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Phase II study of panitumumab combined with capecitabine and oxaliplatin as first-line treatment in metastatic colorectal cancer patients: clinical results including extended tumor genotyping

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Abstract

This clinical trial assessed the efficacy and toxicity of panitumumab combined with oxaliplatin and capecitabine as first-line treatment in KRAS exon 2 wild-type metastatic colorectal cancer (mCRC) patients. Patients with exon 2 KRAS wild-type mCRC received panitumumab 9 mg/Kg, oxaliplatin 130 mg/m2, and capecitabine 2000 mg/m2 repeated every 3 weeks. The primary endpoint was objective response rate (ORR, minimum 42 responses). We retrospectively assessed mutations in genes implicated in CRC with massively parallel sequencing; ERBB2 and EGFR amplification with fluorescence in situ hybridization, and tumor-infiltrating lymphocyte density. Among 78 patients enrolled, 45 (57.7%) completed 6 cycles. Most common grade 3–4 toxicities were skin rash (19.2%), diarrhea (18%), and neuropathy (6.4%). Among 5 (6.4%) potentially treatment-related deaths, 2 (2.6%) were characterized toxic. Objective response occurred in 43 (55.1%) of the patients (complete 6.4% and partial response 48.7%; stable 17.9% and progressive disease 7.7%), while 3.8% were non-evaluable and 15% discontinued their treatment early. Additional mutations in KRAS/NRAS/BRAF were found in 11/62 assessable (18%) tumors. After 51 months median follow-up, median progression-free (PFS) was 8.1 and overall survival 20.2 months, independently of KRAS/NRAS/BRAF or PI3K-pathway mutation status. Patients with TP53 mutations (n = 34; 55%), as well as those with left colon primary tumors (n = 66; 85%), had significantly better PFS, also confirmed in multivariate analysis. Although the clinical trial met its primary endpoint, according to the current standards, the efficacy and tolerability of the drug combination are considered insufficient. Extended genotyping yielded interesting results regarding the significance of TP53 mutations.

ClinicalTrials.gov identifier: NCT01215539, Registration date: Sep 29, 2010.

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Acknowledgements

The authors are indebted to all patients and their families for their trust and participation in the HE6A/09 trial as well as for the provision of biological material for research purposes. The authors wish to thank Dimitra Katsala for monitoring the study, Athina Goudopoulou for clinical safety coordination, and Maria Moschoni for data coordination.

Funding

The study was supported by a research grant from Amgen Ltd. and by an internal Hellenic Cooperative Oncology Group (HeCOG) translational research grant (HER_6A/09).

Author information

Author notes

    Authors and Affiliations

    1. Oncology Section, Second Department of Internal Medicine, Hippokration Hospital, 11527, Athens, Greece

      George Papaxoinis & Dimitrios Pectasides

    2. Department of Pathology, Faculty of Medicine, School of Health Sciences, Aristotle University of Thessaloniki, Thessaloniki, Greece

      Vassiliki Kotoula, Emily Daskalaki & Elisavet Pazarli

    3. Laboratory of Molecular Oncology, Hellenic Foundation for Cancer Research/Aristotle University of Thessaloniki, Thessaloniki, Greece

      Vassiliki Kotoula, Sotirios Lakis, Mattheos Bobos, Elpida Chalaralambous, Kyriakos Chatzopoulos, Sofia Chrisafi & George Fountzilas

    4. Victor Chang Cardiac Research Institute, Darlinghurst, NSW, Australia

      Eleni Giannoulatou

    5. The University of New South Wales, Kensington, NSW, Australia

      Eleni Giannoulatou

    6. Section of Biostatistics, Hellenic Cooperative Oncology Group, Data Office, Athens, Greece

      Georgia-Angeliki Koliou

    7. Department of Medical Oncology, Faculty of Medicine, School of Health Sciences, Papageorgiou Hospital, Aristotle University of Thessaloniki, Thessaloniki, Greece

      Vasilios Karavasilis

    8. Department of Radiology, Aretaieio Hospital, National and Kapodistrian University of Athens, Athens, Greece

      Andreas Koureas

    9. Department of Clinical Therapeutics, Alexandra Hospital, National and Kapodistrian University of Athens School of Medicine, Athens, Greece

      George Tsironis

    10. Third Department of Medical Oncology, Agii Anargiri Cancer Hospital, Athens, Greece

      Epaminontas Samantas

    11. Department of Surgery, School of Health Sciences, General Oncologic Hospital of Kifisia, National and Kapodistrian University of Athens, Athens, Greece

