Panitumumab (Vectibix)
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Latest Research Publications

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Latest Research Publications

Kordes S, van Berge Henegouwen MI, Hulshof MC, et al.
Preoperative chemoradiation therapy in combination with panitumumab for patients with resectable esophageal cancer: the PACT study.
Int J Radiat Oncol Biol Phys. 2014; 90(1):190-6 [PubMed] Related Publications
PURPOSE: Preoperative chemoradiation therapy (CRT) has become the standard treatment strategy for patients with resectable esophageal cancer. This multicenter phase 2 study investigated the efficacy of the addition of the epidermal growth factor receptor (EGFR) inhibitor panitumumab to a preoperative CRT regimen with carboplatin, paclitaxel, and radiation therapy in patients with resectable esophageal cancer.
METHODS AND MATERIALS: Patients with resectable cT1N1M0 or cT2-3N0 to -2M0 tumors received preoperative CRT consisting of panitumumab (6 mg/kg) on days 1, 15, and 29, weekly administrations of carboplatin (area under the curve [AUC] = 2), and paclitaxel (50 mg/m(2)) for 5 weeks and concurrent radiation therapy (41.4 Gy in 23 fractions, 5 days per week), followed by surgery. Primary endpoint was pathologic complete response (pCR) rate. We aimed at a pCR rate of more than 40%. Furthermore, we explored the predictive value of biomarkers (EGFR, HER 2, and P53) for pCR.
RESULTS: From January 2010 until December 2011, 90 patients were enrolled. Patients were diagnosed predominantly with adenocarcinoma (AC) (80%), T3 disease (89%), and were node positive (81%). Three patients were not resected due to progressive disease. The primary aim was unmet, with a pCR rate of 22%. Patients with AC and squamous cell carcinoma reached a pCR of 14% and 47%, respectively. R0 resection was achieved in 95% of the patients. Main grade 3 toxicities were rash (12%), fatigue (11%), and nonfebrile neutropenia (11%). None of the biomarkers was predictive for response.
CONCLUSIONS: The addition of panitumumab to CRT with carboplatin and paclitaxel was safe and well tolerated but could not improve pCR rate to the preset criterion of 40%.

Related: Monoclonal Antibodies Carboplatin Cancer of the Esophagus Esophageal Cancer Paclitaxel Panitumumab (Vectibix)

Hezel AF, Noel MS, Allen JN, et al.
Phase II study of gemcitabine, oxaliplatin in combination with panitumumab in KRAS wild-type unresectable or metastatic biliary tract and gallbladder cancer.
Br J Cancer. 2014; 111(3):430-6 [PubMed] Article available free on PMC after 29/07/2015 Related Publications
BACKGROUND: Current data suggest that platinum-based combination therapy is the standard first-line treatment for biliary tract cancer. EGFR inhibition has proven beneficial across a number of gastrointestinal malignancies; and has shown specific advantages among KRAS wild-type genetic subtypes of colon cancer. We report the combination of panitumumab with gemcitabine (GEM) and oxaliplatin (OX) as first-line therapy for KRAS wild-type biliary tract cancer.
METHODS: Patients with histologically confirmed, previously untreated, unresectable or metastatic KRAS wild-type biliary tract or gallbladder adenocarcinoma with ECOG performance status 0-2 were treated with panitumumab 6 mg kg(-1), GEM 1000 mg m(-2) (10 mg m(-2) min(-1)) and OX 85 mg m(-2) on days 1 and 15 of each 28-day cycle. The primary objective was to determine the objective response rate by RECIST criteria v.1.1. Secondary objectives were to evaluate toxicity, progression-free survival (PFS), and overall survival.
RESULTS: Thirty-one patients received at least one cycle of treatment across three institutions, 28 had measurable disease. Response rate was 45% and disease control rate was 90%. Median PFS was 10.6 months (95% CI 5-24 months) and median overall survival 20.3 months (95% CI 9-25 months). The most common grade 3/4 adverse events were anaemia 26%, leukopenia 23%, fatigue 23%, neuropathy 16% and rash 10%.
CONCLUSIONS: The combination of gemcitabine, oxaliplatin and panitumumab in KRAS wild type metastatic biliary tract cancer showed encouraging efficacy, additional efforts of genetic stratification and targeted therapy is warranted in biliary tract cancer.

