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Bokemeyer C, Ciardiello F, Dubreuil O, Guigay J, Kasper S, Pfeiffer P, Pinto C, Yamaguchi K, Yoshino T, Zielinski C, Esser R, Tabernero J. Cetuximab every 2 weeks versus standard weekly dosing administration schedule. Future Oncol 2024; 20:393-407. [PMID: 37850363 DOI: 10.2217/fon-2023-0282] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/19/2023] Open
Abstract
Cetuximab every 2 weeks (Q2W) dosing schedule is approved by the US FDA and by the Japanese Pharmaceuticals and Medical Devices Agency in patients with metastatic colorectal cancer and squamous cell carcinoma of the head and neck. Phase II trials have found comparable efficacy and safety for the weekly (Q1W) and Q2W schedules, and real-world studies have shown noninferiority of the Q2W compared with the Q1W schedule. Several guidelines recommend cetuximab Q2W administration as an alternative to the Q1W dosing schedule. Cetuximab Q2W can be administered with a Q2W dose of chemotherapy, making it a more convenient option to the Q1W schedule, potentially resulting in reduced costs for administration, increased flexibility for clinical staff and improved patient adherence.
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Affiliation(s)
- Carsten Bokemeyer
- The II Medical Clinic, Department of Oncology, Hematology & BMT with section of Pneumology, University Medical Center of Hamburg-Eppendorf, Hamburg, Germany
| | - Fortunato Ciardiello
- Department of Precision Medicine, University of Campania Luigi Vanvitelli, Naples, Italy
| | - Olivier Dubreuil
- Medical Oncology Unit, Diaconesses-Croix St Simon Hospital, Paris, France
| | - Joel Guigay
- Groupe d'Oncologie Radiothérapie Tête Et Cou (GORTEC), Tours, France
| | - Stefan Kasper
- Department of Medical Oncology, West German Cancer Center, University Hospital Essen, Essen, Germany
| | - Per Pfeiffer
- Department of Oncology, Odense University Hospital, Odense, Denmark
| | - Carmine Pinto
- Medical Oncology, Comprehensive Cancer Center, AUSL-IRCCS of Reggio Emilia, Reggio Emilia, Italy
| | - Kensei Yamaguchi
- Cancer Institute Hospital of the Japanese Foundation for Cancer Research, Tokyo, Japan
| | - Takayuki Yoshino
- Department of Gastroenterology & Gastrointestinal Oncology, National Cancer Center Hospital East, Kashiwa, Japan
| | | | | | - Josep Tabernero
- Medical Oncology Department, Vall d'Hebron Hospital Campus & Institute of Oncology (VHIO), IOB-Quiron, UVic-UCC, Barcelona, Spain
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Li Y, Wang B, Yang W, Ma F, Zou J, Li K, Tan S, Feng J, Wang Y, Qin Z, Chen Z, Ding C. Longitudinal plasma proteome profiling reveals the diversity of biomarkers for diagnosis and cetuximab therapy response of colorectal cancer. Nat Commun 2024; 15:980. [PMID: 38302471 PMCID: PMC10834432 DOI: 10.1038/s41467-024-44911-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/27/2023] [Accepted: 01/03/2024] [Indexed: 02/03/2024] Open
Abstract
Cetuximab therapy is the major treatment for colorectal cancer (CRC), but drug resistance limits its effectiveness. Here, we perform longitudinal and deep proteomic profiling of 641 plasma samples originated from 147 CRC patients (CRCs) undergoing cetuximab therapy with multi-course treatment, and 90 healthy controls (HCs). COL12A1, THBS2, S100A8, and S100A9 are screened as potential proteins to distinguish CRCs from HCs both in plasma and tissue validation cohorts. We identify the potential biomarkers (RRAS2, MMP8, FBLN1, RPTOR, and IMPDH2) for the initial response prediction. In a longitudinal setting, we identify two clusters with distinct fluctuations and construct the model with high accuracy to predict the longitudinal response, further validated in the independent cohort. This study reveals the heterogeneity of different biomarkers for tumor diagnosis, the initial and longitudinal response prediction respectively in the first course and multi-course cetuximab treatment, may ultimately be useful in monitoring and intervention strategies for CRC.
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Affiliation(s)
- Yan Li
- State Key Laboratory of Genetic Engineering and Collaborative Innovation Center for Genetics and Development, School of Life Sciences, Institutes of Biomedical Sciences, Human Phenome Institute, Zhongshan Hospital, Fudan University, Shanghai, China
| | - Bing Wang
- State Key Laboratory of Genetic Engineering and Collaborative Innovation Center for Genetics and Development, School of Life Sciences, Institutes of Biomedical Sciences, Human Phenome Institute, Zhongshan Hospital, Fudan University, Shanghai, China
| | - Wentao Yang
- Department of Gastrointestinal Medical Oncology, Fudan University Shanghai Cancer Center, Shanghai, China
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China
| | - Fahan Ma
- State Key Laboratory of Genetic Engineering and Collaborative Innovation Center for Genetics and Development, School of Life Sciences, Institutes of Biomedical Sciences, Human Phenome Institute, Zhongshan Hospital, Fudan University, Shanghai, China
| | - Jianling Zou
- Department of Gastrointestinal Medical Oncology, Fudan University Shanghai Cancer Center, Shanghai, China
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China
| | - Kai Li
- State Key Laboratory of Genetic Engineering and Collaborative Innovation Center for Genetics and Development, School of Life Sciences, Institutes of Biomedical Sciences, Human Phenome Institute, Zhongshan Hospital, Fudan University, Shanghai, China
| | - Subei Tan
- State Key Laboratory of Genetic Engineering and Collaborative Innovation Center for Genetics and Development, School of Life Sciences, Institutes of Biomedical Sciences, Human Phenome Institute, Zhongshan Hospital, Fudan University, Shanghai, China
| | - Jinwen Feng
- State Key Laboratory of Genetic Engineering and Collaborative Innovation Center for Genetics and Development, School of Life Sciences, Institutes of Biomedical Sciences, Human Phenome Institute, Zhongshan Hospital, Fudan University, Shanghai, China
| | - Yunzhi Wang
- State Key Laboratory of Genetic Engineering and Collaborative Innovation Center for Genetics and Development, School of Life Sciences, Institutes of Biomedical Sciences, Human Phenome Institute, Zhongshan Hospital, Fudan University, Shanghai, China
| | - Zhaoyu Qin
- State Key Laboratory of Genetic Engineering and Collaborative Innovation Center for Genetics and Development, School of Life Sciences, Institutes of Biomedical Sciences, Human Phenome Institute, Zhongshan Hospital, Fudan University, Shanghai, China
| | - Zhiyu Chen
- Department of Gastrointestinal Medical Oncology, Fudan University Shanghai Cancer Center, Shanghai, China.
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China.
| | - Chen Ding
- State Key Laboratory of Genetic Engineering and Collaborative Innovation Center for Genetics and Development, School of Life Sciences, Institutes of Biomedical Sciences, Human Phenome Institute, Zhongshan Hospital, Fudan University, Shanghai, China.
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Parikh AR, Gonzalez-Gugel E, Smolyakova N, Jen MH, Toms N, Lin Y, Kim JS, Kopetz S. Efficacy and Safety of Cetuximab Dosing (biweekly vs weekly) in Patients with KRAS Wild-type Metastatic Colorectal Cancer: A Meta-analysis. Oncologist 2022; 27:371-379. [PMID: 35522557 PMCID: PMC9074967 DOI: 10.1093/oncolo/oyab030] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/21/2021] [Accepted: 09/17/2021] [Indexed: 12/04/2022] Open
Abstract
BACKGROUND Cetuximab 500 mg/m2 biweekly (Q2W) plus chemotherapy is commonly used and recommended by NCCN guidelines. This meta-analysis compares efficacy and safety between Q2W versus weekly (Q1W) cetuximab dosing. METHODS A systematic literature review was performed on Pubmed and RightFind (2007-2017) for patients with KRAS wild-type mCRC who received Q2W or Q1W cetuximab and other treatments. Observational studies and case reports were excluded. Randomized trials comparing Q2W and Q1W dosing, and single-arm trials with only Q2W schedule were included. CRYSTAL, a phase 3 randomized study with Q1W cetuximab dosing was paired with each single-arm study with a Q2W schedule and reweighted to achieve similar demographic/baseline characteristics. Overall survival (OS) and progression-free survival (PFS) with hazard ratios (HR), overall response rate (ORR) with odds ratios, and risk difference of adverse events of special interest (AESI) between Q2W versus Q1W cetuximab were analyzed. RESULTS Five phase 2 studies with cetuximab Q2W/Q1W dosing schedules were identified: CECOG (phase 2; Q2W, n = 77; Q1W, n = 75), NORDIC 7.5 (phase 2; Q2W, n = 152) and NORDIC 7 (arm C of phase 3; Q1W, n = 109), CELINE (n = 60), OPTIMIX (n = 99), and APEC (n = 289) all phase 2, Q2W, single-arm studies paired with CRYSTAL Q1W dosing (n = 303). Efficacy was similar between Q2W versus Q1W administration; OS HR = 0.96, 95% confidence interval (CI) [0.89, 1.04]; PFS HR = 0.96, 95% CI [0.87, 1.05]; ORR odds ratio 1.16, 95% CI [0.96, 1.41]. Mean differences (Q2W-Q1W) across AESI rates were not clinically meaningful with no obvious directionality. CONCLUSION This meta-analysis demonstrated no significant differences in efficacy and safety between Q2W versus Q1W cetuximab administration in mCRC patients.
