Comp Eff Res. 2013; 2(6):533-5 [PubMed] Related Publications
Evaluation of: Vermorken JB, Stohlmacher-Williams J, Davidenko I et al. Cisplatin and fluorouracil with or without panitumumab in patients with recurrent or metastatic squamous-cell carcinoma of the head and neck (SPECTRUM): an open-label Phase 3 randomised trial. Lancet Oncol. 14(8), 697-710 (2013). In recent decades, significant progress has been achieved in the biological understanding of squamous cell carcinoma of the head and neck (SCCHN) and the role of human papillomavirus (HPV) has become more evident. The EGF receptor (EGFR) signaling pathway represents the main target of the new therapeutic agents currently in development and has proven to be efficacious in locally advanced SCCHN. The role of HPV in recurrent and metastatic disease for predicting response to EGFR monoclonal antibodies is still unknown. Today, cetuximab, an anti-EGFR monoclonal antibody, is the only targeted therapy approved for the treatment of SCCHN in patients with recurrent or metastatic disease, in association with platinum-based chemotherapy. The identification of novel tumor targets has stimulated the search for other anti-EGFR agents with a more favorable side-effect profile, such as aspanitumumab, but the SPECTRUM study failed to meet its primary end point, stipulating the need to test these agents in clinical trials with a more appropriate choice of study end point. Overall survival, considered a gold standard, may be difficult to interpret if treatment only takes place in a small subinterval of overall survival, therefore, progression-free survival should be used as a surrogate end point for regulatory approval.

Related: Head and Neck Cancers Head and Neck Cancers - Molecular Biology


Cohen RB
Current challenges and clinical investigations of epidermal growth factor receptor (EGFR)- and ErbB family-targeted agents in the treatment of head and neck squamous cell carcinoma (HNSCC).
Cancer Treat Rev. 2014; 40(4):567-77 [PubMed] Related Publications
Overexpression of the epidermal growth factor receptor (EGFR) is a common characteristic of head and neck squamous cell carcinomas (HNSCC). Cetuximab is a chimeric anti-EGFR monoclonal antibody (mAb) with multiple approved indications in HNSCC, including with radiation therapy (RT) for locoregionally advanced disease, as monotherapy after platinum progression, and with platinum/5-fluorouracil for recurrent or metastatic disease. There remain, however, numerous unanswered questions regarding the optimal use of cetuximab in HNSCC, including patient selection, its mechanisms of action and resistance, the effect of human papillomavirus status on outcomes, its role when combined with induction chemotherapy or adjuvant radiation, and optimal management of skin toxicity and hypersensitivity reactions. In addition, a variety of other anti-EGFR agents (the multitargeted small molecule tyrosine kinase inhibitors [TKIs] lapatinib, dacomitinib, and afatinib and the anti-EGFR mAbs zalutumumab, nimotuzumab, and panitumumab) are currently under investigation in phase II and III clinical trials in different HNSCC therapeutic settings. The anti-EGFR TKI erlotinib is currently in phase III development for oral cancer prevention. Numerous other drugs are in earlier stages of development for HNSCC treatment, including novel anti-EGFR mAbs (MEHD7945A, necitumumab, and RO5083945), small-molecule TKIs (vandetanib, icotinib, and CUDC-101), EGFR antisense, various add-on therapies to radiation and chemotherapy (bevacizumab, interleukin-12, lenalidomide, alisertib, and VTX-2337), and drugs (temsirolimus, everolimus, OSI-906, dasatinib, and PX-866) intended to overcome resistance to anti-EGFR agents. Overall, a wealth of clinical trial data is expected in the coming years, with the potential to modify significantly the approach to anti-EGFR therapy for HNSCC.

