Phase I study of FOLFIRI plus pimasertib as second-line treatment for KRAS-mutated metastatic colorectal cancer

British Journal of Cancer

Volumn 112, Issue 12, 2015, Pages 1874-1881

  Macarulla, T ^a   Cervantes, A ^b   Tabernero, J ^a   Rosello S ^b   Van Cutsem, E ^c   Tejpar, S ^c   Prenen, H ^c   Martinelli, E ^d   Troiani, T ^d   Laffranchi, B ^e   Jego, V ^e   Von Richter, O ^f   Ciardiello, F ^d  

^a HOSPITAL UNIVERSITARI VALL D HEBRON   (Spain)

^b UNIVERSITY OF VALENCIA   (Spain)

^c UNIVERSITY HOSPITALS LEUVEN   (Belgium)

^d SECOND UNIVERSITY OF NAPLES   (Italy)

^e MERCK SERONO S A   (Switzerland)

^f MERCK KGAA   (Germany)

Author keywords

combination therapy second line treatment; FOLFIRI; KRAS mutated metastatic colorectal cancer; MEK inhibitor; pimasertib

Indexed keywords

FIRTECAN; FLUOROURACIL; FOLINIC ACID; IRINOTECAN; PIMASERTIB; ANTINEOPLASTIC AGENT; CAMPTOTHECIN; KRAS PROTEIN, HUMAN; N-(2,3-DIHYDROXYPROPYL)-1-((2-FLUORO-4-IODOPHENYL)AMINO)ISONICOTINAMIDE; NICOTINAMIDE; ONCOPROTEIN; RAS PROTEIN;

ACNE; ADULT; AGED; AREA UNDER THE CURVE; ARTICLE; ASTHENIA; CANCER PATIENT; CLINICAL ARTICLE; DERMATITIS; DIARRHEA; DRUG CLEARANCE; DRUG DOSE ESCALATION; DRUG EFFICACY; DRUG HALF LIFE; DRUG SAFETY; DRUG TOLERABILITY; DRY SKIN; FEMALE; GENE MUTATION; HUMAN; HYPOMAGNESEMIA; MALE; MAXIMUM TOLERATED DOSE; METASTATIC COLORECTAL CANCER; MULTICENTER STUDY; MULTIPLE CYCLE TREATMENT; NAUSEA; NEUTROPENIA; ONCOGENE K RAS; PHASE 1 CLINICAL TRIAL; PRIORITY JOURNAL; RASH; RECOMMENDED DRUG DOSE; RETINA DETACHMENT; RETINA MACULOPATHY; SINGLE DRUG DOSE; STOMATITIS; TREATMENT RESPONSE; VISUAL FIELD DEFECT; VISUAL IMPAIRMENT; VOLUME OF DISTRIBUTION; VOMITING; ANALOGS AND DERIVATIVES; CLINICAL TRIAL; COLORECTAL NEOPLASMS; CONTROLLED STUDY; ENZYMOLOGY; GENETICS; METASTASIS; MIDDLE AGED; MUTATION; ONCOGENE RAS; PATHOLOGY; PHASE 2 CLINICAL TRIAL; RANDOMIZED CONTROLLED TRIAL; TREATMENT OUTCOME; VERY ELDERLY;

AGED; AGED, 80 AND OVER; ANTINEOPLASTIC COMBINED CHEMOTHERAPY PROTOCOLS; CAMPTOTHECIN; COLORECTAL NEOPLASMS; FEMALE; FLUOROURACIL; GENES, RAS; HUMANS; LEUCOVORIN; MALE; MIDDLE AGED; MUTATION; NEOPLASM METASTASIS; NIACINAMIDE; PROTO-ONCOGENE PROTEINS; RAS PROTEINS; TREATMENT OUTCOME;

EID: 84930868888     PISSN: 00070920     EISSN: 15321827     Source Type: Journal    
DOI: 10.1038/bjc.2015.144     Document Type: Article

References (31)

1. Awada A, Delord JP, Houede N, Lebbe C, Lesimple T, Schellens JHM, Rottey S, Kefford R, Rejeb N, Raymond E (2012) Safety and recommended phase II dose (RP2D) of the selective oral MEK1/2 inhibitor pimasertib (MSC1936369B/AS703026): results of a phase I trial. Eur J Cancer 48(Suppl 6): 185-186 (abstract 604).
2. Bokemeyer C, Bondarenko I, Makhson A, Hartmann JT, Aparicio J, de Braud F, Donea S, Ludwig H, Schuch G, Stroh C, Loos AH, Zubel A, Koralewski P (2009) Fluorouracil, leucovorin, and oxaliplatin with and without cetuximab in the first-line treatment of metastatic colorectal cancer. J Clin Oncol 27(5): 663-671.
3. Bokemeyer C, Van Cutsem E, Rougier P, Ciardiello F, Heeger S, Schlichting M, Celik I, Kohne CH (2012) Addition of cetuximab to chemotherapy as first-line treatment for KRAS wild-type metastatic colorectal cancer: pooled analysis of the CRYSTAL and OPUS randomised clinical trials. Eur J Cancer 48(10): 1466-1475.
4. Chapman MS, Miner JN (2011) Novel mitogen-activated protein kinase kinase inhibitors. Expert Opin Invest Drugs 20(2): 209-220.
5. Clark AM, Ma J, Qiu D, Lin J, Syed S, Romanelli A, Spooner E, Shaw J, Rocha C, Tian H (2009) Pharmacokinetics, efficacy and target pathway inhibition in vivo of AS703026, a small molecule inhibitor of MEK. Cancer Res 69(Suppl 9): 3694.
6. De Roock W, Claes B, Bernasconi D, De Schutter J, Biesmans B, Fountzilas G, Kalogeras KT, Kotoula V, Papamichael D, Laurent-Puig P, Penault-Llorca F, Rougier P, Vincenzi B, Santini D, Tonini G, Cappuzzo F, Frattini M, Molinari F, Saletti P, De Dosso S, Martini M, Bardelli A, Siena S, Sartore-Bianchi A, Tabernero J, Macarulla T, Di Fiore F, Gangloff AO, Ciardiello F, Pfeiffer P, Qvortrup C, Hansen TP, Van Cutsem E, Piessevaux H, Lambrechts D, Delorenzi M, Tejpar S (2010) Effects of KRAS, BRAF, NRAS, and PIK3CA mutations on the efficacy of cetuximab plus chemotherapy in chemotherapy-refractory metastatic colorectal cancer: a retrospective consortium analysis. Lancet Oncol 11(8): 753-762.
7. De Roock W, De Vriendt V, Normanno N, Ciardiello F, Tejpar S (2011) KRAS, BRAF, PIK3CA, and PTEN mutations: implications for targeted therapies in metastatic colorectal cancer. Lancet Oncol 12(6): 594-603.
8. Delord JP, Houede N, Awada A, Lebbe C, Lesimple T, Schellens JHM, Rottey S, Kefford R, Rejeb N, Raymond E (2012) Pimasertib (MSC1936369B/AS703026), a selective oral MEK1/2 inhibitor, shows clinical activity in melanoma. Eur J Cancer 48(Suppl 6): 190 (abstract 616).
9. Douillard JY, Oliner KS, Siena S, Tabernero J, Burkes R, Barugel M, Humblet Y, Bodoky G, Cunningham D, Jassem J, Rivera F, Kocakova I, Ruff P, Blasinska-Morawiec M, Smakal M, Canon JL, Rother M, Williams R, Rong A, Wiezorek J, Sidhu R, Patterson SD (2013) Panitumumab-FOLFOX4 treatment and RAS mutations in colorectal cancer. N Engl J Med 369(11): 1023-1034.
10. Douillard JY, Siena S, Cassidy J, Tabernero J, Burkes R, Barugel M, Humblet Y, Bodoky G, Cunningham D, Jassem J, Rivera F, Kocakova I, Ruff P, Blasinska-Morawiec M, Smakal M, Canon JL, Rother M, Oliner KS, Wolf M, Gansert J (2010) Randomized, phase III trial of panitumumab with infusional fluorouracil, leucovorin, and oxaliplatin (FOLFOX4) versus FOLFOX4 alone as first-line treatment in patients with previously untreated metastatic colorectal cancer: the PRIME study. J Clin Oncol 28(31): 4697-4705.
11. Fremin C, Meloche S (2010) From basic research to clinical development of MEK1/2 inhibitors for cancer therapy. J Hematol Oncol 3: 8.
12. Goutopoulos A, Askew BC, Bankston D, Clark A, Dhanabal M, Dong R, Fischer D, Healey B, Jiang X, Josephson K, Lin J, Ma J, Noonan T, Qiu D, Rocha C, Romanelli A, Shutes A, Spooner E, Tian H (2009) AS703026: a novel allosteric MEK inhibitor. Cancer Res 69(Suppl 9): 4776.
13. Houédé N, Delord JP, Awada A, Lebbe C, Lesimple T, Schellens JHM, Rottey S, Kefford R, von Richter O, Raymond E (2012) Pharmacokinetics and pharmacodynamics of a selective oral MEK1/2 inhibitor, pimasertib (MSC1936369B/AS703026), in patients with advanced solid tumors. Eur J Cancer 48(Suppl 6): 184 (abstract 600).
14. Infante JR, Gandhi L, Shapiro G, Burris III HA, Bendell JC, Baselga J, Hsu K, Faivre T, Asatiani E, Heist RS (2012) Phase lb combination trial of a MEK inhibitor, pimasertib (MSC1936369B), and a PI3K/mTOR inhibitor, SAR245409, in patients with locally advanced or metastatic solid tumors. J Clin Oncol 30(Suppl): (abstract TPS3118).
15. Kim K, Kong SY, Fulciniti M, Li X, Song W, Nahar S, Burger P, Rumizen MJ, Podar K, Chauhan D, Hideshima T, Munshi NC, Richardson P, Clark A, Ogden J, Goutopoulos A, Rastelli L, Anderson KC, Tai YT (2010) Blockade of the MEK/ERK signalling cascade by AS703026, a novel selective MEK1/2 inhibitor, induces pleiotropic anti-myeloma activity in vitro and in vivo. Br J Haematol 149(4): 537-549.
16. Machl AW, Ogden JA, Romanelli A (2009) Efficacy of MEK inhibitor AS703026 in various primary tumor explants. Cancer Res 69(Suppl 9): 3698.
17. Martinelli E, Troiani T, D'Aiuto E, Morgillo F, Vitagliano D, Capasso A, Costantino S, Ciuffreda LP, Merolla F, Vecchione L, De Vriendt V, Tejpar S, Nappi A, Sforza V, Martini G, Berrino L, De Palma R, Ciardiello F (2013) Antitumor activity of pimasertib, a selective MEK 1/2 inhibitor, in combination with PI3K/mTOR inhibitors or with multi-targeted kinase inhibitors in pimasertib-resistant human lung and colorectal cancer cells. Int J Cancer 133(9): 2089-2101.
18. Naing A, Mita M, Komarnitsky P, Milner A, von Richter O, Ogden J, Piha-Paul S, Fu S, Asatiani E, Kurzrock R (2012) Phase I dose-escalation trial of a selective oral MEK1/2 inhibitor, pimasertib (MSC1936369B), combined with an mTOR inhibitor, temsirolimus, in patients with advanced solid tumors. Eur J Cancer 48(Suppl 6): 187 (abstract 608).
19. Neumann J, Zeindl-Eberhart E, Kirchner T, Jung A (2009) Frequency and type of KRAS mutations in routine diagnostic analysis of metastatic colorectal cancer. Pathol Res Pract 205(12): 858-862.
20. Prenen H, Tejpar S, Van Cutsem E (2010) New strategies for treatment of KRAS mutant metastatic colorectal cancer. Clin Cancer Res 16(11): 2921-2926.