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Affiliation(s)
- Aparna R Parikh
- Department of Medicine, Division of Hematology & Oncology, Massachusetts General Hospital Cancer Center & Harvard Medical School, Boston, MA, USA
| | | | | | - Min-Hua Jen
- Eli Lilly and Company, Indianapolis, IN, USA
| | - Nikki Toms
- Eli Lilly and Company, Indianapolis, IN, USA
| | - Yong Lin
- Eli Lilly and Company, Indianapolis, IN, USA
| | | | - Scott Kopetz
- Department of Gastrointestinal Medical Oncology, The University of Texas M.D. Anderson Cancer Center, Houston, TX, USA
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Morales ASR, Joy JK, Zbona DM. Administration sequence for multi-agent oncolytic regimens. J Oncol Pharm Pract 2020; 26:933-942. [DOI: 10.1177/1078155219895070] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/17/2022]
Abstract
Purpose The existence of a multitude of oncolytics regimens containing two or more agents (combination) outlines the need to define their most adequate sequence of administration. However, limited resources are currently available to specify a particular sequence, presenting challenges potentially impacting on patient safety, and Pharmacy & Infusion Nursing workflows. Methods A comprehensive literature search was performed leading to the compilation of a document containing drug administration sequencing instructions for our Nursing, Pharmacy, and Oncology providers to follow. Regimens prioritized in our literature review represented regimens selected as part of our approved Clinical Pathways, regimens inquiries from Pharmacy or Nursing, as well as less frequently used regimens. We stratified the regimens by tumor type and arranged them alphabetically by indication. Results A table was compiled containing all the supporting literature for the recommended drug administration sequences. If, in certain instances, no literature support was identified outlining rationale such as enhanced management of adverse effects, a specific institutional decision was made by our enterprise Medical Oncology Committee with recommendations from Pharmacy experts. The primary guiding principles for outlining our recommendations were the following: administration of vesicant agents first; administration of biologic agents first; administration of taxanes prior to platinum agents; and duration of infusion (shorter infusions prioritized). Conclusion This guideline is not exhaustive. The compilation provided here is intended to be utilized as guidance for oncolytics administration sequence. We will continue to review and incorporate treatment sequencing recommendations for additional regimens.
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Affiliation(s)
| | - Jamie K Joy
- Cancer Treatment Centers of America Global, Boca Raton, FL, USA
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Abstract
PURPOSE OF REVIEW Elderly head and neck cancer (HNC) patients are very rarely enrolled in clinical trials, and even more so in dedicated trials in curative or palliative setting. As a result, no standards of treatment exist for this population and thus, adaptation of standard treatments is commonly used. RECENT FINDINGS The choice between a monotherapy and a platinum-cetuximab combination is based on the performance status, which is not suitable and/or sufficient to evaluate the patient ability to receive a systemic treatment combined or not with radiotherapy. The evaluation of functional age using geriatric assessment is recommended. However, access to comprehensive geriatric assessment is limited in many centers, and the choice of the type of treatment is often not based on objective and reproducible criteria. As a result, fragile elderly HNC patients may be overtreated with a risk of increased toxicity and fit patients proposed for suboptimal treatment with a risk of failure of tumor control. SUMMARY It is therefore crucial to develop and evaluate customized treatments by enrolling elderly HNC patients in dedicated therapeutics trials, such as the ELAN (Elderly Head and Neck Cancer) studies or new approaches involving promising immunotherapies. To administer the most suitable therapy, a simple and reproducible geriatric assessment could efficiently guide practitioners.
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Surmeli ZG, Ozveren A, Arslan C, Degirmenci M, Karaca B, Uslu R. Biweekly cetuximab in combination with platinum and 5-fluorouracil in metastatic head and neck carcinoma. Indian J Cancer 2019; 56:4-8. [PMID: 30950435 DOI: 10.4103/ijc.ijc_355_18] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/04/2022]
Abstract
Background and Aim The combination of cetuximab with platinum and 5-fluorouracil (5-FU) chemotherapy prolongs survival in patients with metastatic or recurrent squamous-cell carcinoma of the head and neck (SCCHN). Biweekly (once in 2 weeks) administration of cetuximab requires fewer hospital visits and decreases treatment costs; therefore, it is more convenient both for the patients and for the healthcare providers. Here, we assessed the efficacy, safety, and tolerability of an alternative biweekly regimen of cetuximab in combination with platinum and 5-FU chemotherapy as a first-line treatment for these patients. Methods and Materials Medical records of patients with metastatic or recurrent non-nasopharyngeal SCCHN who were treated with a biweekly regimen of cetuximab (500 mg/m2 on day 1), cisplatin (40 mg/m2 on day 1) or carboplatin (target area under the curve 3.5 mg/ml × min on day 1), folinic acid (400 mg/m2 on day 1), and 5-FU (400 mg/m2 bolus on day 1 followed by continuous infusion of 2,400 mg/m2 5-FU over 46 h) were retrospectively reviewed. Survival estimates were calculated with the Kaplan-Meier method. Results In total, 60 patients were included. The median age of the patients was 60.5. The objective response rate was 53.3% (95% confidence interval [CI] = 40.7-65.9). The median progression-free survival duration was 6.8 months (95% CI = 5.5-8.1) and the median overall survival duration was 13.3 months (95% CI = 8.4-18.2). The most common grade 3 or 4 adverse events were neutropenia (28.3%) and leucopenia (13.3%). Grade 3 or 4 rash was observed in 3.3% of the patients. Conclusion Biweekly administration of cetuximab, cisplatin, and 5-FU is an effective regimen with a favorable toxicity profile for the first-line treatment of metastatic or recurrent SCCHN. These results warrant further evaluation of this regimen in prospective trials.
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Affiliation(s)
- Zeki G Surmeli
- Department of Medical Oncology, Medical Park Hospital, Ankara, Turkey
| | - Ahmet Ozveren
- Department of Medical Oncology, Giresun University Training and Research Hospital, Giresun, Turkey
| | - Cagatay Arslan
- Bahcesehir University Faculty of Medicine, Department of Internal Medicine and Medical Oncology, Istanbul, Turkey
| | - Mustafa Degirmenci
- Department of Medical Oncology, Tepecik Training and Research Hospital, Izmir, Turkey
| | - Burcak Karaca
- Department of Medical Oncology, Ege University, Izmir, Turkey
| | - Ruchan Uslu
- Department of Medical Oncology, Ege University, Izmir, Turkey
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Kienle DL, Dietrich D, Ribi K, Wicki A, Quagliata L, Winterhalder RC, Koeberle D, Horber D, Bastian S, Kueng M, Saletti P, Helbling D, Baertschi D, Lugli A, Bernhard J, Andrieu C, von Moos R. Cetuximab monotherapy and cetuximab plus capecitabine as first-line treatment in older patients with RAS- and BRAF wild-type metastatic colorectal cancer. Results of the multicenter phase II trial SAKK 41/10. J Geriatr Oncol 2019; 10:304-310. [DOI: 10.1016/j.jgo.2018.11.011] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/27/2018] [Revised: 10/23/2018] [Accepted: 11/30/2018] [Indexed: 02/07/2023]
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Osumi H, Shinozaki E, Mashima T, Wakatsuki T, Suenaga M, Ichimura T, Ogura M, Ota Y, Nakayama I, Takahari D, Chin K, Miki Y, Yamaguchi K. Phase II trial of biweekly cetuximab and irinotecan as third-line therapy for pretreated KRAS exon 2 wild-type colorectal cancer. Cancer Sci 2018; 109:2567-2575. [PMID: 29908105 PMCID: PMC6113428 DOI: 10.1111/cas.13698] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/04/2018] [Accepted: 06/12/2018] [Indexed: 12/24/2022] Open
Abstract
Efficacy and safety of biweekly cetuximab plus irinotecan were evaluated to provide guidance for its use in Japan as third-line treatment for pretreated metastatic colorectal cancer (mCRC) patients harboring wild-type KRAS exon 2. Objective response rate (ORR) was used as primary endpoint based on an expected proportion of 0.23 with confidence width of 0.298 (95% CI, 0.105-0.403), which showed 35 to be the minimal participant number. Forty patients, refractory to first- and second-line chemotherapy containing irinotecan, oxaliplatin, and fluoropyrimidine, were enrolled. ORR and disease control rate were 25.0% (95% CI: 11.5-38.4) and 72.5% (95% CI: 56.8-86.4), respectively. Median progression-free survival (PFS), overall survival (OS), and number of courses were 5.70 months (95% CI: 2.7-7.9), 15.1 months (95% CI: 11.8-19.0), and 10.5 (range: 3.0-31.0), respectively. Grade 3 adverse events were skin toxicity (12.5%), diarrhea (10.0%), neutropenia (5.0%), febrile neutropenia (5.0%), nausea (5.0%), anorexia (5.0%), and fatigue (2.5%). Cmax mean was 723.2 μg/mL after first dose. High area under the curve (AUC)last variance was associated with t1/2 range of 131.2-1209.6 hours (median, 174.4 hours). Early tumor shrinkage (ETS) and median depth of response were 25.0% and 13.0%, respectively. Mutation frequencies in KRAS exon 3 or 4, NRAS, BRAF, and PIK3CA were 5.5%, 2.7%, 8.3%, and 5.5%, respectively. Multivariate Cox regression analysis assessed whether any gene mutations and ETS are predictors for PFS, and whether performance status, synchronous metastasis, and ETS are predictors for OS. Importantly, the data provide guidance for a biweekly cetuximab plus irinotecan regimen in mCRC patients.