Related: Head and Neck Cancers Head and Neck Cancers - Molecular Biology


Cheng YD, Yang H, Chen GQ, Zhang ZC
Molecularly targeted drugs for metastatic colorectal cancer.
Drug Des Devel Ther. 2013; 7:1315-22 [PubMed] Free Access to Full Article Related Publications
The survival rate of patients with metastatic colorectal cancer (mCRC) has significantly improved with applications of molecularly targeted drugs, such as bevacizumab, and led to a substantial improvement in the overall survival rate. These drugs are capable of specifically targeting the inherent abnormal pathways in cancer cells, which are potentially less toxic than traditional nonselective chemotherapeutics. In this review, the recent clinical information about molecularly targeted therapy for mCRC is summarized, with specific focus on several of the US Food and Drug Administration-approved molecularly targeted drugs for the treatment of mCRC in the clinic. Progression-free and overall survival in patients with mCRC was improved greatly by the addition of bevacizumab and/or cetuximab to standard chemotherapy, in either first- or second-line treatment. Aflibercept has been used in combination with folinic acid (leucovorin)-fluorouracil-irinotecan (FOLFIRI) chemotherapy in mCRC patients and among patients with mCRC with wild-type KRAS, the outcomes were significantly improved by panitumumab in combination with folinic acid (leucovorin)-fluorouracil-oxaliplatin (FOLFOX) or FOLFIRI. Because of the new preliminary studies, it has been recommended that regorafenib be used with FOLFOX or FOLFIRI as first- or second-line treatment of mCRC chemotherapy. In summary, an era of new opportunities has been opened for treatment of mCRC and/or other malignancies, resulting from the discovery of new selective targeting drugs.

Related: Colorectal (Bowel) Cancer USA


Selzer E, Kornek G
Targeted drugs in combination with radiotherapy for the treatment of solid tumors: current state and future developments.
Expert Rev Clin Pharmacol. 2013; 6(6):663-76 [PubMed] Related Publications
The continuously rising use of novel drugs, especially of molecules belonging to the group of targeted drugs is now shaping the therapeutic landscape. However, treatment combinations of targeted drugs with radiotherapy are still rare. Only the monoclonal antibody cetuximab (Erbitux®) has been approved for the treatment of locally advanced squamous cell cancer of the head and neck in combination with radiotherapy. Several targeted compounds are in advanced stages of clinical development for combination treatments with radiotherapy, of which substances with either anti-EGFR or anti-angiogenic mechanisms, such as trastuzumab, panitumumab, erlotinib, cilengitide and bevacizumab are the most promising. Aim of this article is to provide, mainly from a radio-oncological point of view, an overview about the current state as well as to give an outlook on the near future of the most advanced targeted combined treatment concepts for solid tumors.

Related: Monoclonal Antibodies Cancer Prevention and Risk Reduction


Ciombor KK, Bekaii-Saab T
Emerging treatments in recurrent and metastatic colorectal cancer.
J Natl Compr Canc Netw. 2013; 11 Suppl 4:S18-27 [PubMed] Related Publications
Metastatic colorectal cancer (mCRC) is a prevalent disease for which many new therapies have been developed over the past decade. Currently, standard of care chemotherapeutic regimens for mCRC include doublet cytotoxic chemotherapy with or without the anti-vascular endothelial growth factor (VEGF) monoclonal antibody bevacizumab, anti-epidermal growth factor receptor (EGFR) monoclonal antibodies such as cetuximab and panitumumab with or without chemotherapy, and single-agent cytotoxic chemotherapy or targeted therapy for patients intolerant of combination regimens. Recent studies have investigated the efficacy of triplet cytotoxic chemotherapeutic regimens, bevacizumab in combination with chemotherapy beyond first-line therapy disease progression, dual anti-VEGF and anti-EGFR antibody therapy, and the more novel agents ziv-aflibercept and regorafenib for treatment of mCRC. Furthermore, molecular profiling of CRC has identified several genetic alterations for which targeted therapies are currently being developed. Optimal drug combinations and treatment sequences have yet to be defined, but an expanding armamentarium of therapies with which to treat CRC offers a promising future.

Related: Angiogenesis Inhibitors Colorectal (Bowel) Cancer


de Mello RA, Marques AM, Araújo A
Epidermal growth factor receptor and metastatic colorectal cancer: insights into target therapies.
World J Gastroenterol. 2013; 19(38):6315-8 [PubMed] Free Access to Full Article Related Publications
Colorectal cancer (CRC) has high incidence and mortality worldwide. In 2012, CRC was the second most prevalent cancer among males (9%) and the third among females (8%). In recent decades, standard chemotherapies protocols combining 5-fluorouracil, leucovorin, irinotecan and oxaliplatin were important for improve survival in this set of patients. Further, biological drugs throughout epidermal growth factor receptor (EGFR) pathways showed interesting results in metastatic disease (mCRC) control when in association to standard chemotherapy regimens. Cetuximab and panitumumab are two cornerstones for mCRC treatment and are both approved in Europe and United States based on previous results phase III trials. This paper will briefly summarize those anti-EGFR therapies framework in mCRC and discusses some issues in this regard.

