Limited clinical activity of palbociclib and ribociclib monotherapy in advanced cancers with cyclinD‐CDK4/6 pathway alterations in the DutchDRUPand AustralianMoSTtrials DOI
Laurien J. Zeverijn,

Eleonora J. Looze,

Subotheni Thavaneswaran

et al.

International Journal of Cancer, Journal Year: 2023, Volume and Issue: 153(7), P. 1413 - 1422

Published: July 10, 2023

Abstract The Dutch Drug Rediscovery Protocol (DRUP) and the Australian Cancer Molecular Screening Therapeutic (MoST) Program are similar nonrandomized, multidrug, pan‐cancer trial platforms that aim to identify signals of clinical activity molecularly matched targeted therapies or immunotherapies outside their approved indications. Here, we report results for advanced metastatic cancer patients with tumors harboring cyclin D‐CDK4/6 pathway alterations treated CDK4/6 inhibitors palbociclib ribociclib. We included adult had therapy‐refractory solid malignancies following alterations: amplifications CDK4 , CDK6 CCND1 CCND2 CCND3 complete loss CDKN2A SMARCA4 . Within MoST, all were palbociclib, whereas in DRUP, ribociclib assigned different cohorts (defined by tumor type alteration). primary endpoint this combined analysis was benefit, defined as confirmed objective response stable disease ≥16 weeks. 139 a broad variety types; 116 23 In 112 evaluable patients, rate 0% benefit at 16 weeks 15%. Median progression‐free survival 4 months (95% CI: 3‐5 months), median overall 5 4‐6 months). conclusion, only limited monotherapy pretreated cancers observed. Our findings indicate use is not recommended merging data two precision oncology trials feasible.

Language: Английский

Adjuvant Palbociclib for Early Breast Cancer: The PALLAS Trial Results (ABCSG-42/AFT-05/BIG-14-03) DOI
Michael Gnant, Amylou C. Dueck,

Sophie Frantal

et al.

Journal of Clinical Oncology, Journal Year: 2021, Volume and Issue: 40(3), P. 282 - 293

Published: Dec. 7, 2021

Palbociclib is a cyclin-dependent kinase 4 and 6 inhibitor approved for advanced breast cancer. In the adjuvant setting, potential value of adding palbociclib to endocrine therapy hormone receptor-positive cancer has not been confirmed.

Language: Английский

Citations

177
Computational analysis of protein-ligand interaction by targeting a cell cycle restrainer DOI
Rahul Singh, Rituraj Purohit

Computer Methods and Programs in Biomedicine, Journal Year: 2023, Volume and Issue: 231, P. 107367 - 107367

Published: Jan. 24, 2023

Language: Английский

Citations

54
A review: FDA-approved fluorine-containing small molecules from 2015 to 2022 DOI

Negar Sheikhi,

Maryam Bahraminejad,

Mina Saeedi

et al.

European Journal of Medicinal Chemistry, Journal Year: 2023, Volume and Issue: 260, P. 115758 - 115758

Published: Aug. 24, 2023

Language: Английский

Citations

47
PACE: A Randomized Phase II Study of Fulvestrant, Palbociclib, and Avelumab After Progression on Cyclin-Dependent Kinase 4/6 Inhibitor and Aromatase Inhibitor for Hormone Receptor–Positive/Human Epidermal Growth Factor Receptor–Negative Metastatic Breast Cancer DOI
Erica L. Mayer,

Yue Ren,

Nikhil Wagle

et al.

Journal of Clinical Oncology, Journal Year: 2024, Volume and Issue: 42(17), P. 2050 - 2060

Published: March 21, 2024

Cyclin-dependent kinase (CDK) 4/6 inhibitors (CDK4/6is) are an important component of treatment for hormone receptor-positive/human epidermal growth factor receptor 2-negative (HER2-) metastatic breast cancer (MBC), but it is not known if patients might derive benefit from continuation CDK4/6i with endocrine therapy beyond initial tumor progression or the addition checkpoint inhibitor has value in this setting.