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Affiliation(s)
- Hiroki Osumi
- Department of Gastroenterology, Cancer Institute Hospital, Japanese Foundation for Cancer Research, Tokyo, Japan
| | - Eiji Shinozaki
- Department of Gastroenterology, Cancer Institute Hospital, Japanese Foundation for Cancer Research, Tokyo, Japan
| | - Tetsuo Mashima
- Division of Molecular Biotherapy, Cancer Chemotherapy Center, Japanese Foundation for Cancer Research, Tokyo, Japan
| | - Takeru Wakatsuki
- Department of Gastroenterology, Cancer Institute Hospital, Japanese Foundation for Cancer Research, Tokyo, Japan
| | - Mitsukuni Suenaga
- Department of Gastroenterology, Cancer Institute Hospital, Japanese Foundation for Cancer Research, Tokyo, Japan
| | - Takashi Ichimura
- Department of Gastroenterology, Cancer Institute Hospital, Japanese Foundation for Cancer Research, Tokyo, Japan
| | - Mariko Ogura
- Department of Gastroenterology, Cancer Institute Hospital, Japanese Foundation for Cancer Research, Tokyo, Japan
| | - Yumiko Ota
- Department of Gastroenterology, Cancer Institute Hospital, Japanese Foundation for Cancer Research, Tokyo, Japan
| | - Izuma Nakayama
- Department of Gastroenterology, Cancer Institute Hospital, Japanese Foundation for Cancer Research, Tokyo, Japan
| | - Daisuke Takahari
- Department of Gastroenterology, Cancer Institute Hospital, Japanese Foundation for Cancer Research, Tokyo, Japan
| | - Keisho Chin
- Department of Gastroenterology, Cancer Institute Hospital, Japanese Foundation for Cancer Research, Tokyo, Japan
| | - Yoshio Miki
- Cancer Institute, Japanese Foundation for Cancer Research, Tokyo, Japan
| | - Kensei Yamaguchi
- Department of Gastroenterology, Cancer Institute Hospital, Japanese Foundation for Cancer Research, Tokyo, Japan
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Yang Q, Huang Y, Jiang Z, Wang H, Li W, Zhang B, Xie D. Rechallenge of oxaliplatin-containing regimens in the third- or later-line therapy for patients with heavily treated metastatic colorectal cancer. Onco Targets Ther 2018; 11:2467-2473. [PMID: 29760556 PMCID: PMC5937494 DOI: 10.2147/ott.s154220] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022] Open
Abstract
Purpose The third- or later-line therapy available often yield poor survival benefit in patients metastatic colorectal cancer (mCRC). The retrospective study aimed to evaluate efficacy of rechallenge of oxaliplatin-containing regimens. Patients and methods Patients with mCRC who progressed from fluoropyrimidine, oxaliplatin, and irinotecan in the first- and second-line chemotherapy, were treated by reexposure to oxaliplatin-containing regimen. Patients treated by anti-epidermal growth factor receptor (EGFR) antibodies with irinotecan were included in the control arm. Results Ninety-five and 29 patients were treated with either oxaliplatin reexposure or anti-EGFR antibodies with irinotecan, respectively, as the third- or later-line therapy. The median time to treatment failure (TTF) and overall survival (OS) was 3.77 and 12.17 months in the oxaliplatin arm, with 4.77 months of TTF and 11.37 months of OS in the control arm; there was no significance between the 2 arms (p>0.05). Oxaliplatin reexposure resulted in 6.3% objective response rate with no complete response, 6 partial response, 39 stable disease, and 37 progressive disease. The disease control rate was 47.4% (45/95). The multivariate analysis found that patients who achieved disease control by oxaliplatin reexposure had a superior TTF (6.13 vs 1.7 months, p<0.001) and OS (15.73 vs 6.27 months, p<0.001) compared with those presenting with progressive disease. Conclusion This study showed that rechallenge of oxaliplatin-containing chemotherapy in the third- or later-line therapy may lead to tumor control and improved survival in mCRC patients, which was equivalent to that of anti-EGFR antibodies with irinotecan. Clinical significance Rechallenge of oxaliplatin-containing regimens in the third- or later-line of therapy is a common practice, despite few evidence available. The present study found that rechallenge of oxaliplatin-containing regimens produced equivalent tumor control and survival benefit to that of anti-EGFR antibodies with irinotecan in mCRC.
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Affiliation(s)
- Qiong Yang
- Department of Oncology, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, China.,Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, China.,Medical Research Center, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, China
| | - Yuanyuan Huang
- VIP Region, Sun Yat-sen University Cancer Center, Guangzhou, China.,State Key Laboratory of Oncology in South China, Sun Yat-sen University Cancer Center, Guangzhou, China.,Collaborative Innovation Center for Cancer Medicine, Guangzhou, China
| | - Zhimin Jiang
- Department of Oncology, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, China.,Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, China.,Medical Research Center, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, China
| | - Huizhong Wang
- Department of Oncology, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, China.,Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, China.,Medical Research Center, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, China
| | - Weiyu Li
- Department of Oncology, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, China.,Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, China.,Medical Research Center, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, China
| | - Bei Zhang
- VIP Region, Sun Yat-sen University Cancer Center, Guangzhou, China.,State Key Laboratory of Oncology in South China, Sun Yat-sen University Cancer Center, Guangzhou, China.,Collaborative Innovation Center for Cancer Medicine, Guangzhou, China
| | - Derong Xie
- Department of Oncology, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, China.,Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, China.,Medical Research Center, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, China
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10
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Hong DS, Morris VK, El Osta B, Sorokin AV, Janku F, Fu S, Overman MJ, Piha-Paul S, Subbiah V, Kee B, Tsimberidou AM, Fogelman D, Bellido J, Shureiqi I, Huang H, Atkins J, Tarcic G, Sommer N, Lanman R, Meric-Bernstam F, Kopetz S. Phase IB Study of Vemurafenib in Combination with Irinotecan and Cetuximab in Patients with Metastatic Colorectal Cancer with BRAFV600E Mutation. Cancer Discov 2016; 6:1352-1365. [PMID: 27729313 DOI: 10.1158/2159-8290.cd-16-0050] [Citation(s) in RCA: 183] [Impact Index Per Article: 20.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/11/2016] [Revised: 10/04/2016] [Accepted: 10/06/2016] [Indexed: 12/22/2022]
Abstract
In vitro, EGFR inhibition, combined with the BRAF inhibitor vemurafenib, causes synergistic cytotoxicity for BRAFV600E metastatic colorectal cancer, further augmented by irinotecan. The safety and efficacy of vemurafenib, irinotecan, and cetuximab in BRAF-mutated malignancies are not defined. In this 3+3 phase I study, patients with BRAFV600E-advanced solid cancers received cetuximab and irinotecan with escalating doses of vemurafenib. Nineteen patients (18 with metastatic colorectal cancer and 1 with appendiceal cancer) were enrolled. Three patients experienced dose-limiting toxicities. The MTD of vemurafenib was 960 mg twice daily. Six of 17 evaluable patients (35%) achieved a radiographic response by Response Evaluation Criteria in Solid Tumors 1.1 criteria, consistent with in vivo models demonstrating tumor regressions with the triplet regimen. Median progression-free survival was 7.7 months. BRAFV600E circulating cell-free DNA (cfDNA) trends correlated with radiographic changes, and acquired mutations from cfDNA in genes reactivating MAPK signaling were observed at progression. SIGNIFICANCE Vemurafenib, in combination with irinotecan and cetuximab, was well tolerated in patients with refractory, BRAF-mutated metastatic colorectal cancer, and both survival outcomes and response rates exceeded prior reports for vemurafenib and for irinotecan plus cetuximab in BRAFV600E metastatic colorectal cancer. In vivo models demonstrated regressions with the triplet, in contrast with vemurafenib and cetuximab alone. cfDNA predicted radiographic response and identified mutations reactivating the MAPK pathway upon progression. Cancer Discov; 6(12); 1352-65. ©2016 AACR.This article is highlighted in the In This Issue feature, p. 1293.
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Affiliation(s)
- David S Hong
- Department of Investigational Cancer Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, Texas.
| | - Van K Morris
- Department of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Badi El Osta
- Department of Hematology and Medical Oncology, Atlanta Veterans Affairs Medical Center, Emory University School of Medicine, Atlanta, Georgia
| | - Alexey V Sorokin
- Department of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Filip Janku
- Department of Investigational Cancer Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Siqing Fu
- Department of Investigational Cancer Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Michael J Overman
- Department of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Sarina Piha-Paul
- Department of Investigational Cancer Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Vivek Subbiah
- Department of Investigational Cancer Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Bryan Kee
- Department of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Apostolia M Tsimberidou
- Department of Investigational Cancer Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, Texas
| | - David Fogelman
- Department of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Jorge Bellido
- Department of Investigational Cancer Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Imad Shureiqi
- Department of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Helen Huang
- Department of Investigational Cancer Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Johnique Atkins
- Department of Investigational Cancer Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, Texas
| | | | | | | | - Funda Meric-Bernstam
- Department of Investigational Cancer Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Scott Kopetz
- Department of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas
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Rosa B, de Jesus JP, de Mello EL, Cesar D, Correia MM. Effectiveness and safety of monoclonal antibodies for metastatic colorectal cancer treatment: systematic review and meta-analysis. Ecancermedicalscience 2015; 9:582. [PMID: 26557880 PMCID: PMC4631576 DOI: 10.3332/ecancer.2015.582] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/11/2015] [Indexed: 12/13/2022] Open
Abstract
BACKGROUND The effectiveness of chemotherapy (CT) for select cases of metastatic colorectal cancer (MCRC) has been well established in the literature, however, it provides limited benefits and in many cases constitutes a treatment with high toxicity. The use of specific molecular biological treatments with monoclonal antibodies (MA) has been shown to be relevant, particularly for its potential for increasing the response rate of the host to the tumour, as these have molecular targets present in the cancerous cells and their microenvironment thereby blocking their development. The combination of MA and CT can bring a significant increase in the rate of resectability of metastases, the progression-free survival (PFS), and the global survival (GS) in MCRC patients. OBJECTIVE To assess the effectiveness and safety of MA in the treatment of MCRC. METHODS A systematic review was carried out with a meta-analysis of randomised clinical trials comparing the use of cetuximab, bevacizumab, and panitumumab in the treatment of MCRC. RESULTS Sixteen randomised clinical trials were selected. The quality of the evidence on the question was considered moderate and data from eight randomised clinical trials were included in this meta-analysis. The GS and PFS were greater in the groups which received the MA associated with CT, however, the differences were not statistically significant between the groups (mean of 17.7 months versus 17.1 months; mean difference of 1.09 (CI: 0.10-2.07); p = 0.84; and 7.4 versus 6.9 months. mean difference of 0.76 (CI: 0.08-1.44); p = 0.14 respectively). The meta-analysis was not done for any of the secondary outcomes. CONCLUSION The addition of MA to CT for patients with metastatic colorectal cancer does not prolong GS and PFS.
