Activity and Safety of Palbociclib in Patients with Advanced Gastrointestinal Stromal Tumors Refractory to Imatinib and Sunitinib: A Biomarker-driven Phase II Study.

Abstract

<i>CDKN2A</i> loss is frequent in gastrointestinal stromal tumors (GISTs) and associated with aggressive outcome. Palbociclib is a CDK4 inhibitor with preclinical antitumor efficacy in tumors with P16/CDKN2A loss. This is a multicenter single-arm phase II clinical trial assessing safety and efficacy of palbociclib in patients with advanced GIST bearing <i>CDKN2A</i> gene loss. Adults with unresectable locally advanced or metastatic, refractory to at least imatinib and sunitinib, measurable and documented progressive disease (PD) as per RECIST 1.1, and <i>CDKN2A</i> deletion centrally assessed were eligible. Patients received palbociclib 125 mg orally daily on a 21 days on/7 days off dosing schedule, until PD or unacceptable toxicity. The primary endpoint was 4-month non-PD rate according to RECIST 1.1. As of May 2017, 71 patients had been included in the study, and 29 patients (40.3%) met the molecular eligibility requirement. Twenty-five patients (86.2%) had grade 1-2 adverse events (AEs) and 12 patients (41.4%) grade 3-4 AEs possibly related to the drug. The planned interim statistical analysis performed after central histologic and radiological review showed that 19 (86.4%) out of the first 22 evaluable patients had PD at 4 months. <i>CDKN2A</i> status had no impact either on overall survival or outcome on previous standard lines of treatment. Translational analysis suggested upregulation of <i>CCNE1</i> or downregulation of <i>CDKN1A/P21</i> or <i>LRRC3B</i> as potential mechanisms of resistance. Palbociclib has no significant clinical activity as a single agent in <i>P16/CDKN2A</i> <b>-</b>deleted GIST refractory to imatinib and sunitinib.