Language: Английский

Citations

41
Cyclin-dependent kinase 2 (CDK2) inhibitors and others novel CDK inhibitors (CDKi) in breast cancer: clinical trials, current impact, and future directions DOI Creative Commons
R. Gerosa, Rita De Sanctis, Flavia Jacobs

et al.

Critical Reviews in Oncology/Hematology, Journal Year: 2024, Volume and Issue: 196, P. 104324 - 104324

Published: March 8, 2024

Aberrant cyclin-dependent kinase 2 (CDK2) activation has been identified as a main resistance mechanism to CDK4/6 inhibition in hormone-receptor positive (HR+) breast cancer. Additionally, consistent preclinical evidence states its crucial role MYC and CCNE1 overexpressed cancer survival, such triple-negative cancers (TNBC), thus representing an appealing relatively unexplored target treatment opportunity. Despite emerging initial results of novel CDK2 inhibitors (CDK2i) activity, comprehensive outcomes collection is currently absent from the scientific literature. We aim provide overview ongoing clinical trials involving CDK2i context metastatic (mBC), either monotherapy or combination with other agents. The review extends beyond encompass CDK4 inhibitors, combined CDK2/4/6 well-known pan-CDK including those specifically directed at CDK2. Delving into results, we critically appraise observed efficacy offer valuable insights their potential impact future applications.

Language: Английский

Citations

20
Abemaciclib, Palbociclib, and Ribociclib in Real-World Data: A Direct Comparison of First-Line Treatment for Endocrine-Receptor-Positive Metastatic Breast Cancer DOI Open Access
Mónica Cejuela Solís,

Ana Gil-Torralvo,

María Ángeles Castilla

et al.

International Journal of Molecular Sciences, Journal Year: 2023, Volume and Issue: 24(10), P. 8488 - 8488

Published: May 9, 2023

By the end of 2020, there were more than 8 million women alive who had received a breast cancer diagnosis in previous 5 years, making it most prevalent neoplasia world. About 70% breast-cancer cases present positivity for estrogen and/or progesterone receptors and lack HER-2 overexpression. Endocrine therapy has traditionally been standard care ER-positive HER-2-negative metastatic cancer. In last advent CDK4/6 inhibitors shown that adding them to endocrine doubles PFS. As result, this combination become gold setting. Three have approved by EMA FDA: abemaciclib, palbociclib, ribociclib. They all same indications, is at each physician's discretion choose one or other. The aim our study was perform comparative efficacy analysis three CDK4/6i using real-world data. We selected patients diagnosed with endocrine-receptor-positive HER2-negative treated as first-line reference center. After 42 months retrospective follow up, abemaciclib associated significant benefit terms progression-free survival endocrine-resistant population without visceral involvement. cohort, we found no other statistically differences among inhibitors.

Language: Английский

Citations

35
Selective protection of normal cells from chemotherapy, while killing drug-resistant cancer cells DOI Open Access

Mikhail V. Blagosklonny

Oncotarget, Journal Year: 2023, Volume and Issue: 14(1), P. 193 - 206

Published: March 11, 2023

// Mikhail V. Blagosklonny 1 Roswell Park Comprehensive Cancer Center, Buffalo, NY 14263, USA Correspondence to: Blagosklonny, email: [email protected] , [email protected] Keywords: oncology; resistance; cyclotherapy; trilaciclib; rapamycin Received: January 05, 2023     Accepted: March 01, Published: 11, 2023 Copyright: © Blagosklonny. This is an open access article distributed under the terms of Creative Commons Attribution License (CC BY 3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided original author source are credited. ABSTRACT therapy limited by toxicity normal cells drug-resistance cancer cells. Paradoxically, resistance to certain therapies can be exploited for protection cells, simultaneously enabling selective killing resistant using antagonistic drug combinations, include cytotoxic protective drugs. Depending on mechanisms achieved with inhibitors CDK4/6, caspases, Mdm2, mTOR, mitogenic kinases. When protected, selectivity potency multi-drug combinations further enhanced adding synergistic drugs, theory, eliminating deadliest clones minimal side effects. I also discuss how recent success Trilaciclib may foster similar approaches into clinical practice, mitigate systemic effects chemotherapy patients brain tumors ensure that drugs would only protect (not cells) a particular patient.