Related: Monoclonal Antibodies Gallbladder Cancer KRAS gene Panitumumab (Vectibix) Oxaliplatin Gemcitabine

Cheng L, Ren W, Xie L, et al.
Anti-EGFR MoAb treatment in colorectal cancer: limitations, controversies, and contradictories.
Cancer Chemother Pharmacol. 2014; 74(1):1-13 [PubMed] Related Publications
Anti-epidermal growth-factor receptor (EGFR) monoclonal antibody (MoAb) treatment for chemotherapy refractory or metastatic colorectal cancer has obtained great achievement. However, not every colorectal patient responds to such molecular-targeted agent well. Biomarkers associated with anti-EGFR resistance are not limited to KRAS mutation up to now. It was recently reported that cross-talking molecular effectors interacted with EGFR-related pathway were also negative predictor for anti-EGFR treatment. However, the limited data, controversial results, and contradictories between in vitro and clinical studies restrict the clinical application of these new biomarkers. Although the current theory of tumor microenvironment supported the application of multi-target treatment, the results from the clinical studies were less than expected. Moreover, WHO or RECIST guideline for response assessment in anti-EGFR MoAb treatment was also queried by recent AIO KRK-0306 trial. This review focuses on these controversies, contradictories, and limitations, in order to uncover the unmet needs in current status of anti-EGFR MoAb treatment in colorectal cancer.

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

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] Article available free on PMC after 29/07/2015 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)

Takahashi N, Yamada Y, Taniguchi H, et al.
Combined assessment of endothelial growth factor receptor dual color in situ hybridization and immunohistochemistry with downstream gene mutations in prediction of response to the anti-EGFR therapy for patients with metastatic colorectal cancer.
Arch Med Res. 2014; 45(5):366-74 [PubMed] Related Publications
BACKGROUND AND AIMS: Biomarkers associated with anti-EGFR antibodies therapy have been investigated in metastatic colorectal cancer (CRC). We conducted this study to evaluate the clinical utility of a combined assessment of EGFR status and genomic mutations of the EGFR downstream signal pathway in predicting the efficacy of anti-EGFR antibody treatment.
METHODS: We collected formalin-fixed paraffin-embedded tumor tissues and evaluated the EGFR status by immunohistochemistry (IHC), dual color in situ hybridization (DISH) and genomic analyses of KRAS, BRAF, PIK3CA and NRAS by direct sequencing.
RESULTS: A total of 129 patients were evaluated in our study. Among KRAS wild-type patients, EGFR DISH positivity was associated with a higher response rate than DISH negativity (56.3 vs. 21.1%, p = 0.011). A subgroup with EGFR DISH positivity plus IHC3+ and wild-type of EGFR downstream gene mutations achieved higher response rate and disease control rate. EGFR DISH positivity, KRAS codon 146 mutation and NRAS codon 61 mutation were prognostic factors in both progression-free survival and overall survival by multivariate analyses.
CONCLUSIONS: Combined assessment of DISH plus IHC and EGFR downstream gene mutations was useful to predict the response to anti-EGFR antibodies treatment in metastatic colorectal cancer patients in our study.

