Skip to main content
SpringerLink
Log in

Phase I/II Study of Refametinib (BAY 86-9766) in Combination with Gemcitabine in Advanced Pancreatic cancer

  • Original Research Article
  • Published:
Targeted Oncology Aims and scope Submit manuscript

Abstract

Background

Activating KRAS mutations are reported in up to 90% of pancreatic cancers. Refametinib potently inhibits MEK1/2, part of the MAPK signaling pathway. This phase I/II study evaluated the safety and efficacy of refametinib plus gemcitabine in patients with advanced pancreatic cancer.

Methods

Phase I comprised dose escalation, followed by phase II expansion. Refametinib and gemcitabine plasma levels were analyzed for pharmacokinetics. KRAS mutational status was determined from circulating tumor DNA.

Results

Ninety patients overall received treatment. The maximum tolerated dose was refametinib 50 mg twice daily plus standard gemcitabine (1000 mg/m2 weekly). The combination was well tolerated, with no pharmacokinetic interaction. Treatment-emergent toxicities included thrombocytopenia, fatigue, anemia, and edema. The objective response rate was 23% and the disease control rate was 73%. Overall response rate, disease control rate, progression-free survival, and overall survival were higher in patients without detectable KRAS mutations (48% vs. 28%, 81% vs. 69%, 8.8 vs. 5.3 months, and 18.2 vs. 6.6 months, respectively).

Conclusion

Refametinib plus gemcitabine was well tolerated, with a promising objective response rate, and had an acceptable safety profile and no pharmacokinetic interaction. There was a trend towards improved outcomes in patients without detectable KRAS mutations that deserves future investigation.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5

Similar content being viewed by others

References

  1. Ferlay J, Soerjomataram I, Ervik M, et al. GLOBOCAN 2012 v1.0, Cancer Incidence and Mortality Worldwide: IARC CancerBase No. 11 http://globocan.iarc.fr (2013). Accessed 5 Sept 2016.

  2. Morris JP, Wang SC, Hebrok M. KRAS, Hedgehog, Wnt and the twisted developmental biology of pancreatic ductal adenocarcinoma. Nat Rev Cancer. 2010;10:683–95.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Kanda M, Matthaei H, Wu J, et al. Presence of somatic mutations in most early-stage pancreatic intraepithelial neoplasia. Gastroenterology. 2012;142:730–3.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Eser S, Schnieke A, Schneider G, et al. Oncogenic KRAS signalling in pancreatic cancer. Br J Cancer. 2014;111:817–22.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Roberts PJ, Der CJ. Targeting the Raf-MEK-ERK mitogen-activated protein kinase cascade for the treatment of cancer. Oncogene. 2007;26:3291–310.

    Article  CAS  PubMed  Google Scholar 

  6. Frémin C, Meloche S. From basic research to clinical development of MEK1/2 inhibitors for cancer therapy. J Hematol Oncol. 2010;3:8.

    Article  PubMed  PubMed Central  Google Scholar 

  7. Friday BB, Adjei AA. Advances in targeting the Ras/Raf/MEK/Erk mitogen-activated protein kinase cascade with MEK inhibitors for cancer therapy. Clin Cancer Res. 2008;14:342–6.

    Article  CAS  PubMed  Google Scholar 

  8. National Comprehensive Cancer Network. NCCN Clinical Practice Guidelines in Oncology: Pancreatic Adenocarcinoma (Version 2.2014). http://www.nccn.org/professionals/physician_gls/pdf/pancreatic.pdf (2014). Accessed 5 Sept 2016.

  9. Conroy T, Desseigne F, Ychou M, et al. FOLFIRINOX versus gemcitabine for metastatic pancreatic cancer. N Engl J Med. 2011;364:1817–25.

    Article  CAS  PubMed  Google Scholar 

  10. Von Hoff DD, Ervin T, Arena FP, et al. Increased survival in pancreatic cancer with nab-paclitaxel plus gemcitabine. N Engl J Med. 2013;369:1691–703.

    Article  Google Scholar 

  11. Burris HA, Moore MJ, Andersen J, et al. Improvements in survival and clinical benefit with gemcitabine as first-line therapy for patients with advanced pancreas cancer: a randomized trial. J Clin Oncol. 1997;15:2403–13.

