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Canadian Cancer Trials Group (CCTG) IND215: A phase Ib study of Selumetinib in patients with untreated advanced or metastatic NSCLC who are receiving standard chemotherapy regimens

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Summary

Introduction Selumetinib (AZD6244, ARRY-142886) is a potent inhibitor of MEK1/2, thereby inhibiting phosphorylation of ERK2. We investigated the toxicity and the recommended phase II dose of the combination of selumetinib with two platinum based first line chemotherapy combinations in non-small cell lung cancer. Methods This was a phase I trial of escalating doses of selumetinib with carboplatin (AUC 6), paclitaxel (200 mg/m2) (cohort 1) or pemetrexed (500 mg/m2) and cisplatin (75 mg/m2) (cohort 2) in patients with chemotherapy naïve, advanced or metastatic NSCLC. Patients enrolled on cohort 2 had non-squamous histology. Dose escalation of selumetinib proceeded using a 3 + 3 design: 50 mg b.i.d. days 2–19 (dose level 1); 75 mg b.i.d. days 2–19 (dose level 2); and 75 mg b.i.d. continuously. Adverse events were evaluated using CTC AE v4 and response by RECIST 1.1. Results Thirty-nine patients were enrolled (cohort 1 n = 16; cohort 2, n = 23). There were no dose limiting toxicities in either cohort and the recommended phase II dose for both regimens was standard doses of carboplatin, paclitaxel or pemetrexed and cisplatin with continuous selumetinib at a dose of 75 mg b.i.d. Most adverse events were grade 1 or 2 and were predominantly diarrhea, nausea, stomatitis, peripheral edema, neutropenia, and skin rash. Response rate was 37.5% for cohort 1 and 30.4% for cohort 2. Conclusion Selumetinib at a dose of 75 mg b.i.d continuously can be safely combined with paclitaxel and carboplatin or pemetrexed and cisplatin in patients with advanced or metastatic NSCLC. This trial provided the dose for the regimens used in a randomized phase II trial in NSCLC (CCTG IND.219).

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References

  1. A.C. Society (2015) Global Cancer facts & figures 3rd edition, Atlanta

  2. Lortet-Tieulent J, Soerjomataram I, Ferlay J, Rutherford M, Weiderpass E, Bray F (2014) International trends in lung cancer incidence by histological subtype: adenocarcinoma stabilizing in men but still increasing in women. Lung Cancer 84(1):13–22

    Article  CAS  PubMed  Google Scholar 

  3. Scagliotti GV, Parikh P, von Pawel J, Biesma B, Vansteenkiste J, Manegold C, Serwatowski P, Gatzemeier U, Digumarti R, Zukin M, Lee JS, Mellemgaard A, Park K, Patil S, Rolski J, Goksel T, de Marinis F, Simms L, Sugarman KP, Gandara D (2008) Phase III study comparing cisplatin plus gemcitabine with cisplatin plus pemetrexed in chemotherapy-naive patients with advanced-stage non-small-cell lung cancer. J Clin Oncol 26(21):3543–3551

    Article  CAS  PubMed  Google Scholar 

  4. Reck M, Rodriguez-Abreu D, Robinson AG, Hui R, Csoszi T, Fulop A, Gottfried M, Peled N, Tafreshi A, Cuffe S, O'Brien M, Rao S, Hotta K, Leiby MA, Lubiniecki GM, Shentu Y, Rangwala R, Brahmer JR, Investigators K (2016) Pembrolizumab versus chemotherapy for PD-L1-positive non-small-cell lung Cancer. N Engl J Med 375(19):1823–1833

    Article  CAS  PubMed  Google Scholar 

  5. Martinelli E, Morgillo F, Troiani T, Ciardiello F (2017) Cancer resistance to therapies against the EGFR-RAS-RAF pathway: the role of MEK. Cancer Treat Rev 53:61–69

    Article  CAS  PubMed  Google Scholar 

  6. McCubrey JA, Steelman LS, Chappell WH, Abrams SL, Wong EW, Chang F, Lehmann B, Terrian DM, Milella M, Tafuri A, Stivala F, Libra M, Basecke J, Evangelisti C, Martelli AM, Franklin RA (2007) Roles of the Raf/MEK/ERK pathway in cell growth, malignant transformation and drug resistance. Biochim Biophys Acta 1773(8):1263–1284

    Article  CAS  PubMed  Google Scholar 

  7. Mok TS, Wu YL, Thongprasert S, Yang CH, Chu DT, Saijo N, Sunpaweravong P, Han B, Margono B, Ichinose Y, Nishiwaki Y, Ohe Y, Yang JJ, Chewaskulyong B, Jiang H, Duffield EL, Watkins CL, Armour AA, Fukuoka M (2009) Gefitinib or carboplatin-paclitaxel in pulmonary adenocarcinoma. N Engl J Med 361(10):947–957