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

McRee AJ, Davies JM, Sanoff HG, et al.
A phase I trial of everolimus in combination with 5-FU/LV, mFOLFOX6 and mFOLFOX6 plus panitumumab in patients with refractory solid tumors.
Cancer Chemother Pharmacol. 2014; 74(1):117-23 [PubMed] Related Publications
PURPOSE: This phase I study investigated the safety, dose-limiting toxicity, and efficacy in three cohorts all treated with the mTOR inhibitor everolimus that was delivered (1) in combination with 5-fluorouracil with leucovorin (5-FU/LV), (2) with mFOLFOX6 (5-FU/LV + oxaliplatin), and (3) with mFOLFOX6 + panitumumab in patients with refractory solid tumors.
METHODS: Patients were accrued using a 3-patient cohort design consisting of two sub-trials in which the maximum tolerated combination (MTC) and dose-limiting toxicity (DLT) of everolimus and 5-FU/LV was established in Sub-trial A and of everolimus in combination with mFOLFOX6 and mFOLFOX6 plus panitumumab in Sub-trial B.
RESULTS: Thirty-six patients were evaluable for toxicity, 21 on Sub-trial A and 15 on Sub-trial B. In Sub-trial A, DLT was observed in 1/6 patients enrolled on dose level 1A and 2/3 patients in level 6A. In Sub-trial B, 2/3 patients experienced DLT on level 1B and subsequent patients were enrolled on level 1B-1 without DLT. Three of six patients in cohort 2B-1 experienced grade 3 mucositis, and further study of the combination of everolimus, mFOLFOX6 and panitumumab was aborted. Among the 24 patients enrolled with refractory metastatic colorectal cancer, the median time on treatment was 2.7 months with 45 % of patients remaining on treatment with stable disease for at least 3 months.
CONCLUSIONS: While a regimen of everolimus in addition to 5-FU/LV and mFOLFOX6 appears safe and tolerable, the further addition of panitumumab resulted in an unacceptable level of toxicity that cannot be recommended for further study. Further investigation is warranted to better elucidate the role which mTOR inhibitors play in patients with refractory solid tumors, with a specific focus on mCRC as a potential for the combination of this targeted and cytotoxic therapy in future studies.

Related: Monoclonal Antibodies Colorectal (Bowel) Cancer Fluorouracil Leucovorin Cancer Prevention and Risk Reduction Panitumumab (Vectibix) Everolimus (Afinitor) Oxaliplatin

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, 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)

Sonoda H, Shimizu T, Mekata E, et al.
A complete response to mFOLFOX6 and panitumumab chemotherapy in advanced stage rectal adenocarcinoma: a case report.
World J Surg Oncol. 2014; 12:63 [PubMed] Article available free on PMC after 29/07/2015 Related Publications
BACKGROUND: Pathological complete remission of advanced stage rectal adenocarcinoma by chemotherapy alone is rare. A case of advanced stage, low-lying rectal adenocarcinoma in which a complete response to treatment was obtained with mFOLFOX6 and panitumumab (Pmab) is reported.
CASE PRESENTATION: A 53-year-old man was referred to Shiga University of Medical Science hospital Shiga, Japan, complaining of bloody stool. Gastrointestinal endoscopy was performed, and advanced stage rectal adenocarcinoma was diagnosed. Computed tomography (CT) revealed regional lymph node metastases in the mesorectum. Neoadjuvant chemotherapy (NAC) with mFOLFOX6 and Pmab was planned.Endoscopy following four courses of chemotherapy revealed that the rectal cancer had been markedly reduced, and the results of biopsies of the rectal tumor were negative for cancer. On CT, the mesorectal lymph node metastases had disappeared. Total intersphincteric resection (ISR) with a handsewn coloanal anastomosis was performed. Histological examination showed a complete response to mFOLFOX6 and Pmab in advanced stage rectal cancer.
CONCLUSION: The result seen in this case suggests that short-term NAC with mFOLFOX6 and Pmab was effective for low-lying rectal adenocarcinoma.

Related: Monoclonal Antibodies Fluorouracil Leucovorin Panitumumab (Vectibix)

Sebio A, Stintzing S, Stremitzer S, et al.
Panitumumab : leading to better overall survival in metastatic colorectal cancer?
Expert Opin Biol Ther. 2014; 14(4):535-48 [PubMed] Related Publications
INTRODUCTION: Survival of metastatic colorectal cancer (mCRC) patients has improved greatly over the past few years, essentially due to the appearance of new biological therapies. Among these new therapies, monoclonal antibodies targeting the EGFR are the leading contributors to the so-called personalized medicine. Biomarkers within the EGFR pathway, such as K-Ras mutation, have proved to help better select the patients benefiting from these treatments.
AREAS COVERED: Panitumumab is a fully human monoclonal antibody that targets the EGFR and is currently approved in combination with chemotherapy or in monotherapy for the treatment of mCRC patients. Following a description of the pharmacological and tolerability data, this review focuses on the clinical activity of panitumumab through the description of clinical trials and biomarker research.
EXPERT OPINION: Recent biomarker research with expanded Ras testing has led to an improvement in overall survival for all Ras wild-type patients treated with panitumumab. Furthermore, the thorough evaluation of markers within the EGFR pathway could potentially prevent detrimental effects for patients treated with panitumumab and avoid unnecessary toxicity and costs.

