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Phase I Study of Lapatinib and Pemetrexed in the Second-Line Treatment of Advanced or Metastatic Non-Small-Cell Lung Cancer With Assessment of Circulating Cell Free Thymidylate Synthase RNA as a Potential Biomarker

Lookup NU author(s): Professor Ruth Plummer, Dr Jane Margetts, Professor John LunecORCiD, Dr Joyce Nutt


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In this dose-escalation study we assessed safety and efficacy of lapatinib and pemetrexed in 18 patients with advanced or metastatic nonesmall-cell lung cancer (NSCLC). The primary outcome was identification of the optimal treatment regimen. Lapatinib and pemetrexed was well tolerated and 1250 mg/500 mg (respectively) was determined as the optimal dose level; suggesting potential use for lapatinib combination therapy in NSCLC.Introduction: Lapatinib is a dual tyrosine kinase inhibitor that targets epidermal growth factor receptor and HER2. We report on a dose-escalation study of lapatinib combined with pemetrexed in second-line treatment to evaluate the safety and efficacy in advanced or metastatic nonesmall-cell lung cancer (NSCLC) and an exploratory study in which circulating cell-free thymidylate synthase ribonucleic acid (cfTSmRNA) was measured in all patients and compared with clinical benefit. Patients and Methods: Eligible patients had stage IIIB or IV NSCLC after 1 previous line of chemotherapy and an Eastern Cooperative Oncology Group performance status of 0 to 2. Three dose levels (DLs) of lapatinib (daily)/pemetrexed (every 21 days) were evaluated: DL0, 1250 mg/400 mg; DL1, 1250 mg/500 mg; and DL2, 1500 mg/500 mg, respectively. The primary outcome was identification of the optimal treatment regimen. Results: Eighteen patients were treated (DL0: n = 4; DL1: n = 8; DL2: n = 6). The most common adverse events (any grade) were diarrhea (61%), rash (44%), nausea (33%), anemia, and fatigue (both 28%). DL1 was determined as optimal after 3 dose-limiting toxicities (DLTs) during the first cycle of DL2 (Grade 3 diarrhea and mucositis, Grade 4 lymphocytopenia); no other DLTs were observed. Partial response was detected in 4 patients. cfTSmRNA was at the limit of detection and was not measurable in all patients. Nonsignificant trends were observed, suggesting that higher levels of cfTSmRNA are associated with poorer outcome. Confirmatory studies are required. Conclusion: Lapatinib and pemetrexed was well tolerated, and data suggest a similar response rate to pemetrexed monotherapy.

Publication metadata

Author(s): Ramlau R, Thomas M, Novello S, Plummer R, Reck M, Kaneko T, Lau MR, Margetts J, Lunec J, Nutt J, Scagliotti GV

Publication type: Article

Publication status: Published

Journal: Clinical Lung Cancer

Year: 2015

Volume: 16

Issue: 5

Pages: 348-357

Print publication date: 01/09/2015

Online publication date: 20/01/2015

Acceptance date: 13/01/2015

ISSN (print): 1525-7304

ISSN (electronic): 1938-0690

Publisher: Elsevier


DOI: 10.1016/j.cllc.2015.01.004


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