    Article  CAS  PubMed  Google Scholar 

  8. Barlesi F, Mazieres J, Merlio JP, Debieuvre D, Mosser J, Lena H, Ouafik L, Besse B, Rouquette I, Westeel V, Escande F, Monnet I, Lemoine A, Veillon R, Blons H, Audigier-Valette C, Bringuier PP, Lamy R, Beau-Faller M, Pujol JL, Sabourin JC, Penault-Llorca F, Denis MG, Lantuejoul S, Morin F, Tran Q, Missy P, Langlais A, Milleron B, Cadranel J, Soria JC, Zalcman G, France c B (2016) Routine molecular profiling of patients with advanced non-small-cell lung cancer: results of a 1-year nationwide programme of the French cooperative thoracic intergroup (IFCT). Lancet 387(10026):1415–1426

    Article  CAS  PubMed  Google Scholar 

  9. Janne PA, Shaw AT, Pereira JR, Jeannin G, Vansteenkiste J, Barrios C, Franke FA, Grinsted L, Zazulina V, Smith P, Smith I, Crino L (2013) Selumetinib plus docetaxel for KRAS-mutant advanced non-small-cell lung cancer: a randomised, multicentre, placebo-controlled, phase 2 study. The Lancet Oncol 14(1):38–47

    Article  CAS  PubMed  Google Scholar 

  10. Denton CL, Gustafson DL (2011) Pharmacokinetics and pharmacodynamics of AZD6244 (ARRY-142886) in tumor-bearing nude mice. Cancer Chemother Pharmacol 67(2):349–360

    Article  CAS  PubMed  Google Scholar 

  11. Banerji U, Camidge DR, Verheul HM, Agarwal R, Sarker D, Kaye SB, Desar IM, Timmer-Bonte JN, Eckhardt SG, Lewis KD, Brown KH, Cantarini MV, Morris C, George SM, Smith PD, van Herpen CM (2010) The first-in-human study of the hydrogen sulfate (Hyd-sulfate) capsule of the MEK1/2 inhibitor AZD6244 (ARRY-142886): a phase I open-label multicenter trial in patients with advanced cancer. Clin Cancer Res 16(5):1613–1623

    Article  CAS  PubMed  Google Scholar 

  12. Davies BR, Logie A, McKay JS, Martin P, Steele S, Jenkins R, Cockerill M, Cartlidge S, Smith PD (2007) AZD6244 (ARRY-142886), a potent inhibitor of mitogen-activated protein kinase/extracellular signal-regulated kinase kinase 1/2 kinases: mechanism of action in vivo, pharmacokinetic/pharmacodynamic relationship, and potential for combination in preclinical models. Mol Cancer Ther 6(8):2209–2219

    Article  CAS  PubMed  Google Scholar 

  13. Balko JM, Jones BR, Coakley VL, Black EP (2009) MEK and EGFR inhibition demonstrate synergistic activity in EGFR-dependent NSCLC. Cancer Biol Ther 8(6):522–530

    Article  CAS  PubMed  Google Scholar 

  14. Song JY, Kim CS, Lee JH, Jang SJ, Lee SW, Hwang JJ, Lim C, Lee G, Seo J, Cho SY, Choi J (2013) Dual inhibition of MEK1/2 and EGFR synergistically induces caspase-3-dependent apoptosis in EGFR inhibitor-resistant lung cancer cells via BIM upregulation. Investig New Drugs 31(6):1458–1465

    Article  CAS  Google Scholar 

  15. Kim EY, Kim A, Kim SK, Chang YS (2015) AZD6244 inhibits cisplatin-induced ERK1/2 activation and potentiates cisplatin-associated cytotoxicity in K-ras G12D preclinical models. Cancer Lett 358(1):85–91

    Article  CAS  PubMed  Google Scholar 

  16. Schweyer S, Soruri A, Meschter O, Heintze A, Zschunke F, Miosge N, Thelen P, Schlott T, Radzun HJ, Fayyazi A (2004) Cisplatin-induced apoptosis in human malignant testicular germ cell lines depends on MEK/ERK activation. Br J Cancer 91(3):589–598

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Hainsworth JD, Cebotaru CL, Kanarev V, Ciuleanu TE, Damyanov D, Stella P, Ganchev H, Pover G, Morris C, Tzekova V (2010) A phase II, open-label, randomized study to assess the efficacy and safety of AZD6244 (ARRY-142886) versus pemetrexed in patients with non-small cell lung cancer who have failed one or two prior chemotherapeutic regimens. J Thorac Oncol 5(10):1630–1636

    Article  PubMed  Google Scholar 

  18. Janne PA, van den Heuvel MM, Barlesi F, Cobo M, Mazieres J, Crino L, Orlov S, Blackhall F, Wolf J, Garrido P, Poltoratskiy A, Mariani G, Ghiorghiu D, Kilgour E, Smith P, Kohlmann A, Carlile DJ, Lawrence D, Bowen K, Vansteenkiste J (2017) Selumetinib plus docetaxel compared with docetaxel alone and progression-free survival in patients with KRAS-mutant advanced non-small cell lung Cancer: the SELECT-1 randomized clinical trial. JAMA 317(18):1844–1853

