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
Zeverijn, Laurien J; Looze, Eleonora J; Thavaneswaran, Subotheni; van Berge Henegouwen, J Maxime; Simes, Robert J; Hoes, Louisa R; Sjoquist, Katrin M; van der Wijngaart, Hanneke; Sebastian, Lucille; Geurts, Birgit S; Lee, Chee K; de Wit, Gijsbrecht F; Espinoza, David; Roepman, Paul; Lin, Frank P; Jansen, Anne M L; de Leng, Wendy W J; van der Noort, Vincent; Leek, Lindsay V M; de Vos, Filip Y F L; van Herpen, Carla M L; Gelderblom, Hans; Verheul, Henk M W; Thomas, David M; Voest, Emile E
(2023) International Journal of Cancer, volume 153, issue 7, pp. 1413 - 1422
(Article)
Abstract
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
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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.
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Keywords: CDK4/6 inhibitors, drug rediscovery, monotherapy, precision oncology, targeted therapy, Oncology, Cancer Research, Journal Article
ISSN: 0020-7136
Publisher: Wiley-Liss Inc.
Note: Funding Information: Both investigator initiated studies (DRUP and MoST) received in‐kind and financial support from Novartis and Pfizer. Furthermore, the DRUP trial is supported by the Stelvio for Life foundation [grant number not applicable] and the Dutch Cancer Society [grant number 10014]. Funding Information: Emile E. Voest has, through DRUP, received support from pharmaceutical companies that are participating in the DRUP (Novartis and Pfizer), paid to the Netherlands Cancer Institute. David M. Thomas and Robert J. Simes have, through MoST, received support from Pfizer, paid to the University of Sydney. Katrin M. Sjoquist received honoraria for education events and advisory boards from BMS, Merck, MSD and Servier (all <5000 AUD), within the last 36 months, and reports participation on a Data Safety Monitoring Board for Novotech (2022‐ongoing). Chee K. Lee has participated on the advisory board for AstraZeneca, Roche, Amgen, Janssen, Pfizer, Takeda, MSD, Novartis and GSK, and received funding for clinical trials from Roche, AstraZeneca, Amgen and Merck KGaA. The other authors declare no competing interests. Funding Information: The Drug Rediscovery Protocol teams thanks the Stelvio for Life Foundation and the Dutch Cancer Society for their financial support; Novartis and Pfizer for their in‐kind and financial support; the DRUP Multidisciplinary Expert Board for supporting the central case‐review process; the Independent Data Monitoring Committee for their advice on cohort decisions and the monitoring of preliminary safety data; the Netherlands Cancer Institute's Biobank Facility, Scientific Department and Pharmacy for their facilitating services; M.J.A. de Jonge, L.A. Devriese, G.A. Cirkel, M. Labots, A. Hoeben, L.V. Beerepoot, E.D. Kerver, H.M. Westgeest, A. P. Hamberg, G. Vreugdenhil, T. van Voorthuizen, F.L.G. Erdkamp, J.M. van Rooijen, D. Houtsma, H. de Graaf, M.P. Hendriks, J.W.B. de Groot, S. Boudewijns, E.J.M. Siemerink and F.J.F. Jeurissen for their contributions to trial recruitment; and all participating hospitals for supporting and facilitating the conduct of the DRUP trial. The Molecular Screening and Therapeutics (MoST) Program is funded by the Commonwealth, as well as the NSW governments via the Office of Health and Medical Research, NSW. The authors thank all study participants and their families. We kindly acknowledge Pfizer for funding and provision of palbociclib for the trial. We gratefully thank the site trials team at The Kinghorn Cancer Centre, St Vincent's Hospital: Professor Anthony Joshua (study PI) and Ashley Douglas, Helmut Gensen (trial coordinators). The MoST team at the Garvan Institute: Dr Mandy Ballinger (screening lead), Dr Dominique Hess (former screening lead) and Dr Maya Kansara (MoST correlative science lead). And the MoST team at the NHMRC Clinical Trials Centre at the University of Sydney: Magda Luciuk (Clinical Trial Assistant). Funding Information: The Drug Rediscovery Protocol teams thanks the Stelvio for Life Foundation and the Dutch Cancer Society for their financial support; Novartis and Pfizer for their in-kind and financial support; the DRUP Multidisciplinary Expert Board for supporting the central case-review process; the Independent Data Monitoring Committee for their advice on cohort decisions and the monitoring of preliminary safety data; the Netherlands Cancer Institute's Biobank Facility, Scientific Department and Pharmacy for their facilitating services; M.J.A. de Jonge, L.A. Devriese, G.A. Cirkel, M. Labots, A. Hoeben, L.V. Beerepoot, E.D. Kerver, H.M. Westgeest, A. P. Hamberg, G. Vreugdenhil, T. van Voorthuizen, F.L.G. Erdkamp, J.M. van Rooijen, D. Houtsma, H. de Graaf, M.P. Hendriks, J.W.B. de Groot, S. Boudewijns, E.J.M. Siemerink and F.J.F. Jeurissen for their contributions to trial recruitment; and all participating hospitals for supporting and facilitating the conduct of the DRUP trial. The Molecular Screening and Therapeutics (MoST) Program is funded by the Commonwealth, as well as the NSW governments via the Office of Health and Medical Research, NSW. The authors thank all study participants and their families. We kindly acknowledge Pfizer for funding and provision of palbociclib for the trial. We gratefully thank the site trials team at The Kinghorn Cancer Centre, St Vincent's Hospital: Professor Anthony Joshua (study PI) and Ashley Douglas, Helmut Gensen (trial coordinators). The MoST team at the Garvan Institute: Dr Mandy Ballinger (screening lead), Dr Dominique Hess (former screening lead) and Dr Maya Kansara (MoST correlative science lead). And the MoST team at the NHMRC Clinical Trials Centre at the University of Sydney: Magda Luciuk (Clinical Trial Assistant). Publisher Copyright: © 2023 UICC.
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