Overall Survival with Palbociclib and Fulvestrant in Advanced Breast Cancer

New England Journal of Medicine, Journal Year: 2018, Volume and Issue: 379(20), P. 1926 - 1936

Published: Oct. 20, 2018

The cyclin-dependent kinase 4 and 6 (CDK4/6) inhibitor palbociclib, in combination with fulvestrant therapy, prolongs progression-free survival among patients hormone-receptor-positive, human epidermal growth factor receptor 2 (HER2)-negative advanced breast cancer. We report the results of a prespecified analysis overall survival. randomly assigned HER2-negative cancer who had progression or relapse during previous endocrine therapy to receive palbociclib plus placebo fulvestrant. analyzed survival; effect according stratification factors presence absence sensitivity visceral metastatic disease, menopausal status; efficacy subsequent therapies after disease progression; safety. Among 521 underwent randomization, median was 34.9 months (95% confidence interval [CI], 28.8 40.0) palbociclib-fulvestrant group 28.0 CI, 23.6 34.6) placebo-fulvestrant (hazard ratio for death, 0.81; 95% 0.64 1.03; P=0.09; absolute difference, 6.9 months). CDK4/6 treatment completion trial regimen occurred 16% group. 410 39.7 34.8 45.7) 29.7 23.8 37.9) ratio, 0.72; 0.55 0.94; 10.0 duration similar two groups, time receipt chemotherapy 17.6 group, as compared 8.8 0.58; 0.47 0.73; P<0.001). No new safety signals were observed 44.8 follow-up. resulted longer than placebo-fulvestrant. differences entire not significant. (Funded by Pfizer; PALOMA-3 ClinicalTrials.gov number, NCT01942135 .).

Language: Английский

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Genomic Characterization of Brain Metastases Reveals Branched Evolution and Potential Therapeutic Targets

Cancer Discovery, Journal Year: 2015, Volume and Issue: 5(11), P. 1164 - 1177

Published: Sept. 27, 2015

Abstract Brain metastases are associated with a dismal prognosis. Whether brain harbor distinct genetic alterations beyond those observed in primary tumors is unknown. We performed whole-exome sequencing of 86 matched metastases, tumors, and normal tissue. In all clonally related cancer samples, we branched evolution, where metastatic sites shared common ancestor yet continued to evolve independently. 53% cases, found potentially clinically informative the not detected primary-tumor sample. contrast, spatially temporally separated metastasis were genetically homogenous. Distal extracranial regional lymph node highly divergent from metastases. sensitivity PI3K/AKT/mTOR, CDK, HER2/EGFR inhibitors Genomic analysis provides an opportunity identify sampled nodes, or Significance: Decisions for individualized therapies patients often made biopsies. demonstrate that actionable present frequently biopsies, suggesting biopsies alone may miss substantial number opportunities targeted therapy. Cancer Discov; 5(11); 1164–77. ©2015 AACR. See commentary by Stricker Arteaga, p. 1124. This article highlighted Issue feature, 1111

Language: Английский

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Treating cancer with selective CDK4/6 inhibitors

Nature Reviews Clinical Oncology, Journal Year: 2016, Volume and Issue: 13(7), P. 417 - 430

Published: March 31, 2016

Language: Английский

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Phase III Randomized Study of Ribociclib and Fulvestrant in Hormone Receptor–Positive, Human Epidermal Growth Factor Receptor 2–Negative Advanced Breast Cancer: MONALEESA-3

Journal of Clinical Oncology, Journal Year: 2018, Volume and Issue: 36(24), P. 2465 - 2472

