Ribociclib and everolimus in well-differentiated foregut neuroendocrine tumors

in Endocrine-Related Cancer
Authors:
Nitya Raj Memorial Sloan Kettering Cancer Center, New York, New York, USA

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Youyun Zheng Memorial Sloan Kettering Cancer Center, New York, New York, USA

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Haley Hauser Memorial Sloan Kettering Cancer Center, New York, New York, USA

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Joanne Chou Memorial Sloan Kettering Cancer Center, New York, New York, USA

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Johnathan Rafailov Memorial Sloan Kettering Cancer Center, New York, New York, USA

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Jad Bou-Ayache Memorial Sloan Kettering Cancer Center, New York, New York, USA

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Peter Sawan Memorial Sloan Kettering Cancer Center, New York, New York, USA

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Jamie Chaft Memorial Sloan Kettering Cancer Center, New York, New York, USA

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Jennifer Chan Dana-Farber Cancer Institute, Boston, Massachusetts, USA

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Kimberly Perez Dana-Farber Cancer Institute, Boston, Massachusetts, USA

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Charles Rudin Memorial Sloan Kettering Cancer Center, New York, New York, USA

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Laura Tang Memorial Sloan Kettering Cancer Center, New York, New York, USA

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Diane Reidy-Lagunes Memorial Sloan Kettering Cancer Center, New York, New York, USA

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Correspondence should be addressed to N Raj: rajn@mskcc.org
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The mammalian target of rapamycin inhibitor everolimus is an established therapy for well-differentiated (WD) foregut neuroendocrine tumors (NETs). Pre-clinical data demonstrates a potential synergistic role for cyclin dependent kinase 4/6 inhibition and everolimus to treat this disease. In this phase II multicenter study, patients with advanced foregut WDNETs received combination ribociclib and everolimus until confirmed disease progression or unacceptable toxicity. The first 12 patients received ribociclib 300 mg three weeks in a row with a 1 week break and everolimus 2.5 mg daily (recommended phase II dose). Due to unexpected hematologic and infectious toxicities, the trial was put on hold, modified, and an additional 9 patients received ribociclib 200 mg and everolimus 2.5 mg daily. The primary end point was progression-free survival. Archived pre-treatment tumor was profiled by next-generation sequencing to evaluate for genomic markers of drug response. Twenty-one patients were treated (median age, 56; range, 24 to 77). The study did not meet the pre-specified criteria to advance to stage two. No patients experienced an objective response. Thirteen patients (62%) experienced stable disease. Median progression-free survival was 7.7 months (95% CI, 2.8 months to not reached). Eleven of the first 12 patients (92%) developed grade 2 or more myelosuppression. Ten patients (84%) experienced treatment interruption and 8 patients (67%) required dose reduction. Genetic testing in archival tumor tissue samples failed to identify a predictive biomarker of disease stabilization. The combination of ribociclib and everolimus had insufficient activity to warrant further investigation in foregut WDNETs.

 

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