Reference Detail

Ref Type

Journal Article

PMID

(37424386)

Authors

Zeverijn LJ, Looze EJ, Thavaneswaran S, van Berge Henegouwen JM, Simes RJ, Hoes LR, Sjoquist KM, van der Wijngaart H, Sebastian L, Geurts BS, Lee CK, de Wit GF, Espinoza D, Roepman P, Lin FP, Jansen AML, de Leng WWJ, van der Noort V, Leek LVM, de Vos FYFL, van Herpen CML, Gelderblom H, Verheul HMW, Thomas DM, Voest EE

Title

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.

Journal	Vol	Issue	Date	Pages	Journal Short Title
International journal of cancer			2023 Jul 10		Int J Cancer

URL

Abstract Text

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.

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Molecular Profile	Treatment Approach

Gene Name	Source	Synonyms	Protein Domains	Gene Description	Gene Role

Therapy Name	Drugs	Efficacy Evidence	Clinical Trials

Drug Name	Trade Name	Synonyms	Drug Classes	Drug Description

Gene	Variant	Impact	Protein Effect	Variant Description	Associated with drug Resistance

Molecular Profile	Indication/Tumor Type	Response Type	Therapy Name	Approval Status	Evidence Type	Efficacy Evidence	References
CDKN2A loss	Advanced Solid Tumor	no benefit	Palbociclib	Clinical Study	Actionable	In a combined analysis of 2 clinical trials (DRUP, MoST), Ibrance (palbociclib) or Kisqali (ribociclib) monotherapy had limited efficacy and resulted in no objective responses, a 15% clinical benefit rate at 16 weeks, median progression-free survival of 4 mo, and median overall survival of 5 mo in previously treated advanced solid tumor patients (n=112) with CDKN2A loss, CDK4, CDK6, CCND1, CCND2, or CCND3 amplification, or inactivating SMARCA4 mutations (PMID: 37424386; NCT02925234, ACTRN12616000931471).	37424386
CDKN2A loss	Advanced Solid Tumor	no benefit	Ribociclib	Clinical Study	Actionable	In a combined analysis of 2 clinical trials (DRUP, MoST), Ibrance (palbociclib) or Kisqali (ribociclib) monotherapy had limited efficacy and resulted in no objective responses, a 15% clinical benefit rate at 16 weeks, median progression-free survival of 4 mo, and median overall survival of 5 mo in previously treated advanced solid tumor patients (n=112) with CDKN2A loss, CDK4, CDK6, CCND1, CCND2, or CCND3 amplification, or inactivating SMARCA4 mutations (PMID: 37424386; NCT02925234, ACTRN12616000931471).	37424386
SMARCA4 inact mut	Advanced Solid Tumor	no benefit	Palbociclib	Clinical Study	Actionable	In a combined analysis of 2 clinical trials (DRUP, MoST), Ibrance (palbociclib) or Kisqali (ribociclib) monotherapy had limited efficacy and resulted in no objective responses, a 15% clinical benefit rate at 16 weeks, median progression-free survival of 4 mo, and median overall survival of 5 mo in previously treated advanced solid tumor patients (n=112) with inactivating SMARCA4 mutations, CDKN2A loss, or CDK4, CDK6, CCND1, CCND2, or CCND3 amplification (PMID: 37424386; NCT02925234, ACTRN12616000931471).	37424386