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Affiliation(s)
- Bruno Rosa
- Instituto Nacional de Câncer, Rio de Janeiro 20230-130, Brazil
| | | | | | - Daniel Cesar
- Instituto Nacional de Câncer, Rio de Janeiro 20230-130, Brazil
| | - Mauro M Correia
- Instituto Nacional de Câncer, Rio de Janeiro 20230-130, Brazil
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12
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You B, Chen EX. Anti-EGFR monoclonal antibodies for treatment of colorectal cancers: development of cetuximab and panitumumab. J Clin Pharmacol 2015; 52:128-55. [PMID: 21427284 DOI: 10.1177/0091270010395940] [Citation(s) in RCA: 40] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/30/2023]
Abstract
Over the last decade, anti-epidermal growth factor receptor (EGFR) monoclonal antibodies (mAbs) have been firmly established as essential drugs for the treatment of metastatic colorectal cancer (CRC). Cetuximab and panitumumab have been approved by American and European drug agencies. This review aims at exploring the main outcomes of clinical studies performed during their clinical development, from phase I to III trials, and hence at giving a comprehensive review of the scientific rational and up-to-date evidence sustaining the use of these drugs. Many areas are still under active investigation such as administration schedules, their efficacy in comparison with bevacizumab, their role in adjuvant therapy, molecular predictors, and management of side effects.
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Affiliation(s)
- Benoit You
- Department of Medical Oncology and Hematology, Princess Margaret Hospital, University Health Network, Toronto, Ontario, Canada
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Tariq A, Majeed I, Khurshid A. Types of Cancers Prevailing in Pakistan and their Management Evaluation. Asian Pac J Cancer Prev 2015; 16:3605-16. [DOI: 10.7314/apjcp.2015.16.9.3605] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/10/2023] Open
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FOLFIRI and Cetuximab Every Second Week for First-Line Treatment of KRAS Wild-Type Metastatic Colorectal Cancer According to Phosphatase and Tensin Homolog Expression: A Phase II Study. Clin Colorectal Cancer 2015; 14:162-9. [PMID: 25861836 DOI: 10.1016/j.clcc.2015.02.006] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/05/2014] [Revised: 02/26/2015] [Accepted: 02/26/2015] [Indexed: 12/11/2022]
Abstract
BACKGROUND Retrospective studies have suggested that phosphatase and tensin homolog (PTEN) expression might predict the efficacy of cetuximab in patients with KRAS wild-type metastatic colorectal cancer (mCRC). The present study was designed to prospectively evaluate the efficacy of first-line irinotecan, fluorouracil, and folinate (FOLFIRI) plus cetuximab every second week according to PTEN expression. PATIENTS AND METHODS Originally, patients with KRAS wild-type mCRC were randomly assigned to receive either FOLFIRI or cetuximab plus FOLFIRI (FOLFIRI-C). After a protocol amendment, the FOLFIRI arm was discontinued, and additional patients received FOLFIRI-C. Cox proportional hazard models were used to investigate the effect of PTEN and MET expression and BRAF and phosphatidylinositol-4,5-bisphosphate 3-kinase, catalytic subunit α mutations on progression-free survival (PFS) and overall survival (OS). RESULTS A total of 35 and 54 patients received FOLFIRI and FOLFIRI-C, respectively. For the patients assigned to FOLFIRI and FOLFIRI-C, the median OS was 17.7 and 23.3 months and the median PFS was 8.2 and 6.6 months, respectively. For patients receiving FOLFIRI-C, the loss of PTEN expression did not affect PFS or OS. Significant interactions for PFS were detected between the MET expression levels (P = .047) and BRAF mutation (P = .018) and treatment. On univariate analysis, BRAF mutation was significantly associated with shorter OS for patients receiving either FOLFIRI-C (P = .016) or FOLFIRI (P = .035). Multivariate analysis confirmed the independent prognostic value of BRAF mutation on OS and that of MET expression levels on PFS (P = .025) and OS (P = .028) but only in the patients receiving FOLFIRI alone. Adverse events with FOLFIRI-C were consistent with those expected from FOLFIRI plus weekly cetuximab. CONCLUSION Although prospective analysis of PTEN did not allow a validation of the prognostic value of this biomarker, an every second week cetuximab schedule, in addition to first-line FOLFIRI, was effective and well tolerated. The possible predictive value of MET expression levels warrants additional investigation.
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15
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Fernandez-Plana J, Pericay C, Quintero G, Alonso V, Salud A, Mendez M, Salgado M, Saigi E, Cirera L. Biweekly cetuximab in combination with FOLFOX-4 in the first-line treatment of wild-type KRAS metastatic colorectal cancer: final results of a phase II, open-label, clinical trial (OPTIMIX-ACROSS Study). BMC Cancer 2014; 14:865. [PMID: 25417182 PMCID: PMC4251687 DOI: 10.1186/1471-2407-14-865] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/13/2014] [Accepted: 11/11/2014] [Indexed: 02/04/2023] Open
Abstract
BACKGROUND This phase II study aims to evaluate the efficacy and safety of biweekly cetuximab in combination with oxaliplatin, leucovorin, and fluorouracil (FOLFOX-4) as first-line treatment of metastatic wild-type KRAS colorectal cancer. METHODS Previously untreated patients with wild-type KRAS tumours received biweekly cetuximab (500 mg/m2 on day 1) plus FOLFOX-4 (oxaliplatin 85 mg/m2 on day 1, leucovorin 200 mg/m2 on days 1 and 2, and fluorouracil as a 400 mg/m2 bolus followed by a 22-hour 600 mg/m2 infusion on day 1 and 2). Treatment was continued until disease progression, onset of unacceptable toxicities, metastases surgery, or discontinuation request. The primary endpoint was ORR. RESULTS The intention-to-treat population included 99 patients with a median age of 64.1 years (range, 34-82). The ORR was 60.6% (95% CI, 50.3% to 70.3%). The median follow-up was 17.8 months; the median OS and PFS were 20.8 and 10.1 months, respectively. Metastases from colorectal cancer were surgically resected in 26 (26.3%) patients, with complete resection achieved in 18 (69.2%) patients. Median PFS and OS in patients undergoing metastatic resection were 12.6 and 29.5 months, respectively. The most common grade 3-4 toxicities were neutropenia (32.3%), acne-like rash (15.2%) and diarrhoea (11.1%). CONCLUSIONS The efficacy of the biweekly combination of cetuximab with FOLFOX-4 in patients with wild-type KRAS tumours supports the administration of cetuximab in a dosing regimen more convenient for patients and healthcare providers. The activity of the biweekly administration is similar to what has been reported for the weekly regimen. Reported toxicity was also consistent with the known toxicity profile of weekly cetuximab. TRIAL REGISTRATION EudraCT Number 200800690916.
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Affiliation(s)
| | | | | | | | | | | | - Mercedes Salgado
- />Complejo Hospitalario Universitario de Ourense, Ourense, Spain
| | - Eugeni Saigi
- />Corporación Sanitaria Parc Taulí, Sabadell, Spain
| | - Luis Cirera
- />Hospital Universitario Mútua Terrassa, Plaça del Dr. Robert N°5, Terrassa, Barcelona 08221 Spain
| | - on behalf of the ACROSS Study Group
- />Hospital Universitario Mútua Terrassa, Terrassa, Spain
- />Corporación Sanitaria Parc Taulí, Sabadell, Spain
- />Hospital Universitario Lucus Augusti (HULA), Lugo, Spain
- />Hospital Miguel Servet, Zaragoza, Spain
- />Hospital Arnau de Vilanova, Lleida, Spain
- />Hospital de Móstoles, Móstoles, Spain
- />Complejo Hospitalario Universitario de Ourense, Ourense, Spain
- />Corporación Sanitaria Parc Taulí, Sabadell, Spain
- />Hospital Universitario Mútua Terrassa, Plaça del Dr. Robert N°5, Terrassa, Barcelona 08221 Spain
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16
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Weekly and every 2 weeks cetuximab maintenance therapy after platinum-based chemotherapy plus cetuximab as first-line treatment for non-small cell lung cancer: randomized non-comparative phase IIIb NEXT trial. Target Oncol 2014; 10:255-65. [DOI: 10.1007/s11523-014-0336-7] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/06/2014] [Accepted: 08/29/2014] [Indexed: 11/26/2022]
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Chen Y, Cao D, Bi F, Li Q, Qiu M. Biweekly cetuximab plus FOLFIRI/irinotecan as first/second-line chemotherapy for patients with KRAS wild-type metastatic colorectal cancer: a retrospective analysis in Southwest Chinese population. Med Oncol 2014; 31:935. [PMID: 24683007 DOI: 10.1007/s12032-014-0935-2] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/09/2013] [Accepted: 03/18/2014] [Indexed: 02/05/2023]
Abstract
Weekly cetuximab plus irinotecan-based regiments are standard first- and second-line chemotherapy for patients with KRAS wild-type metastatic colorectal cancer (mCRC). However, the chemotherapy regimens are given every 2 weeks, which is asynchronous with cetuximab weekly administration. This study investigated the efficacy and safety of biweekly cetuximab administration in patients with mCRC. Twenty-six patients with KRAS wild-type mCRC, who received biweekly cetuximab plus FOLFIRI/irinotecan as first/second-line chemotherapy, at least three cycles of cetuximab and once CT evaluation in West China Hospital from May 2010 to February 2013, were retrospectively analyzed. The median number of cetuximab administrations was 8.3 (range 3-20). Fourteen patients received FOLFIRI as first-line therapy; response rate was 50.0%; median PFS was 8.8 months (95% CI 4.9-12.7). Ten patients received FOLFIRI and two patients received irinotecan as second-line therapy; response rate was 33.3%; median PFS was 4.6 months (95% CI 0.9-8.3). The toxicity was similar to weekly cetuximab combination schedules. Rash was observed in 69.2% of evaluable patients (grade 3 in 7.7%). Overall, our results show that biweekly cetuximab plus FOLFIRI/irinotecan may be as effective and safe as the standard weekly schedule.
