Ribociclib and everolimus in well-differentiated foregut neuroendocrine tumors

in Endocrine-Related Cancer
View More View Less
  • 1 Memorial Sloan Kettering Cancer Center, New York, New York, USA
  • 2 Dana-Farber Cancer Institute, Boston, Massachusetts, USA

Correspondence should be addressed to N Raj: rajn@mskcc.org
Restricted access

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.

 

Society for Endocrinology

Sept 2018 onwards Past Year Past 30 Days
Abstract Views 31 31 31
Full Text Views 1 1 1
PDF Downloads 2 2 2
  • Bardia A, Modi S, Gregor MCM, Kittaneh M, Marino AJ, Matano A, Bhansali S, Hewes B & Cortes J 2014 Phase Ib/II study of LEE011, everolimus, and exemestane in postmenopausal women with ER+/HER2-metastatic breast cancer. Journal of Clinical Oncology 32 535.

    • Search Google Scholar
    • Export Citation
  • Chan AO, Kim SG, Bedeir A, Issa JP, Hamilton SR & Rashid A 2003 CpG island methylation in carcinoid and pancreatic endocrine tumors. Oncogene 22 924934. (https://doi.org/10.1038/sj.onc.1206123)

    • Search Google Scholar
    • Export Citation
  • Cheng DT, Mitchell TN, Zehir A, Shah RH, Benayed R, Syed A, Chandramohan R, Liu ZY, Won HH & Scott SN 2015 Memorial sloan kettering-integrated mutation profiling of actionable cancer targets (MSK-IMPACT) a hybridization capture-based next-generation sequencing clinical assay for solid tumor molecular oncology. Journal of Molecular Diagnostics 17 251264. (https://doi.org/10.1016/j.jmoldx.2014.12.006)

    • Search Google Scholar
    • Export Citation
  • Dammann R, Schagdarsurengin U, Liu LM, Otto N, Gimm O, Dralle H, Boehm BO, Pfeifer GP & Hoang-Vu C 2003 Frequent RASSF1A promoter hypermethylation and K-ras mutations in pancreatic carcinoma. Oncogene 22 38063812. (https://doi.org/10.1038/sj.onc.1206582)

    • Search Google Scholar
    • Export Citation
  • Dasari A, Halperin D, Coya T, Zorrilla I, Meric-Bernstam F & Yao J 2019 A pilot study of the cyclin dependent kinases 4, 6 inhibitor ribociclib in patients with foregut neuroendocrine tumors. Pancreas 48 432433.

    • Search Google Scholar
    • Export Citation
  • Gnirke A, Melnikov A, Maguire J, Rogov P, Leproust EM, Brockman W, Fennell T, Giannoukos G, Fisher S & Russ C et al. 2009 Solution hybrid selection with ultra-long oligonucleotides for massively parallel targeted sequencing. Nature Biotechnology 27 182189. (https://doi.org/10.1038/nbt.1523)

    • Search Google Scholar
    • Export Citation
  • House MG, Herman JG, Guo MZ, Hooker CM, Schulick RD, Lillemoe KD, Cameron JL, Hruban RH, Maitra A & Yeo CJ 2003 Aberrant hypermethylation of tumor suppressor genes in pancreatic endocrine neoplasms. Annals of Surgery 238 42343 1; discussion 431. (https://doi.org/10.1097/01.sla.0000086659.49569.9e)

    • Search Google Scholar
    • Export Citation
  • Jiao Y, Shi C, Edil BH, De Wilde RF, Klimstra DS, Maitra A, Schulick RD, Tang LH, Wolfgang CL & Choti MA et al. 2011 DAXX/ATRX, MEN1, and mTOR pathway genes are frequently altered in pancreatic neuroendocrine tumors. Science 331 11991203. (https://doi.org/10.1126/science.1200609)

    • Search Google Scholar
    • Export Citation
  • LEE011 (Ribociclib) Investigator’s Brochure Edition 9, 2016.

  • Lubensky IA & Zhuang Z 2007 Molecular genetic events in gastrointestinal and pancreatic neuroendocrine tumors. Endocrine Pathology 18 156162. (https://doi.org/10.1007/s12022-007-9007-x)

    • Search Google Scholar
    • Export Citation
  • Makker V, Recio FO, Ma L, Matulonis UA, Lauchle JO, Parmar H, Gilbert HN, Ware JA, Zhu R & Lu S et al. 2016 A multicenter, single-arm, open-label, phase 2 study of apitolisib (GDC-0980) for the treatment of recurrent or persistent endometrial carcinoma (MAGGIE study). Cancer 122 35193528. (https://doi.org/10.1002/cncr.30286)

    • Search Google Scholar
    • Export Citation
  • Muscarella P, Melvin WS, Fisher WE, Foor J, Ellison EC, Herman JG, Schirmer WJ, Hitchcock CL, Deyoung BR & Weghorst CM 1998 Genetic alterations in gastrinomas and nonfunctioning pancreatic neuroendocrine tumors: an analysis of p16/MTS1 tumor suppressor gene inactivation. Cancer Research 58 237240.

    • Search Google Scholar
    • Export Citation
  • O’Brien NA, Tomaso ED, Ayala R, Tong L, Issakhanian S, Linnartz R, Finn RS, Hirawat S & Slamon DJ 2014 In vivo efficacy of combined targeting of CDK4/6, ER and PI3K signaling in ER plus breast cancer. Cancer Research 74 4756.

