Phase I Study of Afatinib and Selumetinib in Patients with KRAS -Mutated Colorectal, Non-Small Cell Lung, and Pancreatic Cancer

The oncologist

article

Emilie M.J. van Brummelen¹  Bas Thijssen²  Hilde Rosing²  Alwin Huitema²  Jos Beijnen²  Rene Bernards¹  Jan Schellens³  Sanne Huijberts¹  Carla van Herpen⁴  Ingrid Desar⁴  Frans Opdam⁵  Robin van Geel¹  Serena Marchetti⁵  Neeltje Steeghs⁵  Kim Monkhorst⁷ 

[1]Department of Clinical Pharmacology, The Netherlands Cancer Institute

[2]Department of Pharmacy, The Netherlands Cancer Institute

[3]Department of Clinical Pharmacy, University Medical Center Utrecht, Utrecht University

[4]Department of Medical Oncology, Radboud University Medical Center

[5]Department of Medical Oncology, The Netherlands Cancer Institute

[6]Department of Clinical Pharmacy and Toxicology, Maastricht University Medical Centre

[7]Department of Pathology, The Netherlands Cancer Institute

关键词: Afatinib;    Selumetinib;    KRAS;    Colorectal cancer;    Non-small cell lung cancer;    Pancreatic cancer;   

DOI  :  10.1002/onco.13631

学科分类：地质学

来源: AlphaMed Press Incorporated

【 摘 要 】

Background. Antitumor effects of MEK inhibitors are limited in KRAS-mutated tumors because of feedback activation of upstream epidermal growth factor receptors, which reactivates the MAPK and the phosphoinositide 3-kinase–AKT pathway. Therefore, this phase I trial was initiated with the pan-HER inhibitor afatinib plus the MEK inhibitor selumetinib in patients with KRAS mutant, PIK3CA wild-type tumors. Methods. Afatinib and selumetinib were administered according to a 3+3 design in continuous and intermittent schedules. The primary objective was safety, and the secondary objective was clinical efficacy. Results. Twenty-six patients were enrolled with colorectal cancer (n = 19), non-small cell lung cancer (NSCLC) (n = 6), and pancreatic cancer (n = 1). Dose-limiting toxicities occurred in six patients, including grade 3 diarrhea, dehydration, decreased appetite, nausea, vomiting, and mucositis. The recommended phase II dose (RP2D) was 20 mg afatinib once daily (QD) and 25 mg selumetinib b.i.d. (21 days on/7 days off) for continuous afatinib dosing and for intermittent dosing with both drugs 5 days on/2 days off. Efficacy was limited with disease stabilization for 221 days in a patient with NSCLC as best response. Conclusion. Afatinib and selumetinib can be combined in continuous and intermittentschedules in patients with KRAS mutant tumors. Although target engagement was observed, the clinical efficacy was limited.

【 授权许可】

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