Related: Signal Transduction EGFR


Raghav KP, Shetty AV, Kazmi SM, et al.
Impact of molecular alterations and targeted therapy in appendiceal adenocarcinomas.
Oncologist. 2013; 18(12):1270-7 [PubMed] Article available free on PMC after 01/12/2014 Related Publications
UNLABELLED: Appendiceal adenocarcinomas (AAs) are rare and this has limited their molecular understanding. The purpose of our study was to characterize the molecular profile of AA and explore the role of targeted therapy against cyclooxygenase-2 (COX-2) and epidermal growth factor receptor (EGFR).
PATIENTS AND METHODS: We performed a retrospective review of 607 patients with AA at a single institution. A total of 149 patients underwent molecular testing for at least one of the following: activating mutations in KRAS, BRAF, cKIT, EGFR, or PI3K; protein expression of c-KIT or COX-2; or microsatellite instability (MSI) status by immunohistochemistry. Kaplan-Meier product limit method and log-rank test were used to estimate overall survival (OS) and to determine associations among OS, COX-2 expression, KRAS mutations, and other characteristics.
RESULTS: Age, grade, stage, signet ring cells, mucinous histology, and completeness of cytoreduction score correlated with survival outcomes. COX-2 expression, KRAS, PI3K, and BRAF mutations were seen in 61%, 55%, 17%, and 4% of patients, respectively. High MSI was seen in 6% of patients. KRAS mutation was strongly associated with well differentiated or moderately differentiated AA (p < .01). COX-2 expression (p = .33) and the presence of KRAS mutation (p = .91) had no impact on OS. The use of celecoxib in patients whose tumors expressed COX-2 (p = .84) and the use of cetuximab or panitumumab in patients with KRAS wild-type tumors (p = .83) also had no impact on OS.
CONCLUSION: In this cohort, we demonstrated that COX-2 expression and KRAS mutations were frequently seen in AA, although neither exhibited any prognostic significance. MSI was infrequent in AA. Targeted therapy against COX-2 and EGFR appeared to provide no clinical benefit. Well and moderately differentiated AA were molecularly distinct from poorly differentiated AA.

Related: Monoclonal Antibodies Appendix Cancers PTGS2 BRAF gene KRAS gene Panitumumab (Vectibix) EGFR Cetuximab (Erbitux)


Sohal DP, Mykulowycz K, Uehara T, et al.
A phase II trial of gemcitabine, irinotecan and panitumumab in advanced cholangiocarcinoma.
Ann Oncol. 2013; 24(12):3061-5 [PubMed] Related Publications
BACKGROUND: Current data suggest that chemotherapy combinations may be superior to single agents in biliary tract cancer. The epidermal growth factor receptor (EGFR) pathway appears to be associated with tumor stage, prognosis and response to therapy. This trial was designed to evaluate the tolerability and efficacy of the combination of panitumumab, a monoclonal anti-EGFR antibody, with gemcitabine and irinotecan.
PATIENTS AND METHODS: Patients with advanced (unresectable or metastatic) cholangiocarcinoma, ECOG PS 0-2, and adequate organ function were treated with panitumumab (9 mg/kg) on day 1, and gemcitabine (1000 mg/m(2)) and irinotecan (100 mg/m(2)) on days 1 and 8 of a 21-day cycle. The primary objective was to evaluate the 5-month progression-free survival (PFS). Secondary objectives included overall response rate (ORR) and overall survival (OS). Mutational analyses of EGFR, KRAS and BRAF were carried out when feasible.
RESULTS: Thirty-five patients received a median of 7 (0-30) cycles. The most common grade 3/4 toxic effects were neutropenia (10 patients, 29%), thrombocytopenia (10 patients, 29%), skin rash (13 patients, 37%) and dehydration (9 patients, 26%). Two patients had CR, 9 had partial response (PR), and 15 had SD for a disease-control rate of 74% (by RECIST) in 28 assessable patients. Two patients went on to have surgical resection. The 5-month PFS was 69%. The median PFS was 9.7 months and the median OS was 12.9 months. In 17 testable samples, no EGFR or BRAF mutations were identified; there were 7 KRAS mutations, with no difference in OS by KRAS status.
CONCLUSIONS: This study showed encouraging efficacy of this regimen with good tolerability. Further study in this area is warranted. Clinical Trials Number: The trial was registered with the National Cancer Institute (www.clinicaltrials.gov identifier NCT00948935).