Published: June 3, 2018

Purpose This phase III study evaluated ribociclib plus fulvestrant in patients with hormone receptor-positive/human epidermal growth factor receptor 2-negative advanced breast cancer who were treatment naïve or had received up to one line of prior endocrine therapy the setting. Patients and Methods randomly assigned at a two-to-one ratio placebo fulvestrant. The primary end point was locally assessed progression-free survival. Secondary points included overall survival, response rate, safety. Results A total 484 postmenopausal women fulvestrant, 242 Median survival significantly improved versus fulvestrant: 20.5 months (95% CI, 18.5 23.5 months) 12.8 10.9 16.3 months), respectively (hazard ratio, 0.593; 95% 0.480 0.732; P < .001). Consistent effects observed setting 0.577; 0.415 0.802), as well for disease 0.565; 0.428 0.744). Among measurable disease, rate 40.9% arm 28.7% Grade 3 adverse events reported ≥ 10% either (ribociclib v fulvestrant) neutropenia (46.6% 0%) leukopenia (13.5% 0%); only grade 4 event 5% (6.8% 0%). Conclusion Ribociclib might represent new first- second-line option cancer.

Language: Английский

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Identification of new ALK and RET gene fusions from colorectal and lung cancer biopsies

Nature Medicine, Journal Year: 2012, Volume and Issue: 18(3), P. 382 - 384

Published: Feb. 12, 2012

Language: Английский

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Targeting CDK4 and CDK6: From Discovery to Therapy

Cancer Discovery, Journal Year: 2015, Volume and Issue: 6(4), P. 353 - 367

Published: Dec. 12, 2015

Biochemical and genetic characterization of D-type cyclins, their cyclin D-dependent kinases (CDK4 CDK6), the polypeptide CDK4/6 inhibitor p16(INK4)over two decades ago revealed how mammalian cells regulate entry into DNA synthetic (S) phase cell-division cycle in a retinoblastoma protein-dependent manner. These investigations provided proof-of-principle that inhibitors, particularly when combined with coinhibition allied mitogen-dependent signal transduction pathways, might prove valuable cancer therapy. FDA approval palbociclib used aromatase letrozole for breast treatment highlights long-sought success. The newest findings herald clinical trials targeting other cancers.Rapidly emerging data selective inhibitors have validated these cell-cycle as anticancer drug targets, corroborating longstanding preclinical predictions. This review addresses discovery CDKs regulators, well translation biology to positive outcomes development rational combinatorial therapies.

Language: Английский

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Overall Survival with Ribociclib plus Fulvestrant in Advanced Breast Cancer

New England Journal of Medicine, Journal Year: 2019, Volume and Issue: 382(6), P. 514 - 524

Published: Dec. 11, 2019

In an earlier analysis of this phase 3 trial, ribociclib plus fulvestrant showed a greater benefit with regard to progression-free survival than alone in postmenopausal patients hormone-receptor–positive, human epidermal growth factor receptor 2 (HER2)–negative advanced breast cancer. Here we report the results protocol-specified second interim overall survival.

Language: Английский

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Efficacy and Safety of Abemaciclib, an Inhibitor of CDK4 and CDK6, for Patients with Breast Cancer, Non–Small Cell Lung Cancer, and Other Solid Tumors

Cancer Discovery, Journal Year: 2016, Volume and Issue: 6(7), P. 740 - 753

Published: May 24, 2016

We evaluated the safety, pharmacokinetic profile, pharmacodynamic effects, and antitumor activity of abemaciclib, an orally bioavailable inhibitor cyclin-dependent kinases (CDK) 4 6, in a multicenter study including phase I dose escalation followed by tumor-specific cohorts for breast cancer, non-small cell lung cancer (NSCLC), glioblastoma, melanoma, colorectal cancer. A total 225 patients were enrolled: 33 192 cohorts. Dose-limiting toxicity was grade 3 fatigue. The maximum tolerated 200 mg every 12 hours. most common possibly related treatment-emergent adverse events involved fatigue gastrointestinal, renal, or hematopoietic systems. Plasma concentrations increased with dose, effects observed proliferating keratinocytes tumors. Radiographic responses achieved previously treated NSCLC, melanoma. For hormone receptor-positive overall response rate 31%; moreover, 61% either stable disease lasting ≥6 months.Abemaciclib represents first selective CDK4 CDK6 safety profile allowing continuous dosing to achieve sustained target inhibition. This first-in-human experience demonstrates single-agent advanced other solid Cancer Discov; 6(7); 740-53. