title: Retreatment with anti-EGFR based therapies in metastatic colorectal cancer: impact of intervening time interval and prior anti-EGFR response.
abstract: BACKGROUND
  This retrospective study aims to investigate the activity of retreatment with anti-EGFR-based therapies in order to explore the concept of clonal evolution by evaluating the impact of prior activity and intervening time interval.
  
  
  METHODS
  Eighty-nine KRAS exon 2-wild-type metastatic colorectal patients were retreated on phase I/II clinical trials containing anti-EGFR therapies after progressing on prior cetuximab or panitumumab. Response on prior anti-EGFR therapy was defined retrospectively per physician-records as response or stable disease ≥6 months. Multivariable statistical methods included a multiple logistic regression model for response, and Cox proportional hazards model for progression-free survival.
  
  
  RESULTS
  Retreatment anti-EGFR agents were cetuximab (n = 76) or cetuximab plus erlotinib (n = 13). The median interval time between prior and retreatment regimens was 4.57 months (range: 0.46-58.7). Patients who responded to the prior cetuximab or panitumumab were more likely to obtain clinical benefit to the retreatment compared to the non-responders in both univariate (p = 0.007) and multivariate analyses (OR: 3.38, 95 % CI: 1.27, 9.31, p = 0.019). The clinical benefit rate on retreatment also showed a marginally significant association with interval time between the two anti-EGFR based therapies (p = 0.053). Median progression-free survival on retreatment was increased in prior responders (4.9 months, 95 % CI: 3.6, 6.2) compared to prior non-responders (2.5 months, 95 % CI, 1.58, 3.42) in univariate (p = 0.064) and multivariate analysis (HR: 0.70, 95 % CI: 0.43-1.15, p = 0.156).
  