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

Misale S, Arena S, Lamba S, et al.
Blockade of EGFR and MEK intercepts heterogeneous mechanisms of acquired resistance to anti-EGFR therapies in colorectal cancer.
Sci Transl Med. 2014; 6(224):224ra26 [PubMed] Related Publications
Colorectal cancers (CRCs) that are sensitive to the anti-epidermal growth factor receptor (EGFR) antibodies cetuximab or panitumumab almost always develop resistance within several months of initiating therapy. We report the emergence of polyclonal KRAS, NRAS, and BRAF mutations in CRC cells with acquired resistance to EGFR blockade. Regardless of the genetic alterations, resistant cells consistently displayed mitogen-activated protein kinase kinase (MEK) and extracellular signal-regulated kinase (ERK) activation, which persisted after EGFR blockade. Inhibition of MEK1/2 alone failed to impair the growth of resistant cells in vitro and in vivo. An RNA interference screen demonstrated that suppression of EGFR, together with silencing of MEK1/2, was required to hamper the proliferation of resistant cells. Indeed, concomitant pharmacological blockade of MEK and EGFR induced prolonged ERK inhibition and severely impaired the growth of resistant tumor cells. Heterogeneous and concomitant mutations in KRAS and NRAS were also detected in plasma samples from patients who developed resistance to anti-EGFR antibodies. A mouse xenotransplant from a CRC patient who responded and subsequently relapsed upon EGFR therapy showed exquisite sensitivity to combinatorial treatment with MEK and EGFR inhibitors. Collectively, these results identify genetically distinct mechanisms that mediate secondary resistance to anti-EGFR therapies, all of which reactivate ERK signaling. These observations provide a rational strategy to overcome the multifaceted clonal heterogeneity that emerges when tumors are treated with targeted agents. We propose that MEK inhibitors, in combination with cetuximab or panitumumab, should be tested in CRC patients who become refractory to anti-EGFR therapies.

Related: Colorectal (Bowel) Cancer Signal Transduction

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] Article available free on PMC after 29/07/2015 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)

Matsuhashi N, Takahashi T, Nonaka K, et al.
A case report on efficacy of Abound™ for anti-EGFR antibody-associated skin disorder in metastatic colon cancer.
World J Surg Oncol. 2014; 12:35 [PubMed] Article available free on PMC after 29/07/2015 Related Publications
BACKGROUND: Panitumumab is a full human epidermal growth factor receptor (EGFR) monoclonal antibody, an agent for metastatic colorectal cancer therapy. One of the most general adverse events of anti-EGFR monoclonal antibody therapy is skin disorder. At the present time, although prophylaxis of skin disorder is important for continuation of cancer therapy, there are no effective precautionary treatments.
CASE PRESENTATION: A 73-year-old male with sigmoid colon cancer and synchronous lung metastasis was treated with panitumumab, an alone anti-EGFR monoclonal antibody as the third-line therapy.During the nine courses of the therapy, the response was stable disease (SD), but skin disorder gradually appeared obviously (CTCAE version 4.0: Grade 2). After 1 month of administration of Abound™, symptoms of the skin disorder improved (CTCAE version 4.0: Grade 1), thus the antibody therapy could be continued.
CONCLUSION: We report that Abound™ was apparently effective in the treatment for anti-EGFR antibody-associated skin disorder. In the future, Abound™ could be expected as an agent for skin disorder as one of the side effects of colorectal cancer therapy.

