Alectinib combined with cobimetinib in ALK-Rearranged lung Cancer: A phase IB study

Mené sur 16 patients atteints d'un cancer du poumon ALK+, cet essai de phase IB détermine la dose maximale tolérée de l'alectinib en combinaison avec le cobimétinib (un inhibiteur de MEK) puis évalue l'efficacité de cette combinaison du point de vue de la survie sans progression

Résumé en anglais

Introduction: Anaplastic lymphoma kinase rearranged (ALK + ) lung cancers often develop ALK-independent resistance mechanisms that reactivate the mitogen-activated protein kinase pathway signaling pathway. We therefore evaluated alectinib combined with the MEK inhibitor cobimetinib in metastatic ALK + lung cancer.

Materials and Methods: This phase Ib study employed a 3 + 3 design. Cohort 1 enrolled patients irrespective of prior alectinib exposure. Cohort 2 only enrolled treatment-naive patients. Patients received alectinib 600 mg twice daily (BID) continuously and cobimetinib at either 20 or 40 mg daily on days 1–21 every 28 days. A 2-week alectinib lead-in was incorporated into cohort 2. The primary objective was to determine the maximum tolerated dose (MTD) for cohort 1.

Results: Sixteen patients were enrolled between 9/2017 and 8/2021, ten of whom were in cohort 1. No dose-limiting toxicities (DLTs) were observed with alectinib + cobimetinib 20 mg in cohort 1. On alectinib + cobimetinib 40 mg, DLTs of grade 3–4 creatine phosphokinase elevation and grade 3 rash were observed in 2 of 6 patients, both of whom were alectinib-naïve and required dose reduction. The MTD for cohort 1 was declared as 600 mg alectinib BID + cobimetinib 40 mg. Six alectinib-naïve patients were treated with alectinib + cobimetinib 20 mg in cohort 2. With the lead-in, no patients experienced DLTs. One patient in cohort 2 discontinued cobimetinib for grade 2 pneumonitis. Median progression-free survival was 2.2 months and 49.2 months for alectinib-resistant and alectinib-naïve patients, respectively.

Discussion: Alectinib combined with cobimetinib demonstrated limited activity in alectinib-resistant tumors. Despite dose-limiting dermatologic and muscle enzyme toxicities, durable responses were observed in alectinib-naïve patients.