      Ioannis G. Kaklamanos

    12. Oncology Department, General Hospital of Chania, Crete, Greece

      Ioannis Varthalitis

    13. Department of Surgery, St. Luke’s Hospital, Thessaloniki, Greece

      Athina Konstantara

    14. Oncology Unit GPP, Sotiria General Hospital, National and Kapodistrian University of Athens School of Medicine, Athens, Greece

      Konstantinos N. Syrigos

    15. Department of Medical Oncology, Ioannina University Hospital, Ioannina, Greece

      George Pentheroudakis

    16. Aristotle University of Thessaloniki, Thessaloniki, Greece

      George Fountzilas

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    1. George Papaxoinis
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    Contributions

    GPap conceived the study, participated in its design, contributed to the acquisition, analysis, and interpretation of data, and drafted the manuscript. VKot conceived the study, participated in its design, contributed to the acquisition, analysis, and interpretation of data and drafted the manuscript. EG contributed to the analysis and interpretation of data and revised critically the manuscript. GAK contributed to the analysis and interpretation of data and drafted the manuscript. VKar contributed to the acquisition of data and revised critically the manuscript. SL contributed to the acquisition, analysis, and interpretation of data and revised critically the manuscript. AKou contributed to the acquisition of data and revised critically the manuscript. MB contributed to the acquisition, analysis, and interpretation of data and revised critically the manuscript. EC contributed to the acquisition, analysis, and interpretation of data and revised critically the manuscript. ED contributed to the acquisition, analysis, and interpretation of data and revised critically the manuscript. KC contributed to the acquisition of data and revised critically the manuscript. GT contributed to the acquisition of data and revised critically the manuscript. EP contributed to the acquisition of data and revised critically the manuscript. SC contributed to the acquisition, analysis, and interpretation of data and revised critically the manuscript. ES contributed to the acquisition of data and revised critically the manuscript. IGK contributed to the acquisition of data and revised critically the manuscript. IV contributed to the acquisition of data and revised critically the manuscript. AKon contributed to the acquisition of data and revised critically the manuscript. KNS contributed to the acquisition of data and revised critically the manuscript. GPen conceived the study, participated in its design, contributed to the acquisition, analysis, and interpretation of data, and drafted the manuscript. DP conceived the study, participated in its design, contributed to the acquisition of data, and drafted the manuscript. GF conceived the study, participated in its design, contributed to the acquisition, analysis, and interpretation of data, and drafted the manuscript. All authors approved the final version of the manuscript to be published and agreed to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

    Corresponding author

    Correspondence to George Papaxoinis.

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    Conflict of interest

    VKar: Advisory Board of Amgen, Pfizer, Novartis, BI, Lilly, Astellas, Genesis-Pharma, and Janssen. SL: Employee of NEO New Oncology GmbH and Consultant BioTech AG. ES: Advisory Board of Merck, MSD, Astra-Zeneca, Roche, Amgen, and Genesis. GF: Advisory Board of Pfizer, Sanofi, and Roche. Honoraria from Astra-Zeneca. The rest of the authors declare that they have no conflict of interest.

    Ethical approval

    All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards. The clinical protocol was approved by the Institutional Review Boards of Papageorgiou General Hospital, Ioannina University Hospital, Agii Anargiri Cancer Hospital, Sotiria General Hospital, Alexandra Hospital, Patra University Hospital, Metropolitan Hospital, Hygeia Hospital, Chania General Hospital, Hippokration Hospital, and by the National Organization for Medicines. The trial was registered with the ClinicalTrials.gov identifier: NCT01215539. The translational research protocol was approved by the Institutional Review Board of the Papageorgiou General Hospital (08/04/2009 #233).

    Informed consent

    Informed consent was obtained from all individual participants included in the study. In addition, patients who were willing to provide biological material for future translational research studies signed a separate informed consent.

    Additional information

    George Papaxoinis and Vassiliki Kotoula authors contributed equally to this study.

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    Papaxoinis, G., Kotoula, V., Giannoulatou, E. et al. Phase II study of panitumumab combined with capecitabine and oxaliplatin as first-line treatment in metastatic colorectal cancer patients: clinical results including extended tumor genotyping. Med Oncol 35, 101 (2018). https://doi.org/10.1007/s12032-018-1160-1

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