Related: Monoclonal Antibodies Panitumumab (Vectibix) EGFR

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)

Cappuzzo F, Sacconi A, Landi L, et al.
MicroRNA signature in metastatic colorectal cancer patients treated with anti-EGFR monoclonal antibodies.
Clin Colorectal Cancer. 2014; 13(1):37-45.e4 [PubMed] Related Publications
BACKGROUND: To investigate whether microRNAs are predictive of sensitivity to anti-epidermal growth factor receptor (EGFR) monoclonal antibodies in patients with metastatic colorectal cancer (mCRC).
METHODS: A total of 183 mCRC cases from 2 independent cohorts (cohort 1: 74 cases; validation cohort: 109 cases) treated with cetuximab or panitumumab were included in the study. MiRNA arrays were analyzed using Agilent's miRNA platform.
RESULTS: The study identified the cluster Let-7c/miR-99a/miR-125b as a signature associated with an outcome different from that of anti-EGFR therapies. In the first cohort, patients with high-intensity signatures had a significantly longer progression-free survival (PFS) (6.1 vs. 2.3 mo; P = .02) and longer overall survival (OS) ( 29.8 vs. 7.0 mo, P = .08) than patients with low-intensity signatures. In the validation cohort, patients with high signature had significantly longer PFS and OS than individuals with low-intensity signatures (PFS 7.8 vs. 4.3 mo, P = .02; OS 12.8 vs. 7.5 mo, P = .02). In the KRAS wild-type population (n = 120), high-intensity signature patients had a significantly longer PFS (7.8 vs. 4.6 mo, P = .016) and longer OS (16.1 vs. 10.9 mo, P = .09) than low-signature individuals, with no difference in KRAS mutated patients.
CONCLUSION: The MiR-99a/Let-7c/miR-125b signature may improve the selection of patients with KRAS wild-type mCRC as good candidates for anti-EGFR therapy.

Related: Monoclonal Antibodies Colorectal (Bowel) Cancer Panitumumab (Vectibix) 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] Article available free on PMC after 29/07/2015 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)

Cui D, Cao D, Yang Y, et al.
Effect of BRAF V600E mutation on tumor response of anti-EGFR monoclonal antibodies for first-line metastatic colorectal cancer treatment: a meta-analysis of randomized studies.
Mol Biol Rep. 2014; 41(3):1291-8 [PubMed] Related Publications
Anti-EGFR monoclonal antibodies (anti-EGFR MoAbs) in metastatic colorectal cancer (mCRC) treatment are still not effective in all patients. This study aimed to evaluate the relationship between BRAF V600E mutation and the tumor response of anti-EGFR MoAbs for first-line treatment in mCRC patients. We searched the MEDLINE and EMBASE databases, using the key words that included colorectal cancer, cetuximab, panitumumab, and BRAF mutation and retrieved 445 articles. Among them four were included in the systematic review. Relative risks (RRs) with 95% confidence intervals (CI) for response rate were calculated. BRAF mutation carriers had worse ORR than non-carriers in mCRC patients with KRAS wild-type in first-line treatment whether adding anti-EGFR MoAb to chemotherapy or not (RR = 0.43, [95% CI 0.16-0.75]; RR = 0.38, [95% CI 0.20-0.73]). But in the unselected patients whose KRAS mutation were unknown, BRAF mutation carriers had similar ORR whether adding cetuximab to chemotherapy or not (RR = 0.45, [95% CI 0.18-1.09]; RR = 0.57, [95% CI 0.15-2.23]). In BRAF mutation carriers adding anti-EGFR MoAb to chemotherapy was similar to chemotherapy alone whether in patients with wild-type KRAS or unselected patients (RR = 1.61, [95% CI 0.57-4.47]; RR = 0.71, [95% CI 0.18-2.77]). But in the BRAF mutation non-carriers, adding anti-EGFR MoAb produced a clear benefit in response rate than chemotherapy alone and this advantage was restricted to KRAS wild-type patients (RR = 1.48, [95% CI 1.28-1.71]). BRAF mutation decreases tumor response in first-line treatment whether cetuximab was given or not in patients with KRAS wild-type, and anti-EGFR MoAb produces a clear benefit in response rate in patients with BRAF and KRAS wild-type.

