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

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.