  
  CONCLUSIONS
  Our data lends support to the concept of clonal evolution, though the clinical impact appears less robust than previously reported. Further work to determine which patients benefit from retreatment post progression is needed.
authors.affiliation: Department of Investigational Cancer Therapeutics (Phase 1 Clinical Trials Program), The University of Texas MD Anderson Cancer Center, Unit 455, 1515 Holcombe Blvd, Houston, TX, 77030, USA. xiaochunliu2013@gmail.com.
authors.forename: X
authors.initials: X
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authors.affiliation: Department of Investigational Cancer Therapeutics (Phase 1 Clinical Trials Program), The University of Texas MD Anderson Cancer Center, Unit 455, 1515 Holcombe Blvd, Houston, TX, 77030, USA. GGeorge2@mdanderson.org.
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authors.affiliation: Department of Investigational Cancer Therapeutics (Phase 1 Clinical Trials Program), The University of Texas MD Anderson Cancer Center, Unit 455, 1515 Holcombe Blvd, Houston, TX, 77030, USA. atsimber@mdanderson.org.
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authors.affiliation: Department of Investigational Cancer Therapeutics (Phase 1 Clinical Trials Program), The University of Texas MD Anderson Cancer Center, Unit 455, 1515 Holcombe Blvd, Houston, TX, 77030, USA. anaing@mdanderson.org.
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authors.affiliation: Department of Investigational Cancer Therapeutics (Phase 1 Clinical Trials Program), The University of Texas MD Anderson Cancer Center, Unit 455, 1515 Holcombe Blvd, Houston, TX, 77030, USA. jjwheler@mdanderson.org.
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authors.affiliation: Department of Gastrointestinal Medical Oncology, University of Texas MD Anderson Cancer Center, 1515 Holcombe Boulevard, Unit # 426, Houston, TX, 77030, USA. skopetz@mdanderson.org.
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authors.affiliation: Department of Investigational Cancer Therapeutics (Phase 1 Clinical Trials Program), The University of Texas MD Anderson Cancer Center, Unit 455, 1515 Holcombe Blvd, Houston, TX, 77030, USA. siqingfu@mdanderson.org.
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authors.affiliation: Department of Investigational Cancer Therapeutics (Phase 1 Clinical Trials Program), The University of Texas MD Anderson Cancer Center, Unit 455, 1515 Holcombe Blvd, Houston, TX, 77030, USA. spihapau@mdanderson.org.
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authors.lastname: Piha-Paul
authors.affiliation: Department of Gastrointestinal Medical Oncology, University of Texas MD Anderson Cancer Center, 1515 Holcombe Boulevard, Unit # 426, Houston, TX, 77030, USA. ceng@mdanderson.org.
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authors.affiliation: Department of Investigational Cancer Therapeutics (Phase 1 Clinical Trials Program), The University of Texas MD Anderson Cancer Center, Unit 455, 1515 Holcombe Blvd, Houston, TX, 77030, USA. Gerald.Falchook@scresearch.net.
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authors.affiliation: Department of Investigational Cancer Therapeutics (Phase 1 Clinical Trials Program), The University of Texas MD Anderson Cancer Center, Unit 455, 1515 Holcombe Blvd, Houston, TX, 77030, USA. FJanku@mdanderson.org.
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authors.affiliation: Department of Gastrointestinal Medical Oncology, University of Texas MD Anderson Cancer Center, 1515 Holcombe Boulevard, Unit # 426, Houston, TX, 77030, USA. cgarrett@mdanderson.org.
authors.forename: C
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authors.affiliation: Department of Investigational Cancer Therapeutics (Phase 1 Clinical Trials Program), The University of Texas MD Anderson Cancer Center, Unit 455, 1515 Holcombe Blvd, Houston, TX, 77030, USA. dkarp@mdanderson.org.
authors.forename: D
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authors.affiliation: Division of Hematology and Oncology, University of California San Diego Moores Cancer Center, San Diego, CA, USA. rkurzrock@mail.ucsd.edu.
authors.forename: R
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authors.lastname: Kurzrock
authors.affiliation: Department of Investigational Cancer Therapeutics (Phase 1 Clinical Trials Program), The University of Texas MD Anderson Cancer Center, Unit 455, 1515 Holcombe Blvd, Houston, TX, 77030, USA. rzinner@mdanderson.org.
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authors.affiliation: Department of Gastrointestinal Medical Oncology, University of Texas MD Anderson Cancer Center, 1515 Holcombe Boulevard, Unit # 426, Houston, TX, 77030, USA. KPRaghav@mdanderson.org.
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authors.affiliation: Department of Investigational Cancer Therapeutics (Phase 1 Clinical Trials Program), The University of Texas MD Anderson Cancer Center, Unit 455, 1515 Holcombe Blvd, Houston, TX, 77030, USA. VSubbiah@mdanderson.org.
authors.forename: V
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authors.affiliation: Biostatistics, University of Texas MD Anderson Cancer Center, Houston, TX, USA. khess@mdanderson.org.
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authors.lastname: Hess
authors.affiliation: Department of Investigational Cancer Therapeutics (Phase 1 Clinical Trials Program), The University of Texas MD Anderson Cancer Center, Unit 455, 1515 Holcombe Blvd, Houston, TX, 77030, USA. fmeric@mdanderson.org.
authors.forename: F
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authors.lastname: Meric-Bernstam
authors.affiliation: Department of Investigational Cancer Therapeutics (Phase 1 Clinical Trials Program), The University of Texas MD Anderson Cancer Center, Unit 455, 1515 Holcombe Blvd, Houston, TX, 77030, USA. dshong@mdanderson.org.
authors.forename: D S
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authors.affiliation: Department of Gastrointestinal Medical Oncology, University of Texas MD Anderson Cancer Center, 1515 Holcombe Boulevard, Unit # 426, Houston, TX, 77030, USA. moverman@mdanderson.org.
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mesh_terms: D000328:Adult; D000368:Aged; D000911:Antibodies, Monoclonal / Q000008:administration & dosage*; D061067:Antibodies, Monoclonal, Humanized / Q000008:administration & dosage*; D000068818:Cetuximab / Q000008:administration & dosage; D015179:Colorectal Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D018572:Disease-Free Survival; D066246:ErbB Receptors / Q000037:antagonists & inhibitors / Q000235:genetics*; D000069347:Erlotinib Hydrochloride / Q000008:administration & dosage; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D009362:Neoplasm Metastasis; D000077544:Panitumumab; D016283:Proto-Oncogene Proteins p21(ras) / Q000235:genetics; D019233:Retreatment
chemical_list: D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; C117307:KRAS protein, human; D000077544:Panitumumab; D000069347:Erlotinib Hydrochloride; C512478:EGFR protein, human; D066246:ErbB Receptors; D016283:Proto-Oncogene Proteins p21(ras); D000068818:Cetuximab