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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 |
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| Authors: | 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 Vos Carla M L van Herpen Hans Gelderblom Henk M W Verheul David M Thomas Emile E Voest |
| Institution: | 1. Division of Molecular Oncology & Immunology, Netherlands Cancer Institute, Amsterdam, The Netherlands
Oncode Institute, The Netherlands Cancer Institute, Amsterdam, The Netherlands;2. Division of Pediatric Oncology, Princess Máxima Center for Pediatric Oncology, Utrecht, The Netherlands;3. The Kinghorn Cancer Centre, Garvan Institute of Medical Research, Sydney, New South Wales, Australia St. Vincent's Clinical School, Faculty of Medicine, UNSW Sydney, Sydney, New South Wales, Australia NHMRC Clinical Trials Centre, University of Sydney, Sydney, New South Wales, Australia;4. Oncode Institute, The Netherlands Cancer Institute, Amsterdam, The Netherlands Department of Medical Oncology, Leiden University Medical Center, Leiden, The Netherlands;5. NHMRC Clinical Trials Centre, University of Sydney, Sydney, New South Wales, Australia;6. Oncode Institute, The Netherlands Cancer Institute, Amsterdam, The Netherlands Department of Medical Oncology, Amsterdam University Medical Centers, Vrije Universiteit Amsterdam, Cancer Center Amsterdam, Amsterdam, The Netherlands;7. Hartwig Medical Foundation, Amsterdam, The Netherlands;8. Department of Pathology, University Medical Center Utrecht, Utrecht, The Netherlands;9. Biometrics Department, Netherlands Cancer Institute, Amsterdam, The Netherlands;10. Division of Molecular Oncology & Immunology, Netherlands Cancer Institute, Amsterdam, The Netherlands Oncode Institute, The Netherlands Cancer Institute, Amsterdam, The Netherlands Division of Molecular Carcinogenesis, The Netherlands Cancer Institute, Amsterdam, The Netherlands;11. Department of Medical Oncology, University Medical Center Utrecht, Utrecht, The Netherlands;12. Department of Medical Oncology, Radboud University Medical Center, Nijmegen, The Netherlands;13. Department of Medical Oncology, Leiden University Medical Center, Leiden, The Netherlands;14. Department of Medical Oncology, Erasmus Medical Center, Rotterdam, The Netherlands;15. The Kinghorn Cancer Centre, Garvan Institute of Medical Research, Sydney, New South Wales, Australia St. Vincent's Clinical School, Faculty of Medicine, UNSW Sydney, Sydney, New South Wales, Australia;16. Division of Molecular Oncology & Immunology, Netherlands Cancer Institute, Amsterdam, The Netherlands |
| 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 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. |
| Keywords: | CDK4/6 inhibitors drug rediscovery monotherapy precision oncology targeted therapy |