21. Ravandi F, Pigneux A, DeAngelo D, Dombret H, Delaunay J, Thomas X, Kadia T, Luepfert C, Asatiani E, Donica M, Kantarjian H, Smith BD (2011) Preliminary clinical, pharmacokinetic (PK) and pharmacodynamic (PD) results of the safety run-in part of a phase II trial of orally available MEKinhibitor MSC1936369 in patients (pts) with advanced hematological malignancies (HM). Blood (ASH Annu Meet Abstr) 118: 21 (abstract 615).
22. Renouf DJ, Velazquez-Martin JP, Simpson R, Siu LL, Bedard PL (2012) Ocular toxicity of targeted therapies. J Clin Oncol 30(26): 3277-3286.
23. Santarpia L, Lippman SM, El-Naggar AK (2012) Targeting the MAPK-RAS-RAF signaling pathway in cancer therapy. Expert Opin Ther Targets 16(1): 103-119.
24. Schmoll HJ, Van Cutsem E, Stein A, Valentini V, Glimelius B, Haustermans K, Nordlinger B, van de Velde CJ, Balmana J, Regula J, Nagtegaal ID, Beets-Tan RG, Arnold D, Ciardiello F, Hoff P, Kerr D, Kohne CH, Labianca R, Price T, Scheithauer W, Sobrero A, Tabernero J, Aderka D, Barroso S, Bodoky G, Douillard JY, El Ghazaly H, Gallardo J, Garin A, Glynne-Jones R, Jordan K, Meshcheryakov A, Papamichail D, Pfeiffer P, Souglakos I, Turhal S, Cervantes A (2012) ESMO Consensus Guidelines for management of patients with colon and rectal cancer. a personalized approach to clinical decision making. Ann Oncol 23(10): 2479-2516.
25. Sebolt-Leopold JS (2008) Advances in the development of cancer therapeutics directed against the RAS-mitogen-activated protein kinase pathway. Clin Cancer Res 14(12): 3651-3656.
26. Troiani T, Napolitano S, Vitagliano D, Morgillo F, Capasso A, Sforza V, Nappi A, Ciardiello D, Ciardiello F, Martinelli E (2014) Primary and acquired resistance of colorectal cancer cells to anti-EGFR antibodies converge on MEK/ERK pathway activation and can be overcome by combined MEK/EGFR inhibition. Clin Cancer Res 20(14): 3775-3786.
27. Van Cutsem E, Kohne CH, Hitre E, Zaluski J, Chang Chien CR, Makhson A, D'Haens G, Pinter T, Lim R, Bodoky G, Roh JK, Folprecht G, Ruff P, Stroh C, Tejpar S, Schlichting M, Nippgen J, Rougier P (2009) Cetuximab and chemotherapy as initial treatment for metastatic colorectal cancer. N Engl J Med 360(14): 1408-1417.
28. Van Cutsem E, Kohne CH, Lang I, Folprecht G, Nowacki MP, Cascinu S, Shchepotin I, Maurel J, Cunningham D, Tejpar S, Schlichting M, Zubel A, Celik I, Rougier P, Ciardiello F (2011) Cetuximab plus irinotecan, fluorouracil, and leucovorin as first-line treatment for metastatic colorectal cancer: updated analysis of overall survival according to tumor KRAS and BRAF mutation status. J Clin Oncol 29(15): 2011-2019.
29. Van Cutsem E, Nordlinger B, Cervantes A (2010) Advanced colorectal cancer: ESMO Clinical Practice Guidelines for treatment. Ann Oncol 21(Suppl 5): v93-v97.
30. Ye LC, Liu TS, Ren L, Wei Y, Zhu DX, Zai SY, Ye QH, Yu Y, Xu B, Qin XY, Xu J (2013) Randomized controlled trial of cetuximab plus chemotherapy for patients with KRAS wild-type unresectable colorectal liver-limited metastases. J Clin Oncol 31(16): 1931-1938.
31. Yoon J, Koo KH, Choi KY (2011) MEK1/2 inhibitors AS703026 and AZD6244 may be potential therapies for KRAS mutated colorectal cancer that is resistant to EGFR monoclonal antibody therapy. Cancer Res 71(2): 445-453.