Reference Detail

Ref Type

Journal Article

PMID

(30979737)

Authors

Toulmonde M, Blay JY, Bouche O, Mir O, Penel N, Isambert N, Duffaud F, Bompas E, Esnaud T, Boidot R, Geneste D, Ghiringhelli F, Lucchesi C, Bellera CA, Le Loarer F, Italiano A

Title

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

Journal	Vol	Issue	Date	Pages	Journal Short Title
Clinical cancer research : an official journal of the American Association for Cancer Research	25	15	2019 Aug 01	4611-4615	Clin Cancer Res

URL

Abstract Text

CDKN2A 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 CDKN2A 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 CDKN2A 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. CDKN2A status had no impact either on overall survival or outcome on previous standard lines of treatment. Translational analysis suggested upregulation of CCNE1 or downregulation of CDKN1A/P21 or LRRC3B as potential mechanisms of resistance.Palbociclib has no significant clinical activity as a single agent in P16/CDKN2A-deleted GIST refractory to imatinib and sunitinib.

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Molecular Profile	Treatment Approach

Gene Name	Source	Synonyms	Protein Domains	Gene Description	Gene Role

Therapy Name	Drugs	Efficacy Evidence	Clinical Trials

Drug Name	Trade Name	Synonyms	Drug Classes	Drug Description

Gene	Variant	Impact	Protein Effect	Variant Description	Associated with drug Resistance

Molecular Profile	Indication/Tumor Type	Response Type	Therapy Name	Approval Status	Evidence Type	Efficacy Evidence	References
CDKN2A del	gastrointestinal stromal tumor	no benefit	Palbociclib	Phase II	Actionable	In a Phase II trial, Ibrance (palbociclib) treatment did not demonstrated clinical efficacy in heavily pre-treated gastrointestinal stromal tumor patients harboring CDKN2A homozygous or heterozygous deletion, with 86.4% (19/22) of patients demonstrated progressive disease at 4 months (PMID: 30979737; NCT01907607).	30979737