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Affiliation(s)
- Ye Chen
- Department of Medical Oncology, Cancer Center, the State Key Laboratory of Biotherapy, West China Hospital, West China Medical School, Sichuan University, No. 37, Guo Xue Xiang, Chengdu, 610041, Sichuan Province, China
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Temraz S, Mukherji D, Shamseddine A. Sequencing of treatment in metastatic colorectal cancer: where to fit the target. World J Gastroenterol 2014; 20:1993-2004. [PMID: 24616571 PMCID: PMC3934469 DOI: 10.3748/wjg.v20.i8.1993] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/25/2013] [Revised: 12/01/2013] [Accepted: 01/14/2014] [Indexed: 02/06/2023] Open
Abstract
Colorectal cancer is a lethal disease if not discovered early. Even though appropriate screening and preventive strategies are in place in many countries, a significant number of patients are still diagnosed at late stages of the disease. The management of metastatic colorectal cancer remains a significant clinical challenge to oncologists worldwide. While cytotoxic regimens constitute the main treatment of choice in this patient population, addition of the five biologics (bevacizumab, cetuximab, aflibercept, panitumumab and regorafenib) to these regimens has improved clinical outcomes. The most commonly used cytotoxic regimens include doublet combinations (FOLFOX/XELOX or FOLFIRI). Many clinical trials have been published and others are underway to compare the biologic agents with one another in order to prove the superiority of one regimen over another. Metastatic colorectal cancer patients have many treatment options; however, the optimal use and sequence of targeted agents remain to be determined. This review entails concise and updated clinical data on the management of metastatic colorectal cancer. The aim of the review is to determine where to fit the five biologic targets into the treatment algorithm of metastatic colorectal cancer patients and to derive treatment sequences that would achieve best clinical outcome based on the current available data.
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Prospective study of EGFR intron 1 (CA)n repeats variants as predictors of benefit from cetuximab and irinotecan in chemo-refractory metastatic colorectal cancer (mCRC) patients. THE PHARMACOGENOMICS JOURNAL 2014; 14:322-7. [DOI: 10.1038/tpj.2014.1] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/03/2013] [Revised: 12/30/2013] [Accepted: 01/06/2014] [Indexed: 01/09/2023]
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Sotelo Lezama MJ, Sastre Valera J, Díaz-Rubio García E. Impact of cetuximab in current treatment of metastatic colorectal cancer. Expert Opin Biol Ther 2014; 14:387-99. [PMID: 24479733 DOI: 10.1517/14712598.2014.883376] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
INTRODUCTION Cetuximab is a chimeric monoclonal antibody targeting the EGFR, which has proven effective in patients with metastatic colorectal cancer (mCRC), wild-type Kirsten rat sarcoma viral oncogene homolog (KRAS). AREAS COVERED The aim of this manuscript is to discuss the current impact of cetuximab in the most important scenarios of mCRC. We review the currently available data regarding the role of other biomarkers, such as the mutational status of neuroblastoma RAS viral (v-ras) oncogene homolog in identifying patients who could benefit most from anti-EGFR. In addition, a review is included of the most relevant clinical trials that have assessed the effectiveness of cetuximab in the management of patients with potentially resectable metastatic disease and in the first-line treatment of wild-type KRAS mCRC, as well as the impact of this anti-EGFR agent on patient quality of life. EXPERT OPINION Cetuximab has had a progressive clinical development from the earliest to the later stages of the evolution of mCRC and has been consolidated as a therapeutic option for all scenarios of unresectable disease. Patient selection by analysis of KRAS mutations has been a fundamental event to increase efficiency, being a dynamic process that continues in assessment. There are few comparative data with other biological agents in combination with chemotherapy, although data from a recent study are promising.
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Kennecke H, Chen L, Blanke CD, Cheung WY, Schaff K, Speers C. Panitumumab monotherapy compared with cetuximab and irinotecan combination therapy in patients with previously treated KRAS wild-type metastatic colorectal cancer. ACTA ACUST UNITED AC 2013; 20:326-32. [PMID: 24311948 DOI: 10.3747/co.20.1600] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/02/2023]
Abstract
BACKGROUND The survival benefit for single-agent anti-epidermal growth factor receptor (egfr) therapy compared with combination therapy with irinotecan in KRAS wildtype (wt) metastatic colorectal cancer (mcrc) patients in the third-line treatment setting is not known. The objective of the present study was to describe the characteristics of, and to compare survival outcomes in, two cohorts of patients treated with either singleagent panitumumab or combination therapy with cetuximab and irinotecan. METHODS The study enrolled patients with KRAS wt mcrc previously treated with both irinotecan and oxaliplatin who had received either panitumumab or combination cetuximab-irinotecan before April 1, 2011, at the BC Cancer Agency (bcca). Patients were excluded if they had received anti-egfr agents in earlier lines of therapy. Data were prospectively collected, except for performance status (ps), which was determined by chart review. Information about systemic therapy was extracted from the bcca Pharmacy Database. RESULTS Of 178 eligible patients, 141 received panitumumab, and 37 received cetuximab-irinotecan. Compared with patients treated with cetuximab-irinotecan, panitumumab-treated patients were significantly older and more likely to have an Eastern Cooperative Oncology Group (ecog) ps of 2 or 3 (27.7% vs. 2.7%, p = 0.001). Other baseline prognostic variables and prior and subsequent therapies were similar. Median overall survival was 7.7 months for the panitumumab group and 8.3 months for the cetuximab-irinotecan group. Multivariate analysis demonstrated that survival outcomes were similar regardless of the therapy selected (hazard ratio: 1.28; p = 0.34). An ecog ps of 2 or 3 compared with 0 or 1 was the only significant prognostic factor in this treatment setting (hazard ratio: 3.37; p < 0.01). CONCLUSIONS Single-agent panitumumab and cetuximab-irinotecan are both reasonable third-line treatment options, with similar outcomes, for patients with chemoresistant mcrc.
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Affiliation(s)
- H Kennecke
- Division of Medical Oncology, BC Cancer Agency-Vancouver Centre, Vancouver, BC
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Abstract
PURPOSE Important developments in chemotherapy for advanced colorectal cancer over the past 15 years are reviewed, with an emphasis on the most recently published data from clinical trials of newer multidrug regimens, administration techniques, and dosing schedules. SUMMARY Eight agents are approved by the Food and Drug Administration (FDA) for use in treating patients with advanced colorectal cancer. Fluorouracil and leucovorin still constitute the foundation of most chemotherapy regimens for this population; combination fluorouracil-leucovorin therapy plus either irinotecan (the FOLFIRI regimen) or oxaliplatin (the FOLFOX regimen) are two firmly established first-line treatments shown to produce similar outcomes. In Phase III trials conducted over the past six to seven years, regimens of capecitabine plus oxaliplatin (CapeOx) were demonstrated to have clinical effectiveness comparable to that of FOLFOX therapy. Response rates of 35-55% and median overall survival of ≥20 months have been documented with some of the newer regimens. Research to define the optimal role of the three monoclonal antibody agents approved by FDA for use in managing advanced colorectal cancer is ongoing; bevacizumab has been shown to confer significant survival benefits when added to certain chemotherapy regimens, and other monoclonal antibodies (cetuximab and panitumumab) also appear to offer significant benefits in select patients as first- or second-line therapies. CONCLUSION Over the past 15 years, a shift toward multiagent treatment strategies including a variety of chemotherapy agents and monoclonal antibodies has yielded improved rates of response and prolonged survival among patients with advanced colorectal cancer. The CapeOx, FOLFOX, and FOLFIRI regimens are currently among the most widely used first-line treatments.
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Affiliation(s)
- Robert J Cersosimo
- School of Pharmacy, Bouvé College of Health Sciences, Northeastern University, 360 Huntington Avenue, 206 Mugar Hall, Boston, MA 02115, USA.
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Methods of overcoming treatment resistance in colorectal cancer. Crit Rev Oncol Hematol 2013; 89:217-30. [PMID: 24075059 DOI: 10.1016/j.critrevonc.2013.08.015] [Citation(s) in RCA: 55] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/11/2013] [Revised: 07/28/2013] [Accepted: 08/30/2013] [Indexed: 12/25/2022] Open
Abstract
Metastatic colorectal cancer remains a lethal disease with a poor prognosis in the majority of patients. Multiple drug combinations have been developed in recent years that have significantly improved response rates and overall survival however resistance to these drugs is inevitable. Novel agents are currently being developed and participation in clinical trials should be encouraged. In the absence of other treatment options in a patient with good performance status, there is compelling evidence for re-challenging with previously administered agents in different combinations. The aim of this review is to discuss mechanisms of resistance and methods to overcome treatment resistance in patients with metastatic colorectal cancer who are refractory to 5-FU, irinotecan, oxaliplatin, cetuximab and bevacizumab therapy.