    CAS  PubMed  Google Scholar 

  12. Cunningham D, Chau I, Stocken DD, et al. Phase III randomized comparison of gemcitabine versus gemcitabine plus capecitabine in patients with advanced pancreatic cancer. J Clin Oncol. 2009;27:5513–8.

    Article  CAS  PubMed  Google Scholar 

  13. Nakai Y, Isayama H, Sasaki T, et al. A multicentre randomised phase II trial of gemcitabine alone vs gemcitabine and S-1 combination therapy in advanced pancreatic cancer: GEMSAP study. Br J Cancer. 2012;106:1934–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Moore MJ, Goldstein D, Hamm J, et al. Erlotinib plus gemcitabine compared with gemcitabine alone in patients with advanced pancreatic cancer: a phase III trial of the National Cancer Institute of Canada Clinical Trials Group. J Clin Oncol. 2007;25:1960–6.

    Article  CAS  PubMed  Google Scholar 

  15. Goncalves A, Gilabert M, François E, et al. BAYPAN study: a double-blind phase III randomized trial comparing gemcitabine plus sorafenib and gemcitabine plus placebo in patients with advanced pancreatic cancer. Ann Oncol. 2012;23:2799–805.

    Article  CAS  PubMed  Google Scholar 

  16. Herrmann R, Bodoky G, Ruhstaller T, et al. Gemcitabine plus capecitabine compared with gemcitabine alone in advanced pancreatic cancer: a randomized, multicenter, phase III trial of the Swiss Group for Clinical Cancer Research and the Central European Cooperative Oncology Group. J Clin Oncol. 2007;25:2212–7.

    Article  CAS  PubMed  Google Scholar 

  17. Iverson C, Larson G, Lai C, et al. RDEA119/BAY 869766: a potent, selective, allosteric inhibitor of MEK1/2 for the treatment of cancer. Cancer Res. 2009;69:6839–47.

    Article  CAS  PubMed  Google Scholar 

  18. Puehler F, Scholz A, Kissel M, et al. Allosteric MEK inhibitor BAY 86-9766 (RDEA119) shows anti-tumor efficacy in monotherapy and combination therapy in preclinical models of hepatocellular carcinoma and pancreatic cancer. Poster 151 presented at 22nd EORTC-NCI-AACR Symposium, Berlin, Germany, 16–19 November 2010.

  19. Schmieder R, Puehler F, Neuhaus R, et al. The MEK inhibitor BAY 869766 inhibits tumor growth and metastatic spread, prolongs the survival and acts synergistically with standard of care drugs in models of hepatocellular carcinoma and pancreatic cancer. Mol Cancer Ther. 2011;10 (Suppl 1): (Abstract B247).

  20. Kim D, Pertea G, Trapnell C, et al. TopHat2: accurate alignment of transcriptomes in the presence of insertions, deletions and gene fusions. Genome Biol. 2013;14:R36.

    Article  PubMed  PubMed Central  Google Scholar 

  21. Langmead B, Salzberg SL. Fast gapped-read alignment with Bowtie 2. Nat Methods. 2012;9:357–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Loboda A, Nebozhyn M, Klinghoffer R, et al. A gene expression signature of RAS pathway dependence predicts response to PI3K and RAS pathway inhibitors and expands the population of RAS pathway activated tumors. BMC Med Genomics. 2010;3:26.

    Article  PubMed  PubMed Central  Google Scholar 

  23. Weekes CD, Von Hoff DD, Adjei AA, et al. Multicenter phase I trial of the mitogen-activated protein kinase 1/2 inhibitor BAY 86-9766 in patients with advanced cancer. Clin Cancer Res. 2013;19:1232–43.

    Article  CAS  PubMed  Google Scholar 

  24. Barlési F, Villani P, Doddoli C, et al. Gemcitabine-induced severe pulmonary toxicity. Fundam Clin Pharmacol. 2004;18:85–91.

