A multicenter, open-label phase II clinical trial of combined MEK plus EGFR inhibition for chemotherapy-refractory advanced pancreatic adenocarcinoma

Clinical Cancer Research

Volumn 22, Issue 1, 2016, Pages 61-68

  Ko, Andrew H ^a   Bekaii Saab, Tanios ^b   Van Ziffle, Jessica ^c   Mirzoeva, Olga M ^a   Joseph, Nancy M ^c   Talasaz, Amir Ali ^d   Kuhn, Peter ^e   Tempero, Margaret A ^a   Collisson, Eric A ^a   Kelley, R Kate ^a   Venook, Alan P ^a   Dito, Elizabeth ^a   Ong, Anna ^a   Ziyeh, Sharvina ^a   Courtin, Ryan ^a   Linetskaya, Regina ^a   Tahiri, Sanaa ^b   Korn, W Michael ^a  

^a UNIVERSITY OF CALIFORNIA   (United States)

^b OHIO STATE UNIVERSITY   (United States)

^c UNIVERSITY OF CALIFORNIA   (United States)

^d Guardant Health   (United States)

^e UNIVERSITY OF SOUTHERN CALIFORNIA   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

CA 19-9 ANTIGEN; ERLOTINIB; SELUMETINIB; ANTINEOPLASTIC AGENT; BENZIMIDAZOLE DERIVATIVE; BIOLOGICAL MARKER; DNA;

ADULT; ADVANCED CANCER; ADVERSE OUTCOME; AGED; ANEMIA; ANOREXIA; ARTICLE; CANCER COMBINATION CHEMOTHERAPY; CELL FREE SYSTEM; CIRCULATING TUMOR CELL; CLINICAL ARTICLE; CONTROLLED CLINICAL TRIAL; CONTROLLED STUDY; DIARRHEA; DNA SEQUENCE; DRUG EFFICACY; DRUG SAFETY; DYSGEUSIA; EYE DISEASE; FATIGUE; HUMAN; HYPERTENSION; LEUKOPENIA; MULTICENTER STUDY; MULTIPLE CYCLE TREATMENT; NAUSEA AND VOMITING; NEUTROPENIA; OPEN STUDY; OUTCOME ASSESSMENT; OVERALL SURVIVAL; PANCREAS ADENOCARCINOMA; PHASE 2 CLINICAL TRIAL; POINT MUTATION; PRIORITY JOURNAL; PROGRESSION FREE SURVIVAL; PRURITUS; RASH; SENSITIVITY ANALYSIS; THROMBOCYTOPENIA; THROMBOEMBOLISM; TREATMENT RESPONSE; ADENOCARCINOMA; BLOOD; CANCER STAGING; CLINICAL TRIAL; DRUG RESISTANCE; FEMALE; KAPLAN MEIER METHOD; MALE; MIDDLE AGED; MOLECULARLY TARGETED THERAPY; MORTALITY; PANCREATIC NEOPLASMS; PATHOLOGY; RETREATMENT; TUMOR EMBOLISM; VERY ELDERLY;

ADENOCARCINOMA; ADULT; AGED; AGED, 80 AND OVER; ANTINEOPLASTIC COMBINED CHEMOTHERAPY PROTOCOLS; BENZIMIDAZOLES; BIOMARKERS; DNA, NEOPLASM; DRUG RESISTANCE, NEOPLASM; ERLOTINIB HYDROCHLORIDE; FEMALE; HUMANS; KAPLAN-MEIER ESTIMATE; MALE; MIDDLE AGED; MOLECULAR TARGETED THERAPY; NEOPLASM STAGING; NEOPLASTIC CELLS, CIRCULATING; PANCREATIC NEOPLASMS; RETREATMENT;

EID: 84954568391     PISSN: 10780432     EISSN: 15573265     Source Type: Journal    
DOI: 10.1158/1078-0432.CCR-15-0979     Document Type: Article

References (36)