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Brodowicz T, Ciuleanu TE, Radosavljevic D, Shacham-Shmueli E, Vrbanec D, Plate S, Mrsic-Krmpotic Z, Dank M, Purkalne G, Messinger D, Zielinski CC. FOLFOX4 plus cetuximab administered weekly or every second week in the first-line treatment of patients with KRAS wild-type metastatic colorectal cancer: a randomized phase II CECOG study. Ann Oncol 2013; 24:1769-1777. [PMID: 23559149 DOI: 10.1093/annonc/mdt116] [Citation(s) in RCA: 45] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/07/2023] Open
Abstract
BACKGROUND This randomized phase II study investigated first-line chemotherapy plus cetuximab administered every second week in KRAS wild-type metastatic colorectal cancer. PATIENTS AND METHODS Patients received FOLFOX4 plus either standard weekly cetuximab (arm 1) or cetuximab (500 mg/m(2)) every second week (arm 2), until disease progression or unacceptable toxicity. Primary end point was the objective response rate (ORR). Progression-free survival (PFS), overall survival (OS), disease control rate (DCR) and safety were also investigated. The study was not powered to establish non-inferiority, but aimed at the estimation of treatment differences. RESULTS Of 152 randomized eligible patients, 75 were treated in arm 1 and 77 in arm 2; ORRs [53% versus 62%, odds ratio 1.40, 95% confidence interval (CI) 0.74-2.66], PFS [median 9.5 versus 9.2 months, hazard ratio (HR) 0.92, 95% CI 0.63-1.34], OS (median 25.8 versus 23.0 months, HR 0.86, 95% CI 0.56-1.30) and DCR (87%) were comparable. HRs adjusted for baseline factors were 1.01 and 0.99 for PFS and OS, respectively. Frequencies of grade 3/4 adverse events in arms 1 versus 2 were similar: most common were neutropenia (28% versus 34%) and rash (15% versus 17%). CONCLUSIONS Activity and safety of FOLFOX4 plus either cetuximab administered weekly or every second week were similar.
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Affiliation(s)
- T Brodowicz
- Department of Medicine I, Medical University of Vienna, Vienna; Comprehensive Cancer Centre, Vienna, Austria
| | | | | | - E Shacham-Shmueli
- Division of Oncology, Tel Aviv Souraski Medical Center, Tel Aviv, Israel
| | - D Vrbanec
- Department of Oncology, University Hospital Zagreb/Rebro, Zagreb, Croatia
| | - S Plate
- The Latvian Center of Oncology, Riga, Latvia
| | - Z Mrsic-Krmpotic
- Department of Medical Oncology, University Hospital for Tumors, Zagreb, Croatia
| | - M Dank
- Radiology Clinic, Semmelweis University, Budapest, Hungary
| | - G Purkalne
- P Stradins University Hospital, Riga, Latvia
| | | | - C C Zielinski
- Department of Medicine I, Medical University of Vienna, Vienna; Comprehensive Cancer Centre, Vienna, Austria.
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Cetuximab therapy in the treatment of metastatic colorectal cancer: the future frontier? Int J Surg 2013; 11:507-13. [PMID: 23660586 DOI: 10.1016/j.ijsu.2013.04.014] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/07/2013] [Revised: 04/10/2013] [Accepted: 04/27/2013] [Indexed: 12/14/2022]
Abstract
BACKGROUND To review the outcomes following cetuximab therapy in patients with metastatic colorectal cancer. METHODS Relevant articles were reviewed from the published literature using the Medline database. The search was performed using the keywords "colorectal cancer", "cetuximab", "liver metastases", "liver resection" and "hepatectomy". RESULTS Cetuximab was first used in the palliative setting and an increase in response rates were seen, however with no improvement in overall survival. Published data have observed that cetuximab may be beneficial as part of a down-staging programme. The addition of cetuximab to chemotherapy regimens in patients with KRAS wild-type colorectal cancer has been shown to increase the response rates and the number of patients being down-staged and offered potentially curative resection. The OPUS and CRYSTAL trials observed good response rates following the addition of cetuximab but low resection rates. The CELIM and POCHER studies reported higher resection rates due to better patient selection and study design. However, the majority of published studies tend to report minimal surgical data and lack short- and long-term outcomes. CONCLUSION The use of cetuximab to conventional chemotherapy regimens may improve the efficacy of down-staging programmes, leading to more patients being offered potentially curative resection.
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Rubinson DA, Hochster HS, Ryan DP, Wolpin BM, McCleary NJ, Abrams TA, Chan JA, Iqbal S, Lenz HJ, Lim D, Rose J, Bekaii-Saab T, Chen HX, Fuchs CS, Ng K. Multi-drug inhibition of the HER pathway in metastatic colorectal cancer: results of a phase I study of pertuzumab plus cetuximab in cetuximab-refractory patients. Invest New Drugs 2013; 32:113-22. [PMID: 23568716 DOI: 10.1007/s10637-013-9956-5] [Citation(s) in RCA: 31] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/03/2013] [Accepted: 03/25/2013] [Indexed: 02/06/2023]
Abstract
PURPOSE Resistance to cetuximab, a monoclonal antibody against the epithelial growth factor receptor (EGFR), in colorectal cancer (CRC) may result from compensatory signaling through ErbB receptors, ErbB2/neu/HER2 (HER2) and ErbB3/HER3 (HER3). Pertuzumab is a monoclonal antibody that blocks HER2 hetero-dimerization; thus the combination of pertuzumab and cetuximab could possibly overcome cetuximab resistance. PATIENTS AND METHODS This single-arm, open-label, multicenter phase I/II study was designed to assess the safety and efficacy of pertuzumab and cetuximab in patients with cetuximab-resistant KRAS wild type metastatic CRC. Thirteen patients were enrolled and received cetuximab in combination with pertuzumab at several dose levels in a 3 + 3 design. Patients were assessed for dose-limiting toxicity (DLT) during the first cycle. A phase II portion was planned, but not initiated due to toxicity. RESULTS Six of the thirteen patients (46 %) experienced DLTs, therefore the study was terminated early. Grade 3 or higher DLTs included dermatitis with desquamation and/or acneiform rash (n = 6), mucositis or stomatitis (n = 5), and diarrhea (n = 2). There was one Grade 5 event (myocardial infarction) attributed to underlying disease. Among the 13 patients, seven (54 %) were evaluable for response. The objective response rate was 14 %: one patient had a partial response lasting 6 months. Two patients had stable disease (29 %), and four had progressive disease (57 %). Median progression free survival was 2.1 months (95 % CI, 1.5-4.9) and median overall survival was 3.7 months (95 % CI, 1.6-7.9). CONCLUSION Combination pertuzumab and cetuximab in refractory CRC was associated with potential antitumor activity; however, the combination was not tolerable due to overlapping toxicities.
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Affiliation(s)
- Douglas A Rubinson
- Department of Medical Oncology, Dana-Farber Cancer Institute, 450 Brookline Avenue, Boston, MA, 02215, USA
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Hubbard JM, Alberts SR. Alternate dosing of cetuximab for patients with metastatic colorectal cancer. GASTROINTESTINAL CANCER RESEARCH : GCR 2013; 6:47-55. [PMID: 23745159 PMCID: PMC3674463] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Subscribe] [Scholar Register] [Received: 01/24/2013] [Accepted: 03/25/2013] [Indexed: 06/02/2023]
Abstract
BACKGROUND Many chemotherapeutic regimens used to treat colorectal cancer (CRC), including 5-fluorouracil plus leucovorin in combination with irinotecan (FOLFIRI) or oxaliplatin (FOLFOX), are administered on an every-other-week (q2w) dosing schedule. Chemotherapy in combination with a monoclonal antibody (mAb) directed toward the epidermal growth factor receptor (EGFR) has emerged as an effective treatment option. There are currently 2 anti-EGFR mAbs approved by the United States Food and Drug Administration: cetuximab and panitumumab. Mutations of KRAS, a downstream protein in the EGFR pathway, predict resistance to EGFR mAbs. Thus, cetuximab and panitumumab are indicated for patients without a KRAS mutation (KRAS wild-type). Whereas panitumumab is approved on a q2w dosing schedule, cetuximab is approved as a weekly dose. However, only cetuximab is approved with FOLFIRI for frontline metastatic CRC, whereas panitumumab is approved for third-line. Because concomitant therapies are often administered q2w, the weekly dosing of cetuximab results in additional medical office visits. DESIGN Several studies have assessed the safety and efficacy of cetuximab q2w. For this review, a comprehensive literature search of studies evaluating cetuximab q2w dosing was conducted. Safety and efficacy results of these trials and retrospective analyses were summarized and reviewed. RESULTS In general, results with cetuximab q2w were comparable to those obtained with the weekly regimen. CONCLUSION These data suggest that for patients for whom weekly treatment with cetuximab presents a substantial burden to their quality of life, q2w dosing of cetuximab is a viable treatment option with a benefit:risk profile similar to that of the weekly regimen.
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Abdelwahab S, Azmy A, Abdel-Aziz H, Salim H, Mahmoud A. Anti-EGFR (cetuximab) combined with irinotecan for treatment of elderly patients with metastatic colorectal cancer (mCRC). J Cancer Res Clin Oncol 2012; 138:1487-92. [PMID: 22526166 DOI: 10.1007/s00432-012-1229-8] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/06/2012] [Accepted: 04/05/2012] [Indexed: 01/24/2023]
Abstract
PURPOSE This study was conducted to test the efficacy and toxicity of cetuximab and irinotecan as a biweekly regimen in treatment of elderly patients with metastatic colorectal cancer (mCRC). PATIENTS AND METHODS Forty-nine elderly patients (≥65 years) with mCRC who progressed after at least one previous line of treatment were enrolled into this study from May 2008 to January 2011. All recruited patients received cetuximab 500 mg/m(2) and irinotecan 180 mg/m(2) every 2 weeks. RESULTS Thirty-seven patients (76 %) were men, and 76 % of patients had colonic cancer in origin. Median age was 69 years. Median overall survival time was 7 months, and median progression-free survival was 4 months. Grade 3-4 skin rash occurred in 20 % of patients, grade 3-4 diarrhea in 18 % of patients, and neutropenia in 28 % of patients. CONCLUSION Cetuximab combined with irinotecan when administered biweekly is safe and effective for treatment of pretreated elderly patients with mCRC.