    • Search Google Scholar
    • Export Citation
  • Pavel ME, Hainsworth JD, Baudin E, Peeters M, Hörsch D, Winkler RE, Klimovsky J, Lebwohl D, Jehl V & Wolin EM et al. 2011 Everolimus plus octreotide long-acting repeatable for the treatment of advanced neuroendocrine tumours associated with carcinoid syndrome (RADIANT-2): a randomised, placebo-controlled, phase 3 study. Lancet 378 20052012. (https://doi.org/10.1016/S0140-6736(1161742-X)

    • Search Google Scholar
    • Export Citation
  • Raj N, Shah R, Stadler Z, Mukherjee S, Chou J, Untch B, Li J, Kelly V, Saltz LB & Mandelker D et al. 2018 Real-time genomic characterization of metastatic pancreatic neuroendocrine tumors has prognostic implications and identifies potential germline actionability. JCO Precision Oncology 2018 118. (https://doi.org/10.1200/PO.17.00267)

    • Search Google Scholar
    • Export Citation
  • Rindi G, Kloppel G, Alhman H, Caplin M, Couvelard A, De Herder WW, Erikssson B, Falchetti A, Falconi M & Komminoth P et al. 2006 TNM staging of foregut (neuro)endocrine tumors: a consensus proposal including a grading system. Virchows Archiv 449 395401. (https://doi.org/10.1007/s00428-006-0250-1)

    • Search Google Scholar
    • Export Citation
  • Sanchez-Vega F, Mina M, Armenia J, Chatila WK, Luna A, La KC, Dimitriadoy S, Liu DL, Kantheti HS & Saghafinia S et al. 2018 Oncogenic signaling pathways in the Cancer Genome Atlas. Cell 173 321.e10–337.e10. (https://doi.org/10.1016/j.cell.2018.03.035)

    • Search Google Scholar
    • Export Citation
  • Scarpa A, Chang DK, Nones K, Corbo V, Patch AM, Bailey P, Lawlor RT, Johns AL, Miller DK & Mafficini A et al. 2017 Whole-genome landscape of pancreatic neuroendocrine tumours. Nature 543 6571. (https://doi.org/10.1038/nature21063)

    • Search Google Scholar
    • Export Citation
  • Simon B & Lubomierski N 2004 Implication of the INK4a/ARF locus in gastroenteropancreatic neuroendocrine tumorigenesis. Annals of the New York Academy of Sciences 1014 284299. (https://doi.org/10.1196/annals.1294.033)

    • Search Google Scholar
    • Export Citation
  • Slomovitz BM, Jiang YY, Yates MS, Soliman PT, Johnston T, Nowakowski M, Levenback C, Zhang Q, Ring K & Munsell MF et al. 2015 Phase II study of everolimus and letrozole in patients with recurrent endometrial carcinoma. Journal of Clinical Oncology 33 930–936. (https://doi.org/10.1200/JCO.2014.58.3401)

    • Search Google Scholar
    • Export Citation
  • Tang LH, Contractor T, Clausen R, Klimstra DS, Du YC, Allen PJ, Brennan MF, Levine AJ & Harris CR 2012 Attenuation of the retinoblastoma pathway in pancreatic neuroendocrine tumors due to increased cdk4/cdk6. Clinical Cancer Research 18 46124620. (https://doi.org/10.1158/1078-0432.CCR-11-3264)

    • Search Google Scholar
    • Export Citation
  • Toy W, Shen Y, Won H, Green B, Sakr RA, Will M, Li Z, Gala K, Fanning S & King TA et al. 2013 ESR1 ligand-binding domain mutations in hormone-resistant breast cancer. Nature Genetics 45 14391445. (https://doi.org/10.1038/ng.2822)

    • Search Google Scholar
    • Export Citation
  • Wagle N, Emery C, Berger MF, Davis MJ, Sawyer A, Pochanard P, Kehoe SM, Johannessen CM, Macconaill LE & Hahn WC et al. 2011 Dissecting therapeutic resistance to RAF inhibition in melanoma by tumor genomic profiling. Journal of Clinical Oncology 29 30853096. (https://doi.org/10.1200/JCO.2010.33.2312)

    • Search Google Scholar
    • Export Citation
  • Wagle N, Berger MF, Davis MJ, Blumenstiel B, Defelice M, Pochanard P, Ducar M, Van Hummelen P, Macconaill LE & Hahn WC et al. 2012 High-throughput detection of actionable genomic alterations in clinical tumor samples by targeted, massively parallel sequencing. Cancer Discovery 2 8293. (https://doi.org/10.1158/2159-8290.CD-11-0184)

    • Search Google Scholar
    • Export Citation
  • Yao JC, Lombard-Bohas C, Baudin E, Kvols LK, Rougier P, Ruszniewski P, Hoosen S, St Peter J, Haas T & Lebwohl D et al. 2010 Daily oral everolimus activity in patients with metastatic pancreatic neuroendocrine tumors after failure of cytotoxic chemotherapy: a phase II trial. Journal of Clinical Oncology 28 6976. (https://doi.org/10.1200/JCO.2009.24.2669)

    • Search Google Scholar
    • Export Citation
  • Yao JC, Shah MH, Ito T, Bohas CL, Wolin EM, Van Cutsem E, Hobday TJ, Okusaka T, Capdevila J & De Vries EG et al. 2011 Everolimus for advanced pancreatic neuroendocrine tumors. New England Journal of Medicine 364 514523. (https://doi.org/10.1056/NEJMoa1009290)

    • Search Google Scholar
    • Export Citation
  • Yao JC, Fazio N, Singh S, Buzzoni R, Carnaghi C, Wolin E, Tomasek J, Raderer M, Lahner H & Voi M et al. 2016 Everolimus for the treatment of advanced, non-functional neuroendocrine tumours of the lung or gastrointestinal tract (RADIANT-4): a randomised, placebo-controlled, phase 3 study. Lancet 387 968977. (https://doi.org/10.1016/S0140-6736(1500817-X)

    • Search Google Scholar
    • Export Citation