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
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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/m2, day 1) and LY2603618 (150 mg/m2, 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.
KeywordsCHK1 protein kinase inhibitor LY2603618 Non-small cell lung cancer p53 Pharmacokinetics
The authors thank all patients, their caregivers, and all investigators for their participation in the study. The authors thank Ignacio Garcias-Ribas and Eric Westin formerly of Eli Lilly and Company, now of Takeda Oncology, for their contributions to the CHK1 clinical program; Rodney L. Decker of Eli Lilly and Company for his assistance with the pharmacokinetic analysis; Sunil Kadam of Eli Lilly and Company for designing the p53 analysis; Jill Kolodsick of Eli Lilly and Company and Chastity Bradley of ClinGenuity, LLC for writing assistance; Elizabeth Kumm of InVentiv Health Clinical, LLC for statistical assistance; and Ben Legendre of Transgenomic for assisting with the TP53 functionality analysis.
Compliance with ethical standards
Giorgio Scagliotti has received honoraria from Eli Lilly and Company, AstraZeneca, Pfizer, Roche, and Clovis Oncology. Jin Hyoung Kang is an Advisory board member and has received research support from Eli Lilly and Company. Scott M. Hynes, Ji Lin, Emily Nash Smyth, Sameera Wijayawardana, and Aimee Bence Lin are all employees of Eli Lilly and Company and own Eli Lilly and Company stock.
Conflicts of interest
All remaining authors have declared no conflicts of interest.
Sources of supports
Eli Lilly and Company.
Trial registration ID
A Study of Advanced or Metastatic Non-small Cell Lung Cancer; NCT00988858.
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