Related: Monoclonal Antibodies Extra-Hepatic Bile duct cancer (cholangiocarcinoma) KRAS gene Panitumumab (Vectibix) Irinotecan Gemcitabine


Eder J, Simonitsch-Klupp I, Trautinger F
Treatment of unresectable squamous cell carcinoma of the skin with epidermal growth factor receptor antibodies--a case series.
Eur J Dermatol. 2013 Sep-Oct; 23(5):658-62 [PubMed] Related Publications
BACKGROUND: Non-melanoma skin cancer (NMSC), including squamous cell carcinoma (SCC) and basal cell carcinoma (BCC), is the most common malignancy. Unresectable or metatstatic SCC is rare and therapy can be difficult because of advanced age and comorbidities. Targeted therapy with monoclonal antibodies (mAbs) against EGFR is an option in these patients.
OBJECTIVE: The aim of this presentation is to provide additional evidence on the safety of anti-EGFR mAbs in long-term palliation and adjuvant treatment of advanced SCC.
MATERIALS AND METHODS: This is a retrospective analysis of 4 patients with locally advanced or metastatic SCC who received cetuximab and/or panitumumab.
RESULTS: 3 patients (2 females, 1 male, ages 86 to 93) received cetuximab for the treatment of unresectable SCC. In 2 patients partial remissions were achieved and maintained with continuous treatment for 17 and 18 months. Another patient achieved complete remission after 16 cetuximab treatments and is still free of disease with ongoing therapy after an overall observation period of 16 months. In a fourth patient, with recurrent loco-regional metastatic disease of the scalp and neck, adjuvant cetuximab followed by panitumumab was introduced after extensive surgery. 2 patients had a grade II-III skin rash successfully treated with topical erythromycin, systemic doxycyclin and dose modification.
CONCLUSION: Cetuximab is suitable for palliation in elderly patients, able to maintain remissions and prevent disease progression over extended periods of continuing treatment without significant toxicity. Furthermore, adjuvant anti-EGFR therapy may be a promising treatment strategy in patients with a high risk of recurrence.

Related: Monoclonal Antibodies Skin Cancer Panitumumab (Vectibix) Cetuximab (Erbitux)


Ratti M, Tomasello G
Emerging combination therapies to overcome resistance in EGFR-driven tumors.
Anticancer Drugs. 2014; 25(2):127-39 [PubMed] Related Publications
The epidermal growth factor receptor (EGFR) is responsible for the growth and progression of tumor cells; its overexpression and deregulation of its downstream signaling pathway have been found in many different neoplasms. These characteristics make it an ideal target for cancer treatment. Two classes of EGFR inhibitors, which bind to different parts of this molecule, have been developed and studied: monoclonal antibodies, such as cetuximab and panitumumab and tyrosine kinase inhibitors, including erlotinib and gefitinib. The effectiveness of these new drugs is considerably reduced by a number of mechanisms of resistance developed by tumor cells. Hence, there is a clear need for better characterization of these processes and finding new therapeutic strategies to make the action of these drugs more incisive. Here, we describe some of the mechanisms of resistance to EGFR inhibitors and review the main innovations attempting to overcome these drawbacks.