1. Jones S, Zhang X, Parsons DW, Lin JC, Leary RJ, Angenendt P, et al. Core signaling pathways in human pancreatic cancers revealed by global genomic analyses. Science 2008;321:1801-6.
2. Biankin AV, Waddell N, Kassahn KS, Gingras MC, Muthuswamy LB, Johns AL, et al. Pancreatic cancer genomes reveal aberrations in axon guidance pathway genes. Nature 2012;491:399-405.
3. Britten CD. PI3K and MEK inhibitor combinations: examining the evidence in selected tumor types. Cancer Chemother Pharmacol 2013; 71:1395-409.
4. Shimizu T, Tolcher AW, Papadopoulos KP, Beeram M, Rasco DW, Smith LS, et al. The clinical effect of the dual-targeting strategy involving PI3K/AKT/mTORand RAS/MEK/ERK pathways in patients with advanced cancer. Clin Cancer Res 2012;18:2316-25.
5. Mirzoeva OK, Collisson EA, Schaefer PM, Hann B, Hom YK, Ko AH, et al. Subtype specific MEK-PI3 kinase feedback as a therapeutic target in pancreatic adenocarcinoma. Mol Cancer Ther 2013;12:2213-25.
6. Mirzoeva OK, Das D, Heiser LM, Bhattacharya S, Siwak D, Gendelman R, et al. Basal subtype and MAPK/ERK kinase (MEK)-phosphoinositide 3-kinase feedback signaling determine susceptibility of breast cancer cells to MEK inhibition. Cancer Res 2009;69:565-72.
7. Walters DM, Lindberg JM, Adair SJ, Newhook TE, Cowan CR, Stokes JB, et al. Inhibition of the growth of patient-derived pancreatic cancer xenografts with the MEK inhibitor trametinib is augmented by combined treatment with the epidermal growth factor receptor/HER2 inhibitor lapatinib. Neoplasia 2013;15:143-55.
8. Diep CH, Munoz RM, Choudhary A, Von Hoff DD, Han H. Synergistic effect between erlotinib and MEK inhibitors in KRAS wild-type human pancreatic cancer cells. Clin Cancer Res 2011;17:2744-56.
9. Jimeno A, Rubio-Viqueira B, Amador ML, Grunwald V, Maitra A, Iacobuzio-Donahue C, et al. Dual mitogen-activated protein kinase and epidermal growth factor receptor inhibition in biliary and pancreatic cancer. Mol Cancer Ther 2007;6:1079-88.
10. Navas C, Hernandez-Porras I, Schuhmacher AJ, Sibilia M, Guerra C, Barbacid M. EGF receptor signaling is essential for k-ras oncogene-driven pancreatic ductal adenocarcinoma. Cancer Cell 2012;22:318-30.
11. Ardito CM, Gruner BM, Takeuchi KK, Lubeseder-Martellato C, Teichmann N, Mazur PK, et al. EGF receptor is required for KRAS-induced pancreatic tumorigenesis. Cancer Cell 2012;22:304-17.
12. Conroy T, Desseigne F, Ychou M, Bouche O, Guimbaud R, Becouarn Y, et al. FOLFIRINOX versus gemcitabine for metastatic pancreatic cancer. N Engl J Med 2011;364:1817-25.
13. Von Hoff DD, Ervin T, Arena FP, Chiorean EG, Infante J, Moore M, et al. Increased Survival in Pancreatic Cancer with nab-Paclitaxel plus Gemcitabine. N Engl J Med 2013;369:1691-703.
14. Moore MJ, Goldstein D, Hamm J, Figer A, Hecht JR, Gallinger S, 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.
15. Dias-Santagata D, Akhavanfard S, David SS, Vernovsky K, Kuhlmann G, Boisvert SL, et al. Rapid targeted mutational analysis of human tumours: a clinical platform to guide personalized cancer medicine. EMBO Mol Med 2010;2:146-58.
16. Farina Sarasqueta A, Moerland E, de Bruyne H, de Graaf H, Vrancken T, van Lijnschoten G, et al. SNaPshot and Strip Assay as valuable alternatives to direct sequencing for KRAS mutation detection in colon cancer routine diagnostics. J Mol Diagn 2011;13:199-205.
17. Marrinucci D, Bethel K, Kolatkar A, Luttgen MS, Malchiodi M, Baehring F, et al. Fluid biopsy in patients with metastatic prostate, pancreatic and breast cancers. Phys Biol 2012;9:016003.
18. Hoon D, Huang S, Sebisanovic D, Siew L, Zapanta A, Mortimer S, et al. Identification of multiple informative genomic mutations by deep sequencing of circulating cell-free tumor DNA in plasma of metastatic melanoma patients. J Clin Oncol 32:5s, 2014 (suppl; abstr 9018).
19. Eser S, Schnieke A, Schneider G, Saur D. Oncogenic KRAS signalling in pancreatic cancer. Br J Cancer 2014;111:817-22.
20. Hezel AF, Kimmelman AC, Stanger BZ, Bardeesy N, Depinho RA. Genetics and biology of pancreatic ductal adenocarcinoma. Genes Dev 2006;20: 1218-49.
