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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

  • PHASE II STUDIES
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Summary

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.

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Acknowledgments

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.

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Author notes

  1. Mary Pinder-Schenck

    Present address: GlaxoSmith Kline, Philadelphia, PA, USA

Authors and Affiliations

  1. University of Turin, S. Luigi Hospital, Orbassano, Torino, Italy

    Giorgio Scagliotti & Silvia Novello

  2. The Catholic University of Korea, St. Mary’s Hospital, Seoul, Republic of Korea

    Jin Hyoung Kang

  3. Washington and US Oncology Research, Houston, TX, USA

    David Smith

  4. Arizona Oncology, Tucson, TX, USA

    Richard Rosenberg

  5. Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, South Korea

    Keunchil Park

  6. Asan Medical Center, University of Ulsan College of Medicine, Seoul, South Korea

    Sang-We Kim

  7. National Cheng Kung University, Tainan, Taiwan

    Wu-Chou Su

  8. Willamette Valley Cancer Institute, Eugene, OR, USA

    Thomas E. Boyd

  9. US Oncology Research, Tyler, TX, USA

    Donald A. Richards

  10. Eli Lilly and Company, Indianapolis, IN, USA

    Scott M. Hynes, Ji Lin, Emily Nash Smyth, Sameera Wijayawardana & Aimee Bence Lin

  11. Thermo Fisher Scientific, Ann Arbor, MI, USA

    Scott P. Myrand

  12. Moffitt Cancer Center, Tampa, FL, USA

    Mary Pinder-Schenck

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Corresponding author

Correspondence to Giorgio Scagliotti.

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Financial disclosure

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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Key Message

This open-label, single-arm, phase II trial assessed the overall response rate, safety, and pharmacokinetics of CHK1 inhibitor LY2603618 and pemetrexed in patients with advanced or metastatic non-small cell lung cancer. No significant clinical activity of LY2603618 and pemetrexed combination therapy was observed, with results being comparable with historical pemetrexed single-agent data.

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Scagliotti, G., Kang, J.H., Smith, D. et al. 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. Invest New Drugs 34, 625–635 (2016). https://doi.org/10.1007/s10637-016-0368-1

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