Related: Monoclonal Antibodies Cancer Prevention and Risk Reduction VEGFA


Lawrence D, Maschio M, Leahy KJ, et al.
Economic analysis of bevacizumab, cetuximab, and panitumumab with fluoropyrimidine-based chemotherapy in the first-line treatment of KRAS wild-type metastatic colorectal cancer (mCRC).
J Med Econ. 2013; 16(12):1387-98 [PubMed] Related Publications
OBJECTIVE: Colorectal cancer (CRC) is the third most commonly diagnosed cancer in Canada (excluding non-melanoma skin cancers). Bevacizumab is a recombinant humanized monoclonal antibody that selectively binds to human vascular endothelial growth factor. A sub-study confirmed its effectiveness in KRAS wild-type patients. Recent evidence has shown clinical benefit from anti-epidermal growth factor treatments cetuximab and panitumumab in these patients. The cost-effectiveness, to the Canadian healthcare system, of fluoropyrimidine-based chemotherapy (FBC) in combination with bevacizumab, cetuximab, or panitumumab was assessed for first-line treatment of KRAS wild-type mCRC patients.
METHODS: A Markov model was developed and calibrated to progression-free/overall survival, using separately reported trial survival and adverse event results for each comparator. Health-state resource utilization was derived from published data and oncologist input. Utilities and unit prices were obtained from published literature and standard Canadian sources.
RESULTS: Results per patient are over a lifetime horizon, to a maximum of 10 years, with 5% annual discounting. Comparators are ordered by total cost and the incremental cost-effectiveness ratio (ICER) of each is determined against the previous non-dominated therapy. Compared to FBC alone, bevacizumab + FBC has an ICER of $131,600 per QALY gained. Compared to bevacizumab + FBC, panitumumab + FBC is dominated and cetuximab + FBC has an ICER of $3.8 million per QALY. In probabilistic sensitivity analysis, bevacizumab + FBC had ∼100%, ∼100%, and 98.9% probabilities of being more cost-effective than both of the other combination treatments at thresholds of $50,000/QALY, $100,000/QALY, and $200,000/QALY, respectively.
CONCLUSION: For first-line treatment of KRAS-WT mCRC, bevacizumab + FBC is associated with substantially lower costs as compared to panitumumab + FBC or cetuximab + FBC. Key limitations were that survival curves and adverse event rates were taken from separate clinical trials and that an indirect comparison was not included. Given these findings, bevacizumab is likely to offer the best value for money for this patient population.

Related: Angiogenesis Inhibitors Monoclonal Antibodies Canada Colorectal (Bowel) Cancer KRAS gene Panitumumab (Vectibix) Bevacizumab (Avastin) Cetuximab (Erbitux)


Pichler M, Winter E, Ress AL, et al.
miR-181a is associated with poor clinical outcome in patients with colorectal cancer treated with EGFR inhibitor.
J Clin Pathol. 2014; 67(3):198-203 [PubMed] Related Publications
AIMS: miR-181a expression is frequently altered in different types of cancer. Members of the Wnt/β-catenin signalling pathway, which is commonly altered in colorectal cancer (CRC), have been reported as molecular interaction partners of miR-181. However, the role of miR-181a expression in CRC and its ability to predict survival and response to agents targeting the epidermal growth factor receptor (EGFR) have not been explored yet.
METHODS: In this study, we analysed 80 patients with wild type KRAS CRC undergoing treatment with the EGFR-targeting monoclonal antibodies cetuximab and panitumumab for metastatic CRC. The KRAS mutational status was determined by pyrosequencing and miR-181a expression was measured by quantitative RT-PCR in CRC tumour tissue and corresponding non-neoplastic colon tissue. The microRNA expression levels were correlated with clinicopathological characteristics. Cancer-specific survival was calculated by univariate and multivariate analyses, and progression-free survival (PFS) during treatment with EGFR-targeting agents was also evaluated.
RESULTS: A low miR-181a expression level was associated with poor differentiation of CRC (p=0.04). A Kaplan-Meier curve showed a decreased survival time for patients with low miR-181a expression (p=0.019). Low miR-181a expression was furthermore associated with poor PFS (p=0.015).
CONCLUSIONS: In conclusion, our data suggest that the miR-181a expression level is associated with poor survival in patients with CRC. Furthermore, miR-181a expression might predict PFS in EGFR-targeted therapy.

Related: Monoclonal Antibodies Colorectal (Bowel) Cancer KRAS gene Panitumumab (Vectibix) EGFR Cetuximab (Erbitux)


Er TK, Chen CC, Bujanda L, Herreros-Villanueva M
Clinical relevance of KRAS mutations in codon 13: Where are we?
Cancer Lett. 2014; 343(1):1-5 [PubMed] Related Publications
Recent advances in molecular diagnosis and the trend towards personalized medicine have made colorectal cancer one of the tumors where therapies have significantly improved patient survival after metastasis development. KRAS mutations in codon 12 and 13 are recognized biomarkers that are analyzed in clinic previously for anti-EGFR therapies administration. Since originally mutations in both codons were considered as a predictor of lack of response to cetuximab or panitumumab, the European Medicines Agency and the US Food and Drug Administration suggested that patients harboring any of those mutations should be excluded from the treatment. However, subsequent retrospective analysis has shown that mutations in codon 12 and codon 13 of KRAS gene could be different in their biological characteristics and as a result could confer variable effects in patients. In addition and increasing and sometimes contradictory number of solutions have been published demonstrating that patients with mutations in codon 13 could have worse outcome but could obtain a significant clinical benefit from anti-EGFR therapies. Here, we review and update the latest data on the biological role leading to a predictive outcome and benefit from anti-EGFR antibodies in patients with specific KRAS mutations in codon 13.