    Article  PubMed  Google Scholar 

  25. Infante JR, Somer BG, Park JO, et al. A randomised, double-blind, placebo-controlled trial of trametinib, an oral MEK inhibitor, in combination with gemcitabine for patients with untreated metastatic adenocarcinoma of the pancreas. Eur J Cancer. 2014;50:2072–81.

    Article  CAS  PubMed  Google Scholar 

  26. Rothenberg ML, Moore MJ, Cripps MC, et al. A phase II trial of gemcitabine in patients with 5-FU-refractory pancreas cancer. Ann Oncol. 1996;7:347–53.

    Article  CAS  PubMed  Google Scholar 

  27. Borad MJ, Reddy SG, Bahary N, et al. Randomized phase II trial of gemcitabine plus TH-302 versus gemcitabine in patients with advanced pancreatic cancer. J Clin Oncol. 2015;33:1475–81.

    Article  CAS  PubMed  Google Scholar 

  28. Stein SM, James ES, Deng Y, et al. Final analysis of a phase II study of modified FOLFIRINOX in locally advanced and metastatic pancreatic cancer. Br J Cancer. 2016;114:737–43.

    Article  PubMed  Google Scholar 

  29. van Zweeden AA, van der Vliet HJ, Wilmink JW, et al. Phase I clinical trial to determine the feasibility and maximum tolerated dose of panitumumab to standard gemcitabine-based chemoradiation in locally advanced pancreatic cancer. Clin Cancer Res. 2015;21:4569–75.

    Article  PubMed  Google Scholar 

  30. Kinugasa H, Nouso K, Miyahara K, et al. Detection of K-ras gene mutation by liquid biopsy in patients with pancreatic cancer. Cancer. 2015;121:2271–80.

    Article  CAS  PubMed  Google Scholar 

  31. Kim ST, Lim DH, Jang KT, et al. Impact of KRAS mutations on clinical outcomes in pancreatic cancer patients treated with first-line gemcitabine-based chemotherapy. Mol Cancer Ther. 2011;10:1993–9.

    Article  CAS  PubMed  Google Scholar 

  32. da Cunha Santos G, Dhani N, Tu D, et al. Molecular predictors of outcome in a phase 3 study of gemcitabine and erlotinib therapy in patients with advanced pancreatic cancer. National Cancer Institute of Canada Clinical Trials Group Study PA.3. Cancer. 2010;116:5599–607.

    Article  PubMed  Google Scholar 

  33. Ogura T, Yamao K, Hara K, et al. Prognostic value of K-ras mutation status and subtypes in endoscopic ultrasound-guided fine-needle aspiration specimens from patients with unresectable pancreatic cancer. J Gastroenterol. 2013;48:640–6.

    Article  CAS  PubMed  Google Scholar 

  34. Birnbaum DJ, Adélaïde J, Mamessier E, et al. Genome profiling of pancreatic adenocarcinoma. Genes Chromosomes Cancer. 2011;50:456–65.

    Article  CAS  PubMed  Google Scholar 

  35. Lin Q, Aihara A, Chung W, et al. LRH1 promotes pancreatic cancer metastasis. Cancer Lett. 2014;350:15–24.

    Article  CAS  PubMed  Google Scholar 

  36. Yu S, Lu Z, Liu C, et al. miRNA-96 suppresses KRAS and functions as a tumor suppressor gene in pancreatic cancer. Cancer Res. 2010;70:6015–25.

    Article  CAS  PubMed  Google Scholar 

  37. Xia H, Ooi LL, Hui KM. MiR-214 targets β-catenin pathway to suppress invasion, stem-like traits and recurrence of human hepatocellular carcinoma. PLoS One. 2012;7:e44206.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Higgins MJ, Jelovac D, Barnathan E, et al. Detection of tumor PIK3CA status in metastatic breast cancer using peripheral blood. Clin Cancer Res. 2012;18:3462–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Ignatiadis M, Lee M, Jeffrey SS. Circulating tumor cells and circulating tumor DNA: challenges and opportunities on the path to clinical utility. Clin Cancer Res. 2015;21:4786–800.

    Article  CAS  PubMed  Google Scholar 

  40. Li M, Diehl F, Dressman D, et al. BEAMing up for detection and quantification of rare sequence variants. Nat Methods. 2006;3:95–7.

