The potent and selective cyclin-dependent kinases 4 and 6 inhibitor ribociclib (LEE011) is a versatile combination partner in preclinical cancer models

Kim, Sunkyu; Tiedt, Ralph; Loo, Alice; Horn, Thomas; Delach, Scott; Kovats, Steven; Haas, Kristy; Engstler, Barbara Schacher; Cao, Alexander; Pinzon-Ortiz, Maria; Mulford, Iain J.; Acker, Michael G.; Chopra, Rajiv; Brain, Christopher T.; Tomaso, Emmanuelle di; Sellers, William R.; Caponigro, Giordano

doi:10.18632/oncotarget.26215

Cited by 65 publications

(76 citation statements)

References 48 publications

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“… 26–28 When tumour area reached 0.3 to 0.5 cm 2 , mice were randomised by tumour size to treatment arms. Ribociclib was provided by Novartis and administered daily by oral gavage in 0.5% methylcellulose (75 mg/kg) as previously described, 29 while letrozole was administered by subcutaneous injections at 10 μg daily. 30 During the study period, weekly ultrasounds measured the largest tumour cross-sectional area through day 56.…”

Section: Methodsmentioning

confidence: 99%

Phase II trial of ribociclib and letrozole in patients with relapsed oestrogen receptor-positive ovarian or endometrial cancers

et al. 2020

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ObjectiveWe describe a phase II clinical trial of the combination of ribociclib and letrozole for treatment of relapsed oestrogen receptor (ER)-positive ovarian cancer (OC) and endometrial cancer (EC). The primary endpoint was the proportion of patients alive, progression-free survival (PFS), and still on treatment at 12 weeks (PFS12), with 45% or greater considered positive.MethodsPatients with measurable, relapsed ER-positive OC or EC (platinum-sensitive or resistant) were eligible and treated with 400 mg of oral ribociclib and 2.5 mg of oral letrozole daily. Patient-derived xenografts (PDXs) were created from imaging-guided tumour biopsies.ResultsForty patients (20 OC and 20 EC) were enrolled. A PFS12 of 55% was observed in the EC cohort and 50% in the OC cohort. A PFS greater or equal to 24 weeks (PFS24) was seen in 20% (4/20) of the OC cohort and 35% (7/20) of the EC cohort. The greatest benefit was seen in low-grade serous OC (LGSOC) (3/3, 100% PFS24) and grades 1 and 2 EC (5/11, 45% PFS24). All three LGSOC patients obtained at least a partial response lasting for over 2 years, with two of the three patients still on treatment. PDX tumour engraftment was feasible in 45% of patients. Positive survival effects of the combination of ribociclib and letrozole were observed in two of three EC PDX models.ConclusionRibociclib and letrozole have promising clinical activity in relapsed ER-positive OC and EC, particularly in LGSOC and relapsed ER-positive grade 1 and 2 EC. Generation of PDX models is feasible with positive survival effects observed in EC models.Trial registration numberClinicalTrials.gov registry (NCT02657928).

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Section: Methodsmentioning

confidence: 99%

Phase II trial of ribociclib and letrozole in patients with relapsed oestrogen receptor-positive ovarian or endometrial cancers

et al. 2020

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“…For cell line xenograft studies, fulvestrant (Faslodex, AstraZeneca) was purchased from the UCLA pharmacy. Studies with the HBCx-34 ER+/HER2− breast cancer PDX model were carried out at XenTech (Evry, France) [24]. For this study, supplementary estrogen was supplied via drinking water (β-estradiol, 8.5 mg/L), from the date of tumor implant to the date of initiation of treatment (10 mice per group).…”