Language: Английский

Citations

34
Cyclin-Dependent Kinase 4/6 Inhibitors for Treatment of Hormone Receptor–Positive, ERBB2-Negative Breast Cancer DOI
Ciara C. O’Sullivan, Robert Clarke, Matthew P. Goetz

et al.

JAMA Oncology, Journal Year: 2023, Volume and Issue: 9(9), P. 1273 - 1273

Published: June 29, 2023

Combination therapy with cyclin-dependent kinase 4 and 6 inhibitors (CDK4/6i: palbociclib, ribociclib, abemaciclib) endocrine (ET) has been a major advance for the treatment of hormone receptor-positive (HR+), ERBB2 (formerly HER2)-negative (ERBB2-) advanced or metastatic breast cancer.

Language: Английский

Citations

26
The dilemma of selecting a first line CDK4/6 inhibitor for hormone receptor-positive/HER2-negative metastatic breast cancer DOI Creative Commons
Albert Grinshpun, Sara M. Tolaney, Harold J. Burstein

et al.

npj Breast Cancer, Journal Year: 2023, Volume and Issue: 9(1)

Published: March 22, 2023

The combination of an endocrine agent with a CDK4/6 inhibitor is the standard care in first-line setting for patients hormone receptor-positive, HER2-negative metastatic breast cancer. Randomized trials have demonstrated similar and significant improvements progression-free survival using three available inhibitors led to regulatory approval. However, mature overall data now suggest potential differences among various agents, suggesting evolution selection preferences.

Language: Английский

Citations

25
Open-label, phase II, multicenter study of lasofoxifene plus abemaciclib for treating women with metastatic ER+/HER2− breast cancer and an ESR1 mutation after disease progression on prior therapies: ELAINE 2 DOI Creative Commons
Senthil Damodaran, Ciara C. O’Sullivan, Ahmed Elkhanany

et al.

Annals of Oncology, Journal Year: 2023, Volume and Issue: 34(12), P. 1131 - 1140

Published: Dec. 1, 2023

Acquired ESR1 mutations in estrogen receptor-positive (ER+) metastatic breast cancer (mBC) drive treatment resistance and tumor progression; new strategies are needed. Lasofoxifene, a next-generation, oral, endocrine therapy tissue-specific ER antagonist, provided preclinical antitumor activity, alone or combined with cyclin-dependent kinase 4/6 inhibitor (CDK4/6i) ESR1-mutated mBC.In the open-label, phase II, ELAINE 2 trial (NCT04432454), women ESR1-mutated, ER+/human epidermal growth factor receptor 2-negative (HER2-) mBC who progressed on prior therapies (including CDK4/6i) received lasofoxifene 5 mg/day abemaciclib 150 mg b.i.d until disease progression/toxicity. The primary endpoint was safety/tolerability. Secondary endpoints included progression-free survival (PFS), clinical benefit rate (CBR), objective response (ORR).Twenty-nine (median age 60 years) participated; all but one were previously treated CDK4/6i duration years). lasofoxifene-abemaciclib combination well tolerated primarily grade 1/2 treatment-emergent adverse events (TEAEs), most commonly diarrhea, nausea, fatigue, vomiting. One patient (with no discontinued due to diarrhea. No deaths occurred during study. Median PFS 56.0 weeks [95% confidence interval (CI) 31.9 weeks-not estimable; ∼13 months]; rates at 6, 12, 18 months 76.1%, 56.1%, 38.8%, respectively. CBR 24 65.5% (95% CI 47.3% 80.1%). In patients measurable lesions, ORR 55.6% 33.7% 75.4%). ESR1-mutant circulating DNA (ctDNA) allele fraction decreased from baseline week 4 21/26 (80.8%) patients.Lasofoxifene plus had an acceptable safety profile, tolerated, exhibited meaningful activity ER+/HER2- after progression CDK4/6i. Observed decreases ctDNA concordant suggest target engagement. If findings confirmed initiated, III, 3 trial, these data could be practice-changing help address critical unmet need.

Language: Английский

Citations

25