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Affiliation(s)
- S Abdelwahab
- Department of Clinical Oncology, Ain Shams University, 17 Abbas Akkad street extension, Nasr City, Cairo, 11371, Egypt.
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Huang MY, Chen MJ, Tsai HL, Kuo CH, Ma CJ, Hou MF, Chuang SC, Lin SR, Wang JY. Prospective analysis of KRAS wild-type patients with metastatic colorectal cancer using cetuximab plus FOLFIRI or FOLFOX4 treatment regimens. GENETICS AND MOLECULAR RESEARCH 2011; 10:3002-12. [PMID: 21968808 DOI: 10.4238/2011.october.3.4] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/03/2022]
Abstract
Cetuximab, a monoclonal antibody targeting epidermal growth factor receptor, has proven to be efficient in the treatment of metastatic colorectal cancer. We made a prospective study of the efficacy and toxicities of cetuximab-combination first-line (FOLFOX4) versus second/third-line (FOLFIRI) chemotherapy in 98 KRAS wild-type patients who had metastatic colorectal cancer. Wild-type KRAS had been identified by direct sequencing. Associations between clinical response/progression-free survival/overall survival/toxicities and cetuximab-combination chemotherapy timing were evaluated. The overall response rate was significantly higher for first-line treatment than for second/third-line treatment (relative risk = 1.707, 95% confidence interval = 1.121-2.598). Both progression-free survival and overall survival indicated significantly longer survival of first-line treatment than second/third-line treatment patients. This study is a validation of a molecular analysis of KRAS wild-type status for the prediction of response to cetuximab-combination chemotherapy for metastatic colorectal cancer patients; its predictive role was less prominent in the second/third-line than in the first-line treatment patients.
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Affiliation(s)
- M Y Huang
- Department of Radiation Oncology, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung, Taiwan
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30
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Carneiro BA, Ramanathan RK, Fakih MG, Krishnamurthi SS, Lembersky BC, Stoller RG, Lancaster SL, Pinkerton RA, Crandall TL, Schmotzer AR, Potter DM, Bahary N. Phase II study of irinotecan and cetuximab given every 2 weeks as second-line therapy for advanced colorectal cancer. Clin Colorectal Cancer 2011; 11:53-9. [PMID: 21813336 DOI: 10.1016/j.clcc.2011.05.003] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/01/2011] [Revised: 04/24/2011] [Accepted: 05/06/2011] [Indexed: 10/17/2022]
Abstract
BACKGROUND Irinotecan and weekly cetuximab (I+C) is a standard second-line regimen for metastatic colorectal cancer (mCRC). This study investigated the safety and efficacy of every 2 weeks I+C in patients with mCRC. PATIENTS AND METHODS Patients with mCRC refractory to first-line fluoropyrimidine/oxaliplatin regimens and not previously treated with I+C were eligible. Response rate (RR) was the primary endpoint. Cetuximab 500 mg/m(2) and irinotecan 180 mg/m(2) were administered intravenously (I.V.) on day 1 every 2 weeks. RESULTS Patient characteristics (n = 31): male (n = 17), median age 62; Eastern Cooperative Oncology Group (ECOG) performance status (PS) ≤1 (n = 30), and PS = 2 (n = 1). Median number of cycles = 3 (range, 1-22). I+C doses were modified in 18 and 12 patients, respectively. Grade 3/4 adverse events: acneiform rash (n = 6); neutropenia (n = 6); and diarrhea (n = 5); there was one grade 5 respiratory failure, possibly related to therapy. Two patients had a partial response, 11 had stable disease, and 18 had progressive disease resulting in an overall RR of 6% and disease control rate of 41.9%. Median overall survival (OS) was 9.3 months (95% CI, 5.1-15), and time to progression (TTP) was 2.4 months (95% CI, 1.3-4.6). K-ras and BRAF mutations were detected in 39% and 9%, respectively, of the patients tested. There was a trend toward longer TTP among patients with wild-type K-ras and BRAF (2.6 vs. 1.7 months; P = 0.16), and OS was significantly longer in those patients (14.1 vs. 5.5 months; P = 0.04). CONCLUSIONS The RR and TTP were lower than expected and may reflect the reduced dose intensity due to toxicities. While the OS was consistent with previous publications, the efficacy of this combination was not demonstrated.
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Shitara K, Ura T, Matsuo K, Takahari D, Yokota T, Yuki S, Yoshida M, Utsunomiya S, Sato Y, Yamaura H, Kato M, Inaba Y, Tajika M, Kawai H, Yamazaki K, Komatsu Y, Muro K. Sensitivity to previous irinotecan treatment does not predict the efficacy of combination chemotherapy with cetuximab plus irinotecan for wild-type KRAS metastatic colorectal cancer. Eur J Cancer 2011; 47:2673-80. [PMID: 21652203 DOI: 10.1016/j.ejca.2011.05.015] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/23/2010] [Revised: 04/02/2011] [Accepted: 05/10/2011] [Indexed: 11/29/2022]
Abstract
The aim of this study was to evaluate the association of sensitivity to previous irinotecan-based chemotherapy with efficacy of cetuximab plus irinotecan therapy in metastatic colorectal cancer (MCRC) patients with wild-type KRAS. We analysed a pooled data set consisting of data from 87 MCRC patients from two previous phase II studies (n=60) and a group given off-protocol treatment (n=27) following irinotecan-, oxaliplatin-, and fluoropyrimidine-based chemotherapy. Overall objective response rate to cetuximab plus irinotecan was 28.7%, median progression-free survival (PFS) was 5.3 months, and median overall survival was 12.2 months. Objective response rate did not significantly differ between patients with a favourable response to previous irinotecan (n=23), stable disease (n=38), or progressive disease (n=26), with observed rates of 29.2%, 31.6%, and 23.1%, respectively. Additionally, the non-parametric Spearman rank correlation coefficients (ρ) between the PFS of previous irinotecan-based chemotherapy and that of cetuximab plus irinotecan were quite low (ρ=0.067 and 0.057 in patients with previous irinotecan as first- and second-line therapies, respectively). Although exploratory nature and small sample size may be limitations of this study, these findings indicate that the efficacy of irinotecan plus cetuximab in MCRC patients with wild-type KRAS did not differ by previous sensitivity to irinotecan.
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Affiliation(s)
- Kohei Shitara
- Department of Clinical Oncology, Aichi Cancer Center Hospital, Nagoya, Japan.
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Phase II study of combination chemotherapy with biweekly cetuximab and irinotecan for wild-type KRAS metastatic colorectal cancer refractory to irinotecan, oxaliplatin, and fluoropyrimidines. Invest New Drugs 2010; 30:787-93. [DOI: 10.1007/s10637-010-9615-z] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/05/2010] [Accepted: 11/30/2010] [Indexed: 10/18/2022]
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33
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Herbst RS, Kelly K, Chansky K, Mack PC, Franklin WA, Hirsch FR, Atkins JN, Dakhil SR, Albain KS, Kim ES, Redman M, Crowley JJ, Gandara DR. Phase II selection design trial of concurrent chemotherapy and cetuximab versus chemotherapy followed by cetuximab in advanced-stage non-small-cell lung cancer: Southwest Oncology Group study S0342. J Clin Oncol 2010; 28:4747-54. [PMID: 20921467 PMCID: PMC3020704 DOI: 10.1200/jco.2009.27.9356] [Citation(s) in RCA: 53] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/03/2010] [Accepted: 08/12/2010] [Indexed: 02/07/2023] Open
Abstract
PURPOSE Randomized clinical trials failed to show a survival benefit for epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors plus concurrent chemotherapy in patients with metastatic non-small-cell lung cancer (NSCLC), with preclinical data suggesting potential negative interactions. In contrast, pilot trials of the EGFR-targeted antibody, cetuximab, plus chemotherapy suggested enhanced antitumor activity. This randomized phase II trial was designed to select a cetuximab plus chemotherapy regimen for phase III evaluation. PATIENTS AND METHODS Treatment-naive patients with advanced-stage NSCLC were randomly assigned to receive paclitaxel (225 mg/m(2)) and carboplatin (area under the curve, 6) every 3 weeks plus concurrent cetuximab (400 mg/m(2) loading dose followed by 250 mg/m(2) weekly) for four cycles followed by maintenance cetuximab or sequential paclitaxel-carboplatin for four cycles followed by cetuximab. RESULTS Of 242 patients enrolled, 224 were eligible and assessable for response (106 and 118 patients in the concurrent and sequential arms, respectively). With a median follow-up time of 32 months, the median overall survival was 10.9 months (95% CI, 9.2 to 13.0 months) for patients receiving concurrent therapy and 10.7 months (95% CI, 8.5 to 12.8 months) for patients receiving sequential therapy (P = .57); 1-year survival rates were 45% (95% CI, 36% to 54%) and 44% (95% CI, 35% to 53%), respectively. Response rates and progression-free survival times were similar in both arms, as was grade 3 rash, whereas sensory neuropathy was higher in the concurrent arm (15% v 5% in the sequential arm; P = .036). CONCLUSION Although both regimens met the efficacy criterion for continued evaluation, the concurrent regimen of paclitaxel/carboplatin plus cetuximab was chosen.
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Affiliation(s)
- Roy S Herbst
- Department of Thoracic/Head and Neck Medical Oncology, Section of Thoracic Medical Oncology, The University of Texas M. D. Anderson Cancer Center, Houston, TX 77030-4009, USA.