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Ciuleanu T, Brodowicz T, Zielinski C, Kim JH, Krzakowski M, Laack E, Wu YL, Bover I, Begbie S, Tzekova V, Cucevic B, Pereira JR, Yang SH, Madhavan J, Sugarman KP, Peterson P, John WJ, Krejcy K, Belani CP (2009) Maintenance pemetrexed plus best supportive care versus placebo plus best supportive care for non-small-cell lung cancer: a randomised, double-blind, phase 3 study. Lancet 374(9699):1432–1440

    Article  CAS  PubMed  Google Scholar 

  20. Sandler A, Gray R, Perry MC, Brahmer J, Schiller JH, Dowlati A, Lilenbaum R, Johnson DH (2006) Paclitaxel-carboplatin alone or with bevacizumab for non-small-cell lung cancer. N Engl J Med 355(24):2542–2550

    Article  CAS  PubMed  Google Scholar 

  21. Socinski MA, Bondarenko I, Karaseva NA, Makhson AM, Vynnychenko I, Okamoto I, Hon JK, Hirsh V, Bhar P, Zhang H, Iglesias JL, Renschler MF (2012) Weekly nab-paclitaxel in combination with carboplatin versus solvent-based paclitaxel plus carboplatin as first-line therapy in patients with advanced non-small-cell lung cancer: final results of a phase III trial. J Clin Oncol 30(17):2055–2062

    Article  CAS  PubMed  Google Scholar 

  22. Chen Z, Cheng K, Walton Z, Wang Y, Ebi H, Shimamura T, Liu Y, Tupper T, Ouyang J, Li J, Gao P, Woo MS, Xu C, Yanagita M, Altabef A, Wang S, Lee C, Nakada Y, Pena CG, Sun Y, Franchetti Y, Yao C, Saur A, Cameron MD, Nishino M, Hayes DN, Wilkerson MD, Roberts PJ, Lee CB, Bardeesy N, Butaney M, Chirieac LR, Costa DB, Jackman D, Sharpless NE, Castrillon DH, Demetri GD, Janne PA, Pandolfi PP, Cantley LC, Kung AL, Engelman JA, Wong KK (2012) A murine lung cancer co-clinical trial identifies genetic modifiers of therapeutic response. Nature 483(7391):613–617

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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Funding

This work was supported by the Canadian Cancer Society Research Institute [grant numbers 021039 and 704970]. Drug and partial funding for the trial was provided by Astra Zeneca.

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Author notes

  1. J. R. Goffin and G. Nicholas are the co-first authors and contributed equally to this work.

Authors and Affiliations

  1. Juravinski Cancer Centre at Hamilton Health Sciences, 699 Concession St, Hamilton, ON, L8V 5C2, Canada

    J. R. Goffin, R. Juergens & S. MacFarlan

  2. Ottawa Hospital Research Institute, Ottawa, ON, Canada

    G. Nicholas, S. A. Laurie, G. Goss, M. Reaume & K. Christink

  3. Cancer Centre of Southeastern Ontario, Kingston, ON, Canada

    M. Mates, A. Robinson & C. Maize

  4. Canadian Cancer Trials Group, Queen’s University, Kingston, ON, Canada

    D. Tu, X. Sun, H. Ritter & L. Seymour

  5. Princess Margaret Cancer Centre, University of Toronto, Toronto, ON, Canada

    E. Chen & P. A. Bradbury

  6. BCCA - Vancouver Cancer Centre, Vancouver, BC, Canada

    S. Sun

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  1. J. R. Goffin
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Corresponding author

Correspondence to J. R. Goffin.

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Conflict of interest

Dr. Seymour received funding for the Canadian Cancer Trials Group from AstraZeneca to support this trial. Dr. Goffin has received honorarium from Amgen, Boehringer Ingelheim, and Bristol-Myers Squibb and conference travel support from AstraZeneca. Dr. Juergens has consulted for and has received grant funding from AstraZeneca. All other authors had no conflicts to report.

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. This article does not contain any studies with animals performed by any of the authors. The study was approved by the research ethics boards of the participating institutions.

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Informed consent was obtained from all individual participants included in the study.

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Goffin, J.R., Nicholas, G., Mates, M. et al. Canadian Cancer Trials Group (CCTG) IND215: A phase Ib study of Selumetinib in patients with untreated advanced or metastatic NSCLC who are receiving standard chemotherapy regimens. Invest New Drugs 37, 498–506 (2019). https://doi.org/10.1007/s10637-018-0680-z

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  • DOI: https://doi.org/10.1007/s10637-018-0680-z

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