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.

Abstract

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 non-small-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.

• Authors: Rodryg Ramlau, Michael Thomas, Silvia Novello, Ruth Plummer, Martin Reck, Tomomi Kaneko, Mike R Lau, Jane Margetts, John Lunec, Joyce Nutt, Giorgio V Scagliotti
• Journal: Clinical lung cancer (Clin Lung Cancer) Vol. 16 Issue 5 Pg. 348-57 (Sep 2015) ISSN: 1938-0690 [Electronic] United States
• PMID: 25700774 (Publication Type: Clinical Trial, Phase I, Comparative Study, Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2015 Elsevier Inc. All rights reserved.

Chemical References

• Biomarkers, Tumor
• Quinazolines
• Pemetrexed
• Lapatinib
• Thymidylate Synthase

Topics

• Aged
• Antineoplastic Combined Chemotherapy Protocols (administration & dosage, adverse effects, therapeutic use)
• Biomarkers, Tumor (genetics)
• Carcinoma, Non-Small-Cell Lung (drug therapy, genetics, pathology)
• Dose-Response Relationship, Drug
• Female
• Humans
• Lapatinib
• Lung Neoplasms (drug therapy, genetics, pathology)
• Male
• Middle Aged
• Neoplasm Metastasis
• Pemetrexed (administration & dosage)
• Quinazolines (administration & dosage)
• Thymidylate Synthase (genetics)
• Treatment Outcome