21. Infante JR, Fecher LA, Falchook GS, Nallapareddy S, Gordon MS, Becerra C, et al. Safety, pharmacokinetic, pharmacodynamic, and efficacy data for the oral MEK inhibitor trametinib: a phase 1 dose-escalation trial. Lancet Oncol 2012;13:773-81.
22. Bodoky G, Timcheva C, Spigel DR, La Stella PJ, Ciuleanu TE, Pover G, et al. A phase II open-label randomized study to assess the efficacy and safety of selumetinib (AZD6244 [ARRY-142886]) versus capecitabine in patients with advanced or metastatic pancreatic cancer who have failed first-line gemcitabine therapy. Invest New Drugs 2012;30:1216-23.
23. Walker EJ, Ko AH. Beyond first-line chemotherapy for advanced pancreatic cancer: an expanding array of therapeutic options? World J Gastroenterol 2014;20:2224-36.
24. Oettle H, Riess H, Stieler JM, Heil G, Schwaner I, Seraphin J, et al. Secondline oxaliplatin, folinic acid, and fluorouracil versus folinic acid and fluorouracil alone for gemcitabine-refractory pancreatic cancer: outcomes from the CONKO-003 trial. J Clin Oncol 2014;32:2423-9.
25. Gill S, Ko Y-J, Cripps M, Beaudoin A, Dhesy-Thind S, Zulfiqar M, et al. PANCREOX: A randomized phase 3 study of 5FU/LV with or without oxaliplatin for second-line advanced pancreatic cancer in patients who have received gemcitabine-based chemotherapy (abstract). J Clin Oncol 2014;32:4022.
26. Von Hoff DD, N, Bayever E, Li C, Chen L, Wang-Gillam A, Bodoky G, et al. NAPOLI-1: randomized phase 3 study of MM-398 (nal-iri), with or without 5-fluorouracil and leucovorin, versus 5-fluorouracil and leucovorin, in metastatic pancreatic cancer progressed on or following gemcitabine-based therapy. Ann Oncol 2014;25 (suppl 2):ii105-ii117.
27. Ko AH, Venook AP, Bergsland EK, Kelley RK, Korn WM, Dito E, et al. A phase II study of bevacizumab plus erlotinib for gemcitabine-refractory metastatic pancreatic cancer. Cancer Chemother Pharmacol 2010;66: 1051-7.
28. O'Reilly EM, Niedzwiecki D, Hall M, Hollis D, Bekaii-Saab T, Pluard T, et al. A Cancer and Leukemia Group B phase II study of sunitinib malate in patients with previously treated metastatic pancreatic adenocarcinoma (CALGB 80603). Oncologist 2010;15:1310-9.
29. Chung V, McDonough S, Philip P, Cardin D, Wang-Gillam A, Hui L, et al. SWOG S1115: Randomized phase II trial of selumetinib (AZD6244; ARRY 142886) hydrogen sulfate (NSC-748727) and MK-2206 (NSC-749607) vs. mFOLFOX in pretreated patients with metastatic pancreatic cancer. J Clin Oncol 33, 2015 (suppl; abstr 4119).
30. Collisson EA, Sadanandam A, Olson P, Gibb WJ, Truitt M, Gu S, et al. Subtypes of pancreatic ductal adenocarcinoma and their differing responses to therapy. Nat Med 2011;17:500-3.
31. Hong SM, Li A, Olino K, Wolfgang CL, Herman JM, Schulick RD, et al. Loss of E-cadherin expression and outcome among patients with resectable pancreatic adenocarcinomas. Mod Pathol 2011;24:1237-47.
32. Yamada S, Fuchs BC, Fujii T, Shimoyama Y, Sugimoto H, Nomoto S, et al. Epithelial-to-mesenchymal transition predicts prognosis of pancreatic cancer. Surgery 2013;154:946-54.
33. Singh A, Greninger P, Rhodes D, Koopman L, Violette S, Bardeesy N, et al. A gene expression signature associated with "K-Ras addiction" reveals regulators of EMT and tumor cell survival. Cancer Cell 2009;15:489-500.
34. Witta SE, Gemmill RM, Hirsch FR, Coldren CD, Hedman K, Ravdel L, et al. Restoring E-cadherin expression increases sensitivity to epidermal growth factor receptor inhibitors in lung cancer cell lines. Cancer Res 2006;66: 944-50.
35. Talasaz A, Mortimer S, Schiller B, Mei G, Sebisanovic D, Siew L, et al. Realtime and sequential profiling of cancer through concurrent somatic mutation and gene amplification analysis of cancer by digital sequencing of cellfree DNA from patients with metastatic solid tumors (abstract 3422S), American Society of Human Genetics. San Diego, CA, 2014
36. Zill OA, Greene C, Sebisanovic D, Siew L, Leng J, Vu M, et al. Cell-Free DNA Next-Generation Sequencing in Pancreatobiliary Carcinomas. Cancer Discov 2015. [Epub ahead of print].