Phase I-II open label multicenter study of palbociclib + vemurafenib in BRAFV600MUT metastatic melanoma patients: uncovering CHEK2 as a major response mechanism.

Purpose In BRAFV600MUT metastatic melanoma, cyclin-D-CDK4/6-INK4-Rb pathway alterations are involved in resistance to MAPK inhibitors, suggesting a clinical benefit of CDK4 inhibitors. In this phase I-II study, we aimed to establish the maximum tolerated dose (MTD) of palbociclib when added to vemurafenib. Patients and methods BRAFV600E/KMUT metastatic melanoma patients harboring CDKN2A loss and RB1 expression were included and stratified into 2 groups according to previous BRAF inhibitor treatment (no:strata 1; yes:strata 2). Treatment comprised palbociclib once daily for 14 days followed by a 7-day break + continuous dosing of vemurafenib. The primary endpoint was the occurrence of dose-limiting toxicity (DLT), and the secondary endpoints included the best response, survival, pharmacokinetics and tumor molecular profiling. Results Eighteen patients were enrolled, with 15 in strata 2. Characteristics at inclusion were AJCC stage IVM1c (N=16; 88.9%), high LDH (N=9; 50.0%), and median number of previous treatments of 2. One and five patients experienced DLT in strata 1 and 2, respectively, defining the MTD at palbociclib 25mg and vemurafenib 960mg in strata 2. No significant evidence for drug-drug interactions was highlighted. The median PFS was 2.8 months, and 5 (27.8%) patients showed a clinical response. The baseline differential mRNA expression analysis and in vitro data revealed the role of CHEK2 in the response to palbociclib. Conclusions Although the combination of palbociclib + fixed-dose vemurafenib did not allow an increased palbociclib dosage above 25mg, a significant clinical benefit was achieved in pretreated melanoma patients. An association between the transcriptomic data and clinical response was highlighted.