Ribociclib plus letrozole in early breast cancer: A presurgical, window-of-opportunity study

Curigliano, Giuseppe; Pardo, P. Gómez; Meric‐Bernstam, Funda; Conte, Pierfranco; Lolkema, Martijn P.; Beck, J. Thaddeus; Bardia, Aditya; García, María Martínez; Penault‐Llorca, Frédérique; Dhuria, Shyeilla V.; Tang, Zhongwen; Solovieff, Nadia; Miller, Michelle C.; Tomaso, Emmanuelle di; Hurvitz, Sara A.

doi:10.1016/j.breast.2016.06.008

Cited by 115 publications

(95 citation statements)

References 32 publications

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“…These studies have demonstrated that ribociclib exposure is unaffected by combinations with exemestane, letrozole, or fulvestrant in patients with HR+ ABC (41, 42). Similarly, letrozole exposure when combined with ribociclib was within the range of values observed from single-agent letrozole (41, 43). The addition of ribociclib to exemestane, letrozole, or fulvestrant was also associated with manageable tolerability profiles in all studies (Table 3).…”

Section: Preclinical and Clinical Experience With Ribociclib In Indivsupporting

confidence: 62%

“…In the ribociclib plus letrozole arm, decreased tumor size at the initial evaluation (~Week 8) was observed in 76% of evaluable patients with measurable disease (50). In newly diagnosed Grade II/III HR+, HER2− invasive breast cancer, a randomized pre-surgical study demonstrated an enhanced reduction in expression of the Ki67 marker for cell proliferation upon combination of ribociclib and letrozole (≥92%) versus letrozole alone (69%), further supporting a role for ribociclib in enhancing the antitumor effects of its combination partner (43). An ongoing trial (NCT02712723) is investigating ribociclib plus letrozole in the neoadjuvant setting (Supplementary Table 2).…”

Section: Preclinical and Clinical Experience With Ribociclib In Indivmentioning

confidence: 96%

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Ribociclib (LEE011): Mechanism of Action and Clinical Impact of This Selective Cyclin-Dependent Kinase 4/6 Inhibitor in Various Solid Tumors

Tripathy¹,

Bardia²,

Sellers³

2017

Clin Cancer Res

195

131

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The cyclin D–cyclin-dependent kinase (CDK) 4/6–p16–retinoblastoma (Rb) pathway is commonly disrupted in cancer, leading to abnormal cell proliferation. Therapeutics targeting this pathway have demonstrated antitumor effects in preclinical and clinical studies. Ribociclib is a selective, orally bioavailable inhibitor of CDK4 and CDK6, which was granted priority review by the US Food and Drug Administration in November 2016, and is set to enter the treatment landscape alongside other CDK4/6 inhibitors, including palbociclib and abemaciclib. Here we describe the mechanism of action of ribociclib, and review preclinical and clinical data from Phase I, II, and III trials of ribociclib across different tumor types, within the context of other selective CDK4/6 inhibitors. The pharmacokinetics, pharmacodynamics, safety, tolerability, and clinical responses with ribociclib as a single agent or in combination with other therapies are discussed, and an overview of the broad portfolio of ongoing clinical trials with ribociclib across a wide range of indications is presented. Based on the available data, ribociclib has a manageable tolerability profile and therapeutic potential for a variety of cancer types. Its high selectivity makes it an important partner drug for other targeted therapies and it has been shown to enhance the clinical activity of existing anticancer therapies and delay the development of treatment resistance, without markedly increasing toxicity. Ongoing trials of doublet and triplet targeted therapies containing ribociclib seek to identify optimal CDK4/6-based targeted combination regimens for various tumor types and advance the field of precision therapeutics in oncology.

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Section: Preclinical and Clinical Experience With Ribociclib In Indivsupporting

confidence: 62%

Section: Preclinical and Clinical Experience With Ribociclib In Indivmentioning

confidence: 96%

Ribociclib (LEE011): Mechanism of Action and Clinical Impact of This Selective Cyclin-Dependent Kinase 4/6 Inhibitor in Various Solid Tumors

Tripathy¹,

Bardia²,

Sellers³

2017

Clin Cancer Res

195

131

View full text Add to dashboard Cite

show abstract

“…Although a previous presurgical window-of-opportunity study that randomized patients to receive 2 weeks of letrozole alone (Arm 1, n=2), or with ribociclib (Arm 2, 400mg daily, n=6), or ribociclib (Arm 3, 600mg daily, n=3) reported a mean decrease in Ki67 of 69% (38-100%), 96% (78-100%), and 92% (75-100%), in Arms 1, 2, and 3, respectively, the small sample size limited the ability to conclude on the added anti-proliferative effect of ribociclib to letrozole (35). The current study therefore provides the initial biomarker evidence of enhanced anti-proliferative effect of a CDK4/6 inhibitor over that by an AI alone in primary breast cancers, supporting the investigation of palbociclib in the adjuvant setting for both pre- and postmenopausal women with luminal breast cancer.…”

Section: Discussionmentioning

confidence: 99%

NeoPalAna: Neoadjuvant Palbociclib, a Cyclin-Dependent Kinase 4/6 Inhibitor, and Anastrozole for Clinical Stage 2 or 3 Estrogen Receptor–Positive Breast Cancer

