Reference Detail

Ref Type

Journal Article

PMID

(32642630)

Authors

Weinberg BA, Wang H, Witkiewicz AK, Marshall JL, He AR, Vail P, Knudsen ES, Pishvaian MJ

Title

A Phase I Study of Ribociclib Plus Everolimus in Patients with Metastatic Pancreatic Adenocarcinoma Refractory to Chemotherapy.

Journal	Vol	Issue	Date	Pages	Journal Short Title
Journal of pancreatic cancer	6	1	2020	45-54	J Pancreat Cancer

URL

Abstract Text

Purpose: Metastatic pancreatic adenocarcinoma (mPC) has a poor prognosis. CDK4/6 is often deregulated in mPC due to CDKN2A loss, resulting in the loss of p16INK4a that inhibits CDK4/6. CDK4/6 inhibitor monotherapy is ineffective due to RAS-mediated activation of alternative pathways, including phosphatidylinositol 3-kinase-mammalian target of rapamycin (PI3K-mTOR). We conducted a phase I study combining CDK4/6 and mTOR inhibition in patients with mPC refractory to standard chemotherapy. Materials and Methods: The combination of ribociclib (a CDK4/6 inhibitor) and everolimus (an mTOR inhibitor) was investigated in a phase I study in patients with mPC and progression on 5-fluorouracil- and gemcitabine-based chemotherapy. A 3 + 3 design was used to find the recommended phase II dose (RP2D) of ribociclib (250 or 300 mg daily for days 1-21) in combination with everolimus (2.5 mg daily for days 1-28) every 28 days. Secondary endpoints were median progression-free survival (mPFS), median overall survival (mOS), response rate, safety, and effect on the retinoblastoma pathway. Results: Twelve patients were enrolled, six at each dose level. Only one patient had a dose-limiting toxicity of a grade 3 rash at the 250 mg dose. The RP2D of ribociclib was 300 mg. mPFS was 1.8 months (95% confidence interval [CI] [0.6-2.1]), and mOS was 3.7 months (95% CI [2.3-5.6]). Two patients (17%) had stable disease at 8 weeks. Pharmacodynamic evaluation demonstrated that CDK4/6-regulated gene expression was significantly decreased on treatment (n = 6, p < 0.001). Conclusion: Ribociclib 300 mg daily for days 1-21 plus everolimus 2.5 mg daily was well tolerated and associated with decreased CDK4/6-regulated gene expression. This combination was not effective as a third-line therapy but does pharmacologically target CDK4/6 in mPC, revealing the potential for benefit in other settings.

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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