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Gemcitabine plus erlotinib followed by capecitabine versus capecitabine plus erlotinib followed by gemcitabine in advanced pancreatic cancer: final results of a randomised phase 3 trial of the ‘Arbeitsgemeinschaft Internistische Onkologie’ (AIO-PK0104)
  1. Volker Heinemann1,
  2. Ursula Vehling-Kaiser2,
  3. Dirk Waldschmidt3,
  4. Erika Kettner4,
  5. Angela Märten5,
  6. Cornelia Winkelmann6,
  7. Stefan Klein7,
  8. Georgi Kojouharoff8,
  9. Thomas C Gauler9,
  10. Ludwig Fischer von Weikersthal10,
  11. Michael R Clemens11,
  12. Michael Geissler12,
  13. Tim F Greten13,
  14. Susanna Hegewisch-Becker14,
  15. Oleg Rubanov15,
  16. Gerold Baake16,
  17. Thomas Höhler17,
  18. Yon D Ko18,
  19. Andreas Jung19,
  20. Sascha Neugebauer20,
  21. Stefan Boeck1
  1. 1Department of Internal Medicine III and Comprehensive Cancer Center, Klinikum Grosshadern, Ludwig-Maximilians-University of Munich, Munich, Germany
  2. 2Practice for Medical Oncology, Landshut, Germany
  3. 3Department of Gastroenterology and Hepatology, University of Cologne, Cologne, Germany
  4. 4Department of Hematology/Oncology, Klinikum Magdeburg, Magdeburg, Germany
  5. 5Department of Surgery, University of Heidelberg, Heidelberg, Germany
  6. 6Department of Internal Medicine, Krankenhaus Lutherstadt-Wittenberg, Lutherstadt-Wittenberg, Germany
  7. 7Department of Internal Medicine IV, Klinikum Bayreuth, Bayreuth, Germany
  8. 8Practice for Medical Oncology, Darmstadt, Germany
  9. 9Department of Medicine (Cancer Research), West German Cancer Center, University of Duisburg-Essen, Essen, Germany
  10. 10Department of Oncology, Gesundheitszentrum St. Marien GmbH, Amberg, Germany
  11. 11Department of Internal Medicine I, Klinikum Trier, Trier, Germany
  12. 12Department of Gastroenterology and Oncology, Klinikum Esslingen, Klinikum Esslingen, Germany
  13. 13Department of Gastroenterology, Hepatology and Endocrinology, Medical School of Hannover, Hannover, Germany
  14. 14Practice for Medical Oncology, Hamburg, Germany
  15. 15Practice for Medical Oncology, Hameln, Germany
  16. 16Practice for Medical Oncology, Pinneberg, Germany
  17. 17Department of Internal Medicine I, Prosper Hospital, Recklinghausen, Germany
  18. 18Department of Medical Oncology, Johanniter Krankenhaus, Bonn, Germany
  19. 19Department of Pathology, Ludwig-Maximilians-University of Munich, Munich, Germany
  20. 20WiSP Research Institute, Langenfeld, Germany
  1. Correspondence to Professor Volker Heinemann, Department of Internal Medicine III and Comprehensive Cancer Center, Klinikum Grosshadern, Ludwig-Maximilians University of Munich, Marchioninistr. 15, D-81377 Munich, Germany; volker.heinemann{at}


Objective AIO-PK0104 investigated two treatment strategies in advanced pancreatic cancer (PC): a reference sequence of gemcitabine/erlotinib followed by 2nd-line capecitabine was compared with a reverse experimental sequence of capecitabine/erlotinib followed by gemcitabine.

Methods 281 patients with PC were randomly assigned to 1st-line treatment with either gemcitabine plus erlotinib or capecitabine plus erlotinib. In case of treatment failure (eg, disease progression or toxicity), patients were allocated to 2nd-line treatment with the comparator cytostatic drug without erlotinib. The primary study endpoint was time to treatment failure (TTF) after 1st- and 2nd-line therapy (TTF2; non-inferiority design). KRAS exon 2 mutations were analysed in archival tumour tissue from 173 of the randomised patients.