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgments

The authors would like to thank Tanja Torbica, PhD, at Complete HealthVizion for assistance in the preparation and revision of the draft manuscript, based on detailed discussion and feedback from all the authors.

Author information

Author notes

  1. Patrick Michl

    Present address: Universitätsklinikum Halle - University Hospital Halle (Saale), Ernst-Grube-Straße 40, 06120, Halle (Saale), Germany

Authors and Affiliations

  1. Department of Gastroenterology, Erasme University Hospital, CP 572/10, route de Lennik 808, 1070, Brussels, Belgium

    Jean-Luc Van Laethem

  2. Medical Department, Division of Hematology, Oncology and Tumor Immunology, Charity Hospital, Virchow-Klinikum Campus, Augustenburger Platz 1, 13353, Berlin, Germany

    Hanno Riess

  3. Department of Oncology and Radiotherapy, Medical University of Gdansk, M. Skłodowskiej-Curie 3a Street, Gdansk, 80-210, Poland

    Jacek Jassem

  4. Department of Hematology and Oncology, University of Munich Medical Center, Marchioninistraße 15, 81366, Munich, Germany

    Michael Haas

  5. Department of Hematology and Oncology, Cancer Center Heilbronn-Franken, Am Gesundbrunnen 20-26, 74078, Heilbronn, Germany

    Uwe M. Martens

  6. Division of Medical Oncology, University of Colorado Cancer Center, 1665 Aurora Ct, Aurora, CO, 80045, USA

    Colin Weekes

  7. Department of Oncology, Antwerp University Hospital, Wilrijkstraat 10, 2650, Edegem, Belgium

    Marc Peeters

  8. Department of Medical Oncology, Guy’s & St Thomas’ Hospital, Westminster Bridge Road, London, SE1 7EH, UK

    Paul Ross

  9. Department of Oncology, UCL Cancer Institute, 72 Huntley Street, London, WC1E 6DD, UK

    John Bridgewater

  10. Department of Oncology, Palacky University Medical School and University Hospital Olomouc, Křížkovského 8, 771 47, Olomouc, Czech Republic

    Bohuslav Melichar

  11. Department of Medical Oncology, A.O.U. United Hospitals, Polytechnic University of Marche, Piazza Roma, 22, Ancona, Italy

    Stefano Cascinu

  12. Department of Oncological Gastroenterology, Maria Skłodowska-Curie Memorial Cancer Center, ul. W.K. Roentgena 5, 02-781, Warsaw, Poland

    Piotr Saramak

  13. Department of Gastroenterology, Endocrinology, Metabolism and Infectiology, University Hospital of Giessen and Marburg, Baldingerstraße, 35043, Marburg, Germany

    Patrick Michl

  14. Department of Radiotherapy, UZ Brussels, Avenue du Laerbeek 101, 1090, Brussels, Belgium

    David Van Brummelen

  15. Department of Medical Oncology, Poliambulanza Foundation Hospital Institute, Via Bissolati, 57, Brescia, Italy

    Alberto Zaniboni

  16. Department of Gastroenterology and Hepatology, Medical University Hospital Bochum, Alexandrinenstraße 1, Bochum, 44791, Germany

    Wollf Schmiegel

  17. Department of Oncology, Oslo University Radium Hospital, Trondheimsveien 235, Bjerke, 0514, Oslo, Norway

    Svein Dueland

  18. Bayer Pharma AG, Müllerstraße 178, 13353, Berlin, Germany

    Marius Giurescu, Katrin Roth, Anke Schulz & Henrik Seidel

  19. Bayer S.p.A., Viale Certosa 126-130, 20156, Milan, Italy

    Vittorio L. Garosi

  20. Bayer HealthCare Pharmaceuticals, Inc., 100 Bayer Blvd, Whippany, NJ, 07981, USA

    Prabhu Rajagopalan, Michael Teufel & Barrett H. Childs

Authors
  1. Jean-Luc Van Laethem
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Hanno Riess
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Jacek Jassem
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Michael Haas
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Uwe M. Martens
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Colin Weekes
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Marc Peeters
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Paul Ross
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. John Bridgewater
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Bohuslav Melichar
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Stefano Cascinu
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. Piotr Saramak
    View author publications

