Phase I Study of Afatinib and Selumetinib in Patients with KRAS-Mutated Colorectal, Non-Small Cell Lung, and Pancreatic Cancer
Mené sur 19 patients atteints d'un cancer colorectal, sur 6 patients atteints d'un cancer du poumon non à petites cellules et sur 1 patient atteint d'un cancer du pancréas, présentant tous des mutations du gène KRAS, cet essai de phase I évalue la dose maximale tolérée d'afatinib en combinaison avec le sélumétinib
Background : Anti‐tumor effects of MEK inhibitors are limited in KRAS‐mutated tumors due to feedback activation of upstream epidermal growth factor receptors which reactivates the MAPK and the phosphoinositide 3‐kinase (PI3K)‐AKT pathway. Therefore, this phase I trial was initiated with the pan‐HER inhibitor afatinib plus the MEK inhibitor selumetinib in patients with KRASmt, 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 RP2D was 20 mg afatinib QD and 25 mg selumetinib BID (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 intermittent schedules in patients with KRASmt tumors. Although target engagement was observed, the clinical efficacy was limited.
The Oncologist 2020