Limited clinical activity of palbociclib and ribociclib monotherapy in advanced cancers with cyclin D-CDK4/6 pathway alterations in the Dutch DRUP and Australian MoST trials

Laurien J. Zeverijn, Eleonora J. Looze, Subotheni Thavaneswaran, J. Maxime van Berge Henegouwen, Robert J. Simes, Louisa R. Hoes, Katrin M. Sjoquist, Hanneke van der Wijngaart, Lucille Sebastian, Birgit S. Geurts, Chee K. Lee, Gijsbrecht F. de Wit, David Espinoza, Paul Roepman, Frank P. Lin, Anne M.L. Jansen, Wendy W.J. de Leng, Vincent van der Noort, Lindsay V.M. Leek, Filip Y.F.L. de VosCarla M.L. van Herpen, Hans Gelderblom, Henk M.W. Verheul, David M. Thomas, Emile E. Voest*

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

2 Citations (Scopus)


The Dutch Drug Rediscovery Protocol (DRUP) and the Australian Cancer Molecular Screening and Therapeutic (MoST) Program are similar nonrandomized, multidrug, pan-cancer trial platforms that aim to identify signals of clinical activity of molecularly matched targeted therapies or immunotherapies outside their approved indications. Here, we report results for advanced or metastatic cancer patients with tumors harboring cyclin D-CDK4/6 pathway alterations treated with CDK4/6 inhibitors palbociclib or ribociclib. We included adult patients that had therapy-refractory solid malignancies with the following alterations: amplifications of CDK4, CDK6, CCND1, CCND2 or CCND3, or complete loss of CDKN2A or SMARCA4. Within MoST, all patients were treated with palbociclib, whereas in DRUP, palbociclib and ribociclib were assigned to different cohorts (defined by tumor type and alteration). The primary endpoint for this combined analysis was clinical benefit, defined as confirmed objective response or stable disease ≥16 weeks. We treated 139 patients with a broad variety of tumor types; 116 with palbociclib and 23 with ribociclib. In 112 evaluable patients, the objective response rate was 0% and clinical benefit rate at 16 weeks was 15%. Median progression-free survival was 4 months (95% CI: 3-5 months), and median overall survival 5 months (95% CI: 4-6 months). In conclusion, only limited clinical activity of palbociclib and ribociclib monotherapy in patients with pretreated cancers harboring cyclin D-CDK4/6 pathway alterations was observed. Our findings indicate that monotherapy use of palbociclib or ribociclib is not recommended and that merging data of two similar precision oncology trials is feasible.

Original languageEnglish
Pages (from-to)1413-1422
Number of pages10
JournalInternational Journal of Cancer
Issue number7
Publication statusPublished - 1 Oct 2023

Bibliographical note

Both investigator initiated studies (DRUP and MoST) received in-kindand financial support from Novartis and Pfizer. Furthermore, the DRUPtrial is supported by the Stelvio for Life foundation [grant number notapplicable] and the Dutch Cancer Society [grant number 10014].

Publisher Copyright: © 2023 UICC.


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