Related: Colorectal (Bowel) Cancer KRAS gene Cetuximab (Erbitux)


Fletcher EV, Love-Homan L, Sobhakumari A, et al.
EGFR inhibition induces proinflammatory cytokines via NOX4 in HNSCC.
Mol Cancer Res. 2013; 11(12):1574-84 [PubMed] Article available free on PMC after 01/12/2014 Related Publications
UNLABELLED: Chronic inflammation plays a fundamental role in tumor promotion, migration, and invasion. With the use of microarray profiling, a profound increase was observed for those transcripts involved in proinflammatory signaling in epidermal growth factor receptor (EGFR) inhibitor-treated head and neck squamous cell carcinoma (HNSCC) cells as compared with their respective controls. As such, it was hypothesized that EGFR inhibitor efficacy is offset by the proinflammatory response that these therapeutics conjure in HNSCC. Systematic evaluation of the clinical EGFR inhibitors-erlotinib, cetuximab, lapatinib, and panitumumab-revealed increased secretion of proinflammatory cytokines such as interleukins (IL-2, IL-4, IL-6, IL-8), granulocyte-macrophage colony-stimulating factor, TNF-α, and IFN-γ. Mechanistic focus on IL-6 revealed that erlotinib induced a time-dependent increase in IL-6 mRNA and protein expression. Importantly, exogenous IL-6 protected HNSCC cells from erlotinib-induced cytotoxicity, whereas tocilizumab, an IL-6 receptor antagonist, sensitized cells to erlotinib in vitro and in vivo. Inhibitors of NF-κB, p38, and JNK suppressed erlotinib-induced IL-6 expression, suggesting critical roles for NF-κB and MAPK in IL-6 regulation. Furthermore, knockdown of NADPH oxidase 4 (NOX4) suppressed erlotinib-induced proinflammatory cytokine expression. Taken together, these results demonstrate that clinical EGFR inhibitors induce the expression of proinflammatory cytokines via NOX4.
IMPLICATIONS: The antitumor activity of EGFR inhibitors is reduced by activation of NOX4-mediated proinflammatory pathways in HNSCC.

Related: Monoclonal Antibodies Cytokines Head and Neck Cancers Head and Neck Cancers - Molecular Biology Panitumumab (Vectibix) Lapatinib (Tyverb) Erlotinib (Tarceva) Cetuximab (Erbitux)


Douillard JY, Oliner KS, Siena S, et al.
Panitumumab-FOLFOX4 treatment and RAS mutations in colorectal cancer.
N Engl J Med. 2013; 369(11):1023-34 [PubMed] Related Publications
BACKGROUND: Patients with metastatic colorectal cancer that harbors KRAS mutations in exon 2 do not benefit from anti-epidermal growth factor receptor (EGFR) therapy. Other activating RAS mutations may also be negative predictive biomarkers for anti-EGFR therapy.
METHODS: In this prospective-retrospective analysis, we assessed the efficacy and safety of panitumumab plus oxaliplatin, fluorouracil, and leucovorin (FOLFOX4) as compared with FOLFOX4 alone, according to RAS (KRAS or NRAS) or BRAF mutation status. A total of 639 patients who had metastatic colorectal cancer without KRAS mutations in exon 2 had results for at least one of the following: KRAS exon 3 or 4; NRAS exon 2, 3, or 4; or BRAF exon 15. The overall rate of ascertainment of RAS status was 90%.
RESULTS: Among 512 patients without RAS mutations, progression-free survival was 10.1 months with panitumumab-FOLFOX4 versus 7.9 months with FOLFOX4 alone (hazard ratio for progression or death with combination therapy, 0.72; 95% confidence interval [CI], 0.58 to 0.90; P=0.004). Overall survival was 26.0 months in the panitumumab-FOLFOX4 group versus 20.2 months in the FOLFOX4-alone group (hazard ratio for death, 0.78; 95% CI, 0.62 to 0.99; P=0.04). A total of 108 patients (17%) with nonmutated KRAS exon 2 had other RAS mutations. These mutations were associated with inferior progression-free survival and overall survival with panitumumab-FOLFOX4 treatment, which was consistent with the findings in patients with KRAS mutations in exon 2. BRAF mutations were a negative prognostic factor. No new safety signals were identified.
CONCLUSIONS: Additional RAS mutations predicted a lack of response in patients who received panitumumab-FOLFOX4. In patients who had metastatic colorectal cancer without RAS mutations, improvements in overall survival were observed with panitumumab-FOLFOX4 therapy. (Funded by Amgen and others; PRIME ClinicalTrials.gov number, NCT00364013.).