Results Of the 274 eligible patients, 43 had locally advanced and 231 had metastatic disease; 140 (51%) received 2nd-line chemotherapy. Median TTF2 was estimated with 4.2 months in both arms; median overall survival was 6.2 months with gemcitabine/erlotinib followed by capecitabine and 6.9 months with capecitabine/erlotinib followed by gemcitabine, respectively (HR 1.02, p=0.90). TTF for 1st-line therapy (TTF1) was significantly prolonged with gemcitabine/erlotinib compared to capecitabine/erlotinib (3.2 vs 2.2 months; HR 0.69, p=0.0034). Skin rash was associated with both TTF2 (rash grade 0/1/2–4:2.9/4.3/6.7 months, p<0.0001) and survival (3.4/7.0/9.6 months, p<0.0001). Each arm showed a safe and manageable toxicity profile during 1st- and 2nd-line therapy. A KRAS wild-type status (52/173 patients, 30%) was associated with an improved overall survival (HR 1.68, p=0.005).

Conclusion Both treatment strategies are feasible and demonstrated comparable efficacy; KRAS may serve as biomarker in patients with advanced PC treated with erlotinib.

Trial registration number This study was registered at, number NCT00440167.

Significance of this study

What is already known on this subject?

What is already known on this subject?

  • Gemcitabine-based chemotherapy remains an international standard of care for patients with non-resectable, advanced pancreatic cancer (PC).

  • Anti-EGFR treatment with the tyrosine kinase inhibitor erlotinib, as well as chemotherapy intensification by application of the FOLFIRINOX regimen, both significantly improved overall survival in randomised phase 3 trials.

  • The optimal (sequential) regimen for the use of gemcitabine, erlotinib and the oral fluoropyrimidine capecitabine remains unclear in advanced PC.

  • Molecular predictors for the efficacy of anti-EGFR treatments in PC have not been defined up to now.

What are the new findings?

What are the new findings?

  • The sequential use of gemcitabine, erlotinib and capecitabine is safe and equally effective in PC; gemcitabine appears to be more effective in 1st- and 2nd-line therapy than capecitabine and therefore remains the preferred combination partner for erlotinib.

  • Skin rash is strongly correlated with efficacy outcome measures in PC patients treated with erlotinib.

  • KRAS wild-type status appears to be associated with improved overall survival in patients treated with erlotinib in this AIO study.

Significance of this study

How might it impact on clinical practice in the foreseeable future?

How might it impact on clinical practice in the foreseeable future?

  • The benefit of adding erlotinib to chemotherapy is restricted to patients that experience skin rash during treatment; non-rash patients are characterised by a very poor outcome and need to be offered novel treatment strategies.

  • Second-line salvage chemotherapy is effective and safe in selected PC patients.

  • KRAS could serve as the first biomarker for improved survival in erlotinib-treated patients; the predictive value of KRAS for erlotinib efficacy remains to be defined prospectively.

  • Erlotinib
  • capecitabine
  • gemcitabine
  • KRAS
  • pancreatic cancer
  • chemotherapy
  • cancer
  • chemotherapy
  • pancreatic cancer

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  • Previous presentation 46th ASCO Annual Meeting, 4–8 June, 2010, Chicago, IL and 35th ESMO Congress, 8–12 October, 2010, Milan, Italy.

  • Funding This work was supported by Hoffmann-La Roche, Germany.

  • Competing interests VH: Roche (consultant, honoraria for scientific presentations, research funding). UV-K: none. DW: none. EK: none. AM: none. CW: none. SK: none. GK: none. TCG: none. LFvW: none. MRC: Roche (honoraria for scientific presentations, research funding, travel grants). MG: none. TFG: none. SH-B: none. OR: none. GB: none. TH: none. YDK: none. AJ: none. SN: none. SB: Roche (honoraria for scientific presentations, research funding, travel grants).

  • Ethics approval This study was conducted with the approval of the ethics committee of the Ludwig-Maximilians University of Munich, Germany.

  • Provenance and peer review Not commissioned; externally peer reviewed.

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