Related: Monoclonal Antibodies Colorectal (Bowel) Cancer BRAF gene Panitumumab (Vectibix) EGFR 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] Article available free on PMC after 29/07/2015 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

Mahipal A, Kothari N, Gupta S
Epidermal growth factor receptor inhibitors: coming of age.
Cancer Control. 2014; 21(1):74-9 [PubMed] Related Publications
BACKGROUND: Agents targeting the epidermal growth factor (EGFR)-mediated signaling pathway are used in the treatment of various solid tumors, including lung, breast, pancreatic, colorectal, and head and neck cancers.
METHODS: Clinical evidence supporting the benefits of targeted agents directed against EGFR/HER1 in various solid tumors is discussed, as well as the survival end points used in the pivotal clinical trials, current applications, and future research directions. Agents reviewed include the monoclonal antibodies cetuximab and panitumumab, both of which block ligand binding to the extracellular domain, and the small-molecule tyrosine kinase inhibitors gefitinib, erlotinib, and afatinib that exert their effects at the intracellular portion of the receptor to prevent tyrosine kinase phosphorylation and the activation of signal transduction pathways.
RESULTS: EGFR inhibitors have a mechanism of action distinct from traditional cytotoxic therapies, and combining these agents with chemotherapy produces synergistic anticancer activity without overlapping toxicity profiles. The level of EGFR expression does not correlate with agent response, and many tumors are resistant to treatment. Even if tumors are initially sensitive to these agents, they inevitably acquire resistance through complex, poorly understood molecular mechanisms.
CONCLUSIONS: EGFR-directed therapies have changed the treatment paradigms in metastatic lung, colorectal, and head and neck cancers and improved outcomes. A better understanding of mechanisms of resistance to these agents is crucial for effective drug development. Predictive biomarkers are being developed to deliver personalized therapies.

Related: Cancer Prevention and Risk Reduction EGFR

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] Article available free on PMC after 29/07/2015 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)

Roskoski R
The ErbB/HER family of protein-tyrosine kinases and cancer.
Pharmacol Res. 2014; 79:34-74 [PubMed] Related Publications
The human epidermal growth factor receptor (EGFR) family consists of four members that belong to the ErbB lineage of proteins (ErbB1-4). These receptors consist of a glycosylated extracellular domain, a single hydrophobic transmembrane segment, and an intracellular portion with a juxtamembrane segment, a protein kinase domain, and a carboxyterminal tail. Seven ligands bind to EGFR including epidermal growth factor and transforming growth factor α, none bind to ErbB2, two bind to ErbB3, and seven ligands bind to ErbB4. The ErbB proteins function as homo and heterodimers. The heterodimer consisting of ErbB2, which lacks a ligand, and ErbB3, which is kinase impaired, is surprisingly the most robust signaling complex of the ErbB family. Growth factor binding to EGFR induces a large conformational change in the extracellular domain, which leads to the exposure of a dimerization arm in domain II of the extracellular segment. Two ligand-EGFR complexes unite to form a back-to-back dimer in which the ligands are on opposite sides of the aggregate. Following ligand binding, EGFR intracellular kinase domains form an asymmetric homodimer that resembles the heterodimer formed by cyclin and cyclin-dependent kinase. The carboxyterminal lobe of the activator kinase of the dimer interacts with the amino-terminal lobe of the receiver kinase thereby leading to its allosteric stimulation. Downstream ErbB signaling modules include the phosphatidylinositol 3-kinase/Akt (PKB) pathway, the Ras/Raf/MEK/ERK1/2 pathway, and the phospholipase C (PLCγ) pathway. Several malignancies are associated with the mutation or increased expression of members of the ErbB family including lung, breast, stomach, colorectal, head and neck, and pancreatic carcinomas and glioblastoma (a brain tumor). Gefitinib, erlotinib, and afatinib are orally effective protein-kinase targeted quinazoline derivatives that are used in the treatment of ERBB1-mutant lung cancer. Lapatinib is an orally effective quinazoline derivative used in the treatment of ErbB2-overexpressing breast cancer. Trastuzumab, pertuzumab, and ado-trastuzumab emtansine, which are given intravenously, are monoclonal antibodies that target the extracellular domain and are used for the treatment of ErbB2-positive breast cancer; ado-trastuzumab emtansine is an antibody-drug conjugate that delivers a cytotoxic drug to cells overexpressing ErbB2. Cetuximab and panitumumab are monoclonal antibodies that target ErbB1 and are used in the treatment of colorectal cancer. Cancers treated with these targeted drugs eventually become resistant to them. The role of combinations of targeted drugs or targeted drugs with cytotoxic therapies is being explored in an effort to prevent or delay drug resistance in the treatment of these malignancies.