Section: Xenograft Efficacy Studiesmentioning

confidence: 99%

Targeting activated PI3K/mTOR signaling overcomes acquired resistance to CDK4/6-based therapies in preclinical models of hormone receptor-positive breast cancer

et al. 2020

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Background: Combined targeting of CDK4/6 and ER is now the standard of care for patients with advanced ER+/ HER2− breast cancer. However, acquired resistance to these therapies frequently leads to disease progression. As such, it is critical to identify the mechanisms by which resistance to CDK4/6-based therapies is acquired and also identify therapeutic strategies to overcome resistance. Methods: In this study, we developed and characterized multiple in vitro and in vivo models of acquired resistance to CDK4/6-based therapies. Resistant models were screened by reverse phase protein array (RPPA) for cell signaling changes that are activated in resistance. Results: We show that either a direct loss of Rb or loss of dependence on Rb signaling confers cross-resistance to inhibitors of CDK4/6, while PI3K/mTOR signaling remains activated. Treatment with the p110α-selective PI3K inhibitor, alpelisib (BYL719), completely blocked the progression of acquired CDK4/6 inhibitor-resistant xenografts in the absence of continued CDK4/6 inhibitor treatment in models of both PIK3CA mutant and wild-type ER+/HER2− breast cancer. Triple combination therapy against PI3K:CDK4/6:ER prevented and/or delayed the onset of resistance in treatment-naive ER+/HER2− breast cancer models. Conclusions: These data support the clinical investigation of p110α-selective inhibitors of PI3K, such as alpelisib, in patients with ER+/HER2− breast cancer who have progressed on CDK4/6:ER-based therapies. Our data also support the investigation of PI3K:CDK4/6:ER triple combination therapy to prevent the onset of resistance to the combination of endocrine therapy plus CDK4/6 inhibition.

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“…However, a recent paper argues that the potency of ribociclib and palbociclib are very similar across many cell lines. 15 Therefore, the IC 50 value of palbociclib in EFM-19 was also used for ribociclib. Abemaciclib has three active metabolites in addition to parent.…”

Section: Parp Inhibitorsmentioning

confidence: 99%

Optimizing the Therapeutic Window of Targeted Drugs in Oncology: Potency‐Guided First‐in‐Human Studies

Goldstein

Peters

Weber

et al. 2020

Clinical Translational Sci

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Many targeted therapies are administered at or near the maximum tolerated dose (MTD). With the advent of precision medicine, a larger therapeutic window is expected. Therefore, dose optimization will require a new approach to early clinical trial design. We analyzed publicly available data for 21 therapies targeting six kinases, and four poly (ADP‐ribose) polymerase inhibitors, focusing on potency and exposure to gain insight into dose selection. The free average steady‐state concentration (C ss ) at the approved dose was compared to the in vitro cell potency (half‐maximal inhibitory concentration (IC 50 )). Average steady‐state area under the plasma concentration‐time curve, the fraction unbound drug in plasma, and the cell potency were taken from the US drug labels, US and European regulatory reviews, and peer‐reviewed journal articles. The C ss was remarkably similar to the IC 50 . The median C ss /IC 50 value was 1.2, and 76% of the values were within 3‐fold of unity. However, three drugs (encorafenib, erlotinib, and ribociclib) had a C ss /IC 50 value > 25. Seven other therapies targeting the same 3 kinases had much lower C ss /IC 50 values ranging from 0.5 to 4. These data suggest that these kinase inhibitors have a large therapeutic window that is not fully exploited; lower doses may be similarly efficacious with improved tolerability. We propose a revised first‐in‐human trial design in which dose cohort expansion is initiated at doses less than the MTD when there is evidence of clinical activity and C ss exceeds a potency threshold. This potency‐guided approach is expected to maximize the therapeutic window thereby improving patient outcomes.

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The potent and selective cyclin-dependent kinases 4 and 6 inhibitor ribociclib (LEE011) is a versatile combination partner in preclinical cancer models

Cited by 65 publications

References 48 publications

Phase II trial of ribociclib and letrozole in patients with relapsed oestrogen receptor-positive ovarian or endometrial cancers

Phase II trial of ribociclib and letrozole in patients with relapsed oestrogen receptor-positive ovarian or endometrial cancers

Targeting activated PI3K/mTOR signaling overcomes acquired resistance to CDK4/6-based therapies in preclinical models of hormone receptor-positive breast cancer

Optimizing the Therapeutic Window of Targeted Drugs in Oncology: Potency‐Guided First‐in‐Human Studies

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