Related: Monoclonal Antibodies Colorectal (Bowel) Cancer Fluorouracil Leucovorin BRAF gene KRAS gene Panitumumab (Vectibix) NRAS gene


Watanabe K, Kawahara H, Enomoto H, et al.
Impact of chemotherapy with S-1 and oxaliplatin (SOX) in combination with molecular-targeting agents on colorectal liver metastases.
Anticancer Res. 2013; 33(9):3941-6 [PubMed] Related Publications
AIM: The aim of this study was to evaluate the impact of chemotherapy with molecular-targeting agents on liver metastases from colorectal cancer.
PATIENTS AND METHODS: Six patients with synchronous colorectal liver metastases who underwent hepatectomy after chemotherapy with S-1 and oxaliplatin (SOX) between January 2010 and December 2011 at the Department of Surgery, Kashiwa Hospital, the Jikei University School of Medicine were enrolled. Two patients received only SOX as chemotherapy, while the others received SOX in combination with one of the three molecular-targeting agents, bevacizumab, cetuximab, and panitumumab.
RESULTS: In the two patients who received SOX alone, liver metastases completely disappeared at more than six months after starting chemotherapy as shown by computed tomographic (CT) scan. However, malignant cells were diffusely detected by pathological examination at the site of liver metastases, as detected by CT scan before chemotherapy. In the other four patients who received SOX in combination with molecular targets, the size of liver metastases appeared unchanged at three months after limited chemotherapy by CT scan. Pathologically, few malignant cells were detected, only at the borderline of the tumor, while most tumor cells inside the tumor were necrotized and been replaced by fibroconnective tissue.
CONCLUSION: Molecular-targeting agents may induce tumor necrosis rapidly from inside the tumor, which might not be detected by CT scan before surgery.

Related: Monoclonal Antibodies Colorectal (Bowel) Cancer Tegafur-uracil Panitumumab (Vectibix) Oxaliplatin Cetuximab (Erbitux)


Lange A, Prenzler A, Frank M, et al.
A systematic review of cost-effectiveness of monoclonal antibodies for metastatic colorectal cancer.
Eur J Cancer. 2014; 50(1):40-9 [PubMed] Related Publications
UNLABELLED: Metastatic colorectal cancer (mCRC) imposes a substantial health burden on patients and society. In recent years, advances in the treatment of mCRC have mainly resulted from the introduction of monoclonal antibodies (MoAbs). However, the application of these MoAbs considerably increases treatment costs. The objective of this article is to review and assess the economic evidence of MoAB treatment in mCRC. A systematic literature review was conducted and cost-effectiveness (CE) as well as cost-utility-studies were identified. For this, Medline, Embase, SciSearch, Cochrane, and nine other databases were searched from 2000 through February 2013 for full-text publications. The quality of the studies was assessed via a validated assessment tool (Quality of Health Economic Studies (QHES)). A total of 843 publications were screened. Of those, 15 studies involving the MoAbs bevacizumab, cetuximab and panitumumab met all inclusion criteria. Four studies analysed the CE of first-line treatment with bevacizumab and nine the CE of cetuximab in subsequent treatment lines. Two studies dealt with the CE of panitumumab. The analysis of sequential regimes and the direct comparison of two MoABs were analysed by only one study each. The quality of the included studies was high with the exception of one study.
CONCLUSIONS: The treatment with bevacizumab, cetuximab and panitumumab is mainly considered to be not cost-effective in patients with mCRC. However, testing for Kirsten ras oncogene (KRAS) mutation prior to the treatment with cetuximab or panitumumab is found to be clearly cost-effective compared to no testing. Future research should focus on the CE of first-line treatment with cetuximab or panitumumab and studies on upcoming agents like regorafenib and aflibercept.

Related: Monoclonal Antibodies Colorectal (Bowel) Cancer


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