Related: Cancer Prevention and Risk Reduction Signal Transduction

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)

Tonini G, Imperatori M, Vincenzi B, et al.
Rechallenge therapy and treatment holiday: different strategies in management of metastatic colorectal cancer.
J Exp Clin Cancer Res. 2013; 32:92 [PubMed] Article available free on PMC after 29/07/2015 Related Publications
Fluoropyrimidines, oxaliplatin, irinotecan and biologic therapies (Bevacizumab, Panitumumab, and Cetuximab) represent the backbone of metastatic colorectal cancer (CRC) treatment. The improvement in survival for mCRC patient led to two main outstanding issues: 1) there is a significant number of patients progressing beyond the third or fourth line of treatment still suitable for further therapy when enrollment into clinical trial is not possible. In this situation, the role of any therapy rechallenge (either chemotherapy alone, chemotherapy and biologic therapy or biologic therapy alone) is still not clear, particularly in patients who had previously responded, and if treatment choice is based on traditional dogma of primary and secondary resistance, rechallenge does not seem to be justified. 2) Prolonged intensive treatment is burdened from the high risk of cumulative toxicity, worsening in quality of life and a not well defined possibility of early acquired resistance.Different hypothesis could justify the research of different strategy in treatment of mCRC:1) Epigenetic changes might drive resistance and treatment could induce these changes. Re-expression of silenced tumor suppressive genes might resensitize tumors to therapy. It is therefore possible that a drug holiday (intermittent treatment) could allow reversion to a previous epigenetic profile. Moreover an intermittent treatment could delay acquired resistance. 2) It is plausible that tumor grows as a polyclonal mass. If it responds but then becomes resistant to one or more treatments, retreatment might be successful if changing therapies allows to that clone of cells to re-emerge. On these basis, we focused this review on the actual evidences in management of mCRC patients in terms of chemotherapy or biological therapies rechallenge and intermittent treatment. Moreover, we will discuss the potential biological mechanisms of the observed results of early clinical trials.

Related: Colorectal (Bowel) Cancer

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

Rautenberg T, Siebert U, Arnold D, et al.
Economic outcomes of sequences which include monoclonal antibodies against vascular endothelial growth factor and/or epidermal growth factor receptor for the treatment of unresectable metastatic colorectal cancer.
J Med Econ. 2014; 17(2):99-110 [PubMed] Related Publications
BACKGROUND: Patients with unresectable, metastatic colorectal cancer with wild type Kirsten ras mutational status are eligible for sequential treatments which include monoclonal antibodies as first line (1L), second line (2L), or third line (3L) regimens.
OBJECTIVE: To compare the economic outcomes of different sequences which include monoclonal antibodies for the treatment of unresectable metastatic colorectal cancer.
METHODS: Individual drug regimens for 1L, 2L, and 3L treatments were compiled according to the clinical studies in the Summary of Product Characteristics for monoclonal antibodies. They were combined into plausible treatment sequences. Health outcomes were approximated using additive median PFS benefit, and economic outcomes were calculated with a treatment sequencing costing tool. Limitations of the analysis include the clinical trial data sources, cost assumptions, and the additive PFS approach.
RESULTS: Seventeen sequences were evaluated. Results of the analysis show that sequences including 1L anti-EGFRs generally have relatively low-to-medium health outcomes at the highest comparative sequence costs compared to sequences including 2L anti-EGFRs, which have lower health outcomes at the lowest cost. Sequences including 3L anti-EGFRs (sequential bevazicumab-based 1L and 2L) have the highest health outcomes, with potential cost savings of €5972-€11,676 if replacing 2L anti-EGFRs or an additional cost of €5909-€12,708 if replacing 1L anti-EGFR regimens.
CONCLUSION: Clinical sequences consisting of 1L and 2L line bevacizumab followed by 3L anti-EGFR potentially yield the greatest health outcomes associated with a reasonable trade-off in additional cost when replacing 1L anti-EGFRs and are potentially cost-saving if replacing 2L anti-EGFRs, per patient per lifetime. To maximize health outcomes, optimal sequences include anti-EGFRs as 3L regimen, with an approximately equivalent trade-off in costs between the most costly (anti-EGFR 2L) and least costly (anti-EGFR 1L) sequences.

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

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