Cynthia

Gao

Luo

et al. 2017

Clinical Cancer Research

283

234

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Purpose Cyclin-dependent kinase (CDK) 4/6 drives cell proliferation in estrogen receptor positive (ER+) breast cancer. This single-arm phase II neoadjuvant trial (NeoPalAna) assessed the anti-proliferative activity of the CDK4/6 inhibitor palbociclib in primary breast cancer as a prelude to adjuvant studies. Experimental Design Eligible patients with clinical stage II/III ER+/HER2- breast cancer received anastrozole 1mg daily for 4 weeks (cycle 0) (with goserelin if premenopausal), followed by adding palbociclib (125mg daily on days 1-21) on cycle 1 day 1 (C1D1) for four 28-day cycles unless C1D15 Ki67>10%, in which case patients went off study due to inadequately response. Anastrozole was continued until surgery, which occurred 3-5 weeks post palbociclib exposure. Later patients received additional 10-12 days of palbociclib (Cycle 5) immediately before surgery. Serial biopsies at baseline, C1D1, C1D15, and surgery were analyzed for Ki67, gene expression and mutation profiles. The primary endpoint was Complete Cell Cycle Arrest (CCCA: central Ki67<2.7%). Results Fifty patients enrolled. The CCCA rate was significantly higher after adding palbociclib to anastrozole (C1D15 87% vs C1D1 26%, p<0.001). Palbociclib enhanced cell cycle control over anastrozole monotherapy regardless of luminal subtype (A vs B) and PIK3CA status with activity observed across a broad range of clinicopathological and mutation profiles. Ki67 recovery at surgery following palbociclib washout was suppressed by cycle 5 palbociclib. Resistance was associated with non-luminal subtypes and persistent E2F-target gene expression. Conclusions Palbociclib is an active anti-proliferative agent for early-stage breast cancer resistant to anastrozole, however, prolonged administration may be necessary to maintain its effect.

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“…Libraries were constructed using Illumina TruSeq Nano DNA Library Prep kit, enriched for a 566-gene PanCancer gene panel (Table S1) using Agilent SureSelect XT Custom baits, and sequenced on an Illumina HiSeq 2500 sequencer to a median of 105 million reads, yielding a median coverage of 1195X. 18 Sequence data was aligned to the hg19 reference genome. Variants were called with Pindel, Socrates, PureCN, and MuTect using the default 0.5% lower threshold.…”

Section: Methodsmentioning

confidence: 99%

Tracking the Evolution of Resistance to ALK Tyrosine Kinase Inhibitors Through Longitudinal Analysis of Circulating Tumor DNA

Dagogo‐Jack¹,

Brannon²,

Ferris³

et al. 2018

JCO Precision Oncology

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Purpose ALK rearrangements predict for sensitivity to ALK tyrosine kinase inhibitors (TKIs). However, responses to ALK TKIs are generally short-lived. Serial molecular analysis is an informative strategy for identifying genetic mediators of resistance. Although multiple studies support the clinical benefits of repeat tissue sampling, the clinical utility of longitudinal circulating tumor DNA analysis has not been established in ALK-positive lung cancer. Methods Using a 566-gene hybrid-capture next-generation sequencing (NGS) assay, we performed longitudinal analysis of plasma specimens from 22 ALK-positive patients with acquired resistance to ALK TKIs to track the evolution of resistance during treatment. To determine tissue-plasma concordance, we compared plasma findings to results of repeat biopsies. Results At progression, we detected an ALK fusion in plasma from 19 (86%) of 22 patients, and identified ALK resistance mutations in plasma specimens from 11 (50%) patients. There was 100% agreement between tissue- and plasma-detected ALK fusions. Among 16 cases where contemporaneous plasma and tissue specimens were available, we observed 100% concordance between ALK mutation calls. ALK mutations emerged and disappeared during treatment with sequential ALK TKIs, suggesting that plasma mutation profiles were dependent on the specific TKI administered. ALK G1202R, the most frequent plasma mutation detected after progression on a second-generation TKI, was consistently suppressed during treatment with lorlatinib. Conclusions Plasma genotyping by NGS is an effective method for detecting ALK fusions and ALK mutations in patients progressing on ALK TKIs. The correlation between plasma ALK mutations and response to distinct ALK TKIs highlights the potential for plasma analysis to guide selection of ALK-directed therapies.

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Ribociclib plus letrozole in early breast cancer: A presurgical, window-of-opportunity study

Abstract: The results suggest absence of a drug-drug interaction between ribociclib and letrozole and indicate ribociclib plus letrozole may reduce Ki67 expression in HR+, HER2- BC (NCT01919229).

Cited by 115 publications

References 32 publications

Ribociclib (LEE011): Mechanism of Action and Clinical Impact of This Selective Cyclin-Dependent Kinase 4/6 Inhibitor in Various Solid Tumors

Ribociclib (LEE011): Mechanism of Action and Clinical Impact of This Selective Cyclin-Dependent Kinase 4/6 Inhibitor in Various Solid Tumors

NeoPalAna: Neoadjuvant Palbociclib, a Cyclin-Dependent Kinase 4/6 Inhibitor, and Anastrozole for Clinical Stage 2 or 3 Estrogen Receptor–Positive Breast Cancer

Tracking the Evolution of Resistance to ALK Tyrosine Kinase Inhibitors Through Longitudinal Analysis of Circulating Tumor DNA

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