    You can also search for this author in PubMed Google Scholar

  13. Patrick Michl
    View author publications

    You can also search for this author in PubMed Google Scholar

  14. David Van Brummelen
    View author publications

    You can also search for this author in PubMed Google Scholar

  15. Alberto Zaniboni
    View author publications

    You can also search for this author in PubMed Google Scholar

  16. Wollf Schmiegel
    View author publications

    You can also search for this author in PubMed Google Scholar

  17. Svein Dueland
    View author publications

    You can also search for this author in PubMed Google Scholar

  18. Marius Giurescu
    View author publications

    You can also search for this author in PubMed Google Scholar

  19. Vittorio L. Garosi
    View author publications

    You can also search for this author in PubMed Google Scholar

  20. Katrin Roth
    View author publications

    You can also search for this author in PubMed Google Scholar

  21. Anke Schulz
    View author publications

    You can also search for this author in PubMed Google Scholar

  22. Henrik Seidel
    View author publications

    You can also search for this author in PubMed Google Scholar

  23. Prabhu Rajagopalan
    View author publications

    You can also search for this author in PubMed Google Scholar

  24. Michael Teufel
    View author publications

    You can also search for this author in PubMed Google Scholar

  25. Barrett H. Childs
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Jean-Luc Van Laethem.

Ethics declarations

Funding

This study was supported by Bayer HealthCare Pharmaceuticals, Inc. John Bridgewater is partly supported by the UCLH/UCL Biomedical Research Centre.

Conflict of Interest

HR has performed a consulting or advisory role for Boehringer Ingelheim, Bayer, GlaxoSmithKline, Bristol-Myers Squibb, Roche, and Sanofi-Aventis. JJ has performed a consulting or advisory role for Eli Lilly, Pfizer, AstraZeneca, and Celgene; participated in a speaker bureau for Roche; received research funding from GlaxoSmithKline, Roche, and Novartis; and received travel, accommodation, and other expenses from Boehringer Ingelheim. MH has received honoraria from Celgene, research funding from Roche and Boehringer Ingelheim, and travel, accommodation, and other expenses from Celgene and Boehringer Ingelheim. MP has received honoraria and research funding from Bayer. PR has received honoraria from Roche, Sirtex, Bayer, and Celgene; performed a consulting or advisory role for Roche, Sirtex, Sanofi-Aventis, Celgene, Baxter, Merck Serono, and Daiichi Sankyo; received research funding from Sanofi-Aventis, Bayer, Roche, and Merrimack; and received travel, accommodation, and other expenses from Roche, Merck Serono, Celgene, and Sanofi-Aventis. JB is partly supported by the UCLH/UCL Biomedical Research Centre. He has performed a consulting or advisory role for Roche, Merck Serono, and AstraZeneca, and has received travel, accommodation, and other expenses from Merck Serono and the European Society for Medical Oncology. BM has received honoraria from, and has performed a consulting or advisory role for, Bayer. SC has performed a consulting or advisory role for Roche, Sanofi-Aventis, and Celgene. PM has received honoraria from Ipsen, Bayer, and Celgene, and has received research funding from Ipsen. DVB has received travel, accommodation, and other expenses from Amgen. MG, KR, AS, and HS are employees of Bayer Pharma AG. VLG is an employee of Bayer S.p.A. PRa is an employee of Bayer HealthCare Pharmaceuticals, Inc. and has stock or other ownership interests in Bayer HealthCare Pharmaceuticals, Inc. MT and BHC are employees of Bayer HealthCare Pharmaceuticals, Inc. J-LVL, UMM, CW, PS, AZ, WS, and SD have no conflicts of interest to declare.

Electronic supplementary material

Below is the link to the electronic supplementary material.

ESM 1

(DOCX 553 kb)

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Van Laethem, JL., Riess, H., Jassem, J. et al. Phase I/II Study of Refametinib (BAY 86-9766) in Combination with Gemcitabine in Advanced Pancreatic cancer. Targ Oncol 12, 97–109 (2017). https://doi.org/10.1007/s11523-016-0469-y

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11523-016-0469-y

Keywords

Search

Navigation