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Tabernero J, Ciardiello F, Rivera F, Rodriguez-Braun E, Ramos F, Martinelli E, Vega-Villegas M, Roselló S, Liebscher S, Kisker O, Macarulla T, Baselga J, Cervantes A. Cetuximab administered once every second week to patients with metastatic colorectal cancer: a two-part pharmacokinetic/pharmacodynamic phase I dose-escalation study. Ann Oncol 2010; 21:1537-1545. [DOI: 10.1093/annonc/mdp549] [Citation(s) in RCA: 62] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/23/2023] Open
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Fakih M, Wong R. Efficacy of the monoclonal antibody EGFR inhibitors for the treatment of metastatic colorectal cancer. Curr Oncol 2010; 17 Suppl 1:S3-17. [PMID: 20680105 PMCID: PMC2901794 DOI: 10.3747/co.v17is1.616] [Citation(s) in RCA: 54] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/05/2023] Open
Abstract
Two anti-epidermal growth factor receptor (EGFR) monoclonal antibodies (MoAbs) have been approved in Canada for the treatment of metastatic colorectal cancer (mCRC) - cetuximab, a mouse-human chimeric MoAb, and panitumumab, a fully human MoAb. This paper reviews the efficacy of the anti-EGFR monoclonal antibodies cetuximab and panitumumab - both as monotherapy and in combination with cytotoxic chemotherapy - in the treatment of mCRC. Both cetuximab and panitumumab have demonstrated clinical efficacy in monotherapy in patients with mCRC, an advantage that has recently been found to be limited largely to those with wild-type KRAS tumors. Advantages of using these agents in monotherapy include reduced cost and toxicity. While the addition of cetuximab to irinotecan has shown superior progression-free survival and response compared with cetuximab monotherapy, there is currently no evidence for a benefit of panitumumab in combination with irinotecan.
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Affiliation(s)
- M Fakih
- Department of Medicine, Roswell Park Cancer Institute, Buffalo, New York.
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Abstract
Cetuximab, a chimeric IgG(1) monoclonal antibody directed against the ligand-binding domain of the epidermal growth factor receptor, offers a paradigm for the combination of molecularly targeted therapies with cytotoxic agents. In preclinical models, the addition of cetuximab to chemotherapy or radiation therapy enhances antitumor activity. Proposed mechanisms include reducing tumor cell proliferation, angiogenesis, and DNA repair capacity; increasing apoptosis; and inducing cell cycle arrest at treatment-sensitive points. These effects may enhance and restore tumor sensitivity to cytotoxic therapies. In clinical trials, the addition of cetuximab to chemotherapy improves outcomes of patients who had previously failed such agents, as illustrated in irinotecan-resistant and oxaliplatin-refractory metastatic colorectal cancer. As initial therapy, the addition of cetuximab to chemotherapy extends survival in colorectal cancer, lung cancer, and head and neck cancer. Combining cetuximab with radiation therapy extends survival in locally advanced head and neck cancer. As predictive biomarkers are identified, it may become possible to select patients most likely to benefit from such combinations.
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Affiliation(s)
- David E Gerber
- Division of Hematology-Oncology, Department of Internal Medicine, University of Texas Southwestern Medical Center, 5323 Harry Hines Boulevard, Mail Code 8852, Dallas, TX, 75390-8852, USA.
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Shitara K, Yokota T, Takahari D, Shibata T, Ura T, Komatsu Y, Yuki S, Yoshida M, Takiuchi H, Utsunomiya S, Yatabe Y, Muro K. Phase II Study of Combination Chemotherapy with Biweekly Cetuximab and Irinotecan for Pre-treated Metastatic Colorectal Cancer Harboring Wild-type KRAS. Jpn J Clin Oncol 2010; 40:699-701. [DOI: 10.1093/jjco/hyq026] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022] Open
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Hoag JB, Azizi A, Doherty TJ, Lu J, Willis RE, Lund ME. Association of cetuximab with adverse pulmonary events in cancer patients: a comprehensive review. J Exp Clin Cancer Res 2009; 28:113. [PMID: 19682368 PMCID: PMC2735734 DOI: 10.1186/1756-9966-28-113] [Citation(s) in RCA: 31] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/26/2009] [Accepted: 08/14/2009] [Indexed: 12/16/2022] Open
Abstract
Compounds derived from biologic sources, or biologicals, are increasingly utilized as therapeutic agents in malignancy. Development of anti-cancer targeted therapies from biologics is increasingly being utilized. Cetuximab, a chimeric monoclonal antibody, is one such anti-cancer targeted therapeutic that has shown efficacy in quelling the rate of patient decline in colorectal, head/neck, and non-small cell lung cancer. However, due to the relatively recent addition of biologic compounds to the therapeutic arsenal, information related to adverse reactions is less well known than those seen in traditional chemotherapeutics. Dermatologic reactions have been demonstrated as the most frequent side effect cited during cetuximab therapy for malignancy; however, other effects may lead to greater morbidity. In general, pulmonary complications of therapeutics can lead to significant morbidity and mortality. The purpose of this review is to compile the various pulmonary side effects seen in patients treated with cetuximab for various malignancies, and to compare the incidence of these adverse reactions to standard therapies.
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Affiliation(s)
- Jeffrey B Hoag
- Cancer Treatment Centers of America, Eastern Regional Medical Center, Philadelphia, PA, USA
- Drexel University College of Medicine, Philadelphia, PA, USA
| | - Aimel Azizi
- Drexel University College of Medicine, Philadelphia, PA, USA
| | | | - Jason Lu
- Drexel University College of Medicine, Philadelphia, PA, USA
| | - Rudolph E Willis
- Cancer Treatment Centers of America, Eastern Regional Medical Center, Philadelphia, PA, USA
| | - Mark E Lund
- Cancer Treatment Centers of America, Eastern Regional Medical Center, Philadelphia, PA, USA
- Drexel University College of Medicine, Philadelphia, PA, USA
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Schuch G, Kobold S, Bokemeyer C. Evolving role of cetuximab in the treatment of colorectal cancer. Cancer Manag Res 2009; 1:79-88. [PMID: 21188126 PMCID: PMC3004666] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/22/2009] [Indexed: 11/23/2022] Open
Abstract
In recent years, the monoclonal epidermal growth factor receptor (EGFR)-targeting antibody cetuximab was introduced into systemic therapy of colorectal cancer and gained an established role in the treatment of this disease. Cetuximab was shown to be active as a single agent in chemorefractory metastatic disease as well as in combination with varying chemotherapies. Recently, randomized trials demonstrated the activity of cetuximab combinations in the first-line setting of metastatic colorectal cancer. Interestingly, the activity of cetuximab was restricted to patients with KRAS wildtype tumors, as was seen with panitumumab, another EGFR antibody. While 60%-70% of tumors harbor KRAS wildtype genes, 30%-40% of tumors express oncogenic KRAS with mutations in codons 12 and 13 causing constitutive activation of signaling cascades downstream of EGFR and resistance to EGFR blockade. Since proof of KRAS wildtype status became a prerequisite for cetuximab treatment, KRAS testing is being established throughout the world. Future trials will address the question which part of the KRAS wildtype cohort will benefit from EGFR inhibition and how to identify those patients. Additionally, new strategies for treatment of KRAS mutated tumors are strongly needed. Recent developments and future strategies will be summarized.
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Affiliation(s)
- Gunter Schuch
- Department of Oncology, Hematology, and Bone Marrow Transplantation with Section of Pneumology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Sebastian Kobold
- Department of Oncology, Hematology, and Bone Marrow Transplantation with Section of Pneumology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Carsten Bokemeyer
- Department of Oncology, Hematology, and Bone Marrow Transplantation with Section of Pneumology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
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Current status of treatment of metastatic colorectal cancer with special reference to cetuximab and elderly patients. Onco Targets Ther 2009; 2:17-27. [PMID: 20616891 PMCID: PMC2886318] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/29/2022] Open
Abstract
PURPOSE Elderly cancer patients often have co-morbidities and other characteristics that make the selection of optimal treatment more complex. The introduction of targeted therapies in colorectal cancer has further complicated this problem. This review will focus on the role of the EGFR antibody cetuximab in elderly patients. METHODS We have reviewed the available evidence in the literature to evaluate the results of therapy with cetuximab, alone or in combination with chemotherapy, with a focus on elderly patients with metastatic colorectal cancer (mCRC). RESULTS In patients with mCRC, combination chemotherapy prolongs median survival to more than 18 months and even around 24 months in combination with cetuximab in selected patients. No prospective studies have evaluated cetuximab in elderly patients. However, subgroup analyses from randomized trials and retrospective analysis suggest that the efficacy of chemotherapy and cetuximab is maintained in fit elderly patients, but with slightly increased but acceptable toxicity. CONCLUSION No prospective cetuximab studies have been conducted solely in a population of elderly patients. However, available data suggest that outcomes in the fit elderly mirror results observed in younger patients.
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Peeters M, Price T, Van Laethem JL. Anti-epidermal growth factor receptor monotherapy in the treatment of metastatic colorectal cancer: where are we today? Oncologist 2009; 14:29-39. [PMID: 19144681 DOI: 10.1634/theoncologist.2008-0167] [Citation(s) in RCA: 53] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022] Open
Abstract
Over the past 10 years there has been a significant increase in the armamentarium of agents available for use in the treatment of advanced colorectal cancer (CRC). Among these new agents are two monoclonal antibodies targeting the epidermal growth factor receptor (EGFR): cetuximab, a mouse-human chimeric monoclonal antibody, and panitumumab, a fully human monoclonal antibody. Both are approved as monotherapy for the treatment of chemotherapy-refractory advanced CRC. Cetuximab is also indicated for use in combination with irinotecan. Here, we review 10 reports of phase II and III clinical studies of patients treated with panitumumab or cetuximab monotherapy. The clinical trials demonstrate similar efficacy profiles for advanced CRC patients treated with panitumumab and cetuximab monotherapy, with some differences in their adverse event profiles. In addition, the recent results of retrospective tumor KRAS gene mutational analyses in CRC patients treated with anti-EGFR monotherapy are reviewed. Data from the clinical trials reviewed here clearly demonstrate that anti-EGFR monotherapy is an effective treatment modality for patients with chemotherapy-refractory advanced CRC.
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Affiliation(s)
- Marc Peeters
- Department of Hepatogastroenterology, Digestive Oncology Unit, University Hospital Ghent, Gent, Belgium.
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