title: Phase II evaluation of LY2603618, a first-generation CHK1 inhibitor, in combination with pemetrexed in patients with advanced or metastatic non-small cell lung cancer.
abstract: Introduction LY2603618 is a selective inhibitor of checkpoint kinase 1 (CHK1) protein kinase, a key regulator of the DNA damage checkpoint, and is predicted to enhance the effects of antimetabolites, such as pemetrexed. This phase II trial assessed the overall response rate, safety, and pharmacokinetics (PK) of LY2603618 and pemetrexed in patients with non-small cell lung cancer (NSCLC). Methods In this open-label, single-arm trial, patients with advanced or metastatic NSCLC progressing after a prior first-line treatment regimen (not containing pemetrexed) and Eastern Cooperative Oncology Group performance status ≤2 received pemetrexed (500 mg/m(2), day 1) and LY2603618 (150 mg/m(2), day 2) every 21 days until disease progression. Safety was assessed using Common Terminology Criteria for Adverse Events v3.0. Serial blood samples were collected for PK analysis after LY2603618 and pemetrexed administration. Expression of p53, as measured by immunohistochemistry and genetic variant analysis, was assessed as a predictive biomarker of response. Results Fifty-five patients were enrolled in the study. No patients experienced a complete response; a partial response was observed in 5 patients (9.1 %; 90 % CI, 3.7-18.2) and stable disease in 20 patients (36.4 %). The median progression-free survival was 2.3 months (range, 0-27.1). Safety and PK of LY2603618 in combination with pemetrexed were favorable. No association between p53 status and response was observed. Conclusions There was no significant clinical activity of LY2603618 and pemetrexed combination therapy in patients with advanced NSCLC. The results were comparable with historical pemetrexed single-agent data, with similar safety and PK profiles being observed.
authors.affiliation: University of Turin, S. Luigi Hospital, Orbassano, Torino, Italy. scagliotti@ihnet.it.
authors.forename: Giorgio
authors.identifier: 0000-0002-9621-8738
authors.initials: G
authors.lastname: Scagliotti
authors.affiliation: The Catholic University of Korea, St. Mary's Hospital, Seoul, Republic of Korea.
authors.forename: Jin Hyoung
authors.initials: JH
authors.lastname: Kang
authors.affiliation: Washington and US Oncology Research, Houston, TX, USA.
authors.forename: David
authors.initials: D
authors.lastname: Smith
authors.affiliation: Arizona Oncology, Tucson, TX, USA.
authors.forename: Richard
authors.initials: R
authors.lastname: Rosenberg
authors.affiliation: Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, South Korea.
authors.forename: Keunchil
authors.initials: K
authors.lastname: Park
authors.affiliation: Asan Medical Center, University of Ulsan College of Medicine, Seoul, South Korea.
authors.forename: Sang-We
authors.initials: SW
authors.lastname: Kim
authors.affiliation: National Cheng Kung University, Tainan, Taiwan.
authors.forename: Wu-Chou
authors.initials: WC
authors.lastname: Su
authors.affiliation: Willamette Valley Cancer Institute, Eugene, OR, USA.
authors.forename: Thomas E
authors.initials: TE
authors.lastname: Boyd
authors.affiliation: US Oncology Research, Tyler, TX, USA.
authors.forename: Donald A
authors.initials: DA
authors.lastname: Richards
authors.affiliation: University of Turin, S. Luigi Hospital, Orbassano, Torino, Italy.
authors.forename: Silvia
authors.initials: S
authors.lastname: Novello
authors.affiliation: Eli Lilly and Company, Indianapolis, IN, USA.
authors.forename: Scott M
authors.initials: SM
authors.lastname: Hynes
authors.affiliation: Thermo Fisher Scientific, Ann Arbor, MI, USA.
authors.forename: Scott P
authors.initials: SP
authors.lastname: Myrand
authors.affiliation: Eli Lilly and Company, Indianapolis, IN, USA.
authors.forename: Ji
authors.initials: J
authors.lastname: Lin
authors.affiliation: Eli Lilly and Company, Indianapolis, IN, USA.
authors.forename: Emily Nash
authors.initials: EN
authors.lastname: Smyth
authors.affiliation: Eli Lilly and Company, Indianapolis, IN, USA.
authors.forename: Sameera
authors.initials: S
authors.lastname: Wijayawardana
authors.affiliation: Eli Lilly and Company, Indianapolis, IN, USA.
authors.forename: Aimee Bence
authors.initials: AB
authors.lastname: Lin
authors.affiliation: Moffitt Cancer Center, Tampa, FL, USA.|GlaxoSmith Kline, Philadelphia, PA, USA.
authors.forename: Mary
authors.initials: M
authors.lastname: Pinder-Schenck
mesh_terms: D000328:Adult; D000368:Aged; D000970:Antineoplastic Agents / Q000009:adverse effects / Q000493:pharmacokinetics / Q000494:pharmacology / Q000627:therapeutic use; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects / Q000493:pharmacokinetics / Q000494:pharmacology / Q000627:therapeutic use; D014408:Biomarkers, Tumor / Q000235:genetics / Q000378:metabolism; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism; D000071877:Checkpoint Kinase 1 / Q000037:antagonists & inhibitors; D005260:Female; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D000068437:Pemetrexed / Q000009:adverse effects / Q000493:pharmacokinetics / Q000494:pharmacology / Q000627:therapeutic use; D010671:Phenylurea Compounds / Q000009:adverse effects / Q000493:pharmacokinetics / Q000494:pharmacology / Q000627:therapeutic use; D047428:Protein Kinase Inhibitors / Q000009:adverse effects / Q000493:pharmacokinetics / Q000494:pharmacology / Q000627:therapeutic use; D011719:Pyrazines / Q000009:adverse effects / Q000493:pharmacokinetics / Q000494:pharmacology / Q000627:therapeutic use; D016896:Treatment Outcome; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism
chemical_list: D000970:Antineoplastic Agents; D014408:Biomarkers, Tumor; C582547:LY2603618; D010671:Phenylurea Compounds; D047428:Protein Kinase Inhibitors; D011719:Pyrazines; D016159:Tumor Suppressor Protein p53; D000068437:Pemetrexed; C000605867:CHEK1 protein, human; D000071877:Checkpoint Kinase 1
keywords: CHK1 protein kinase inhibitor; LY2603618; Non-small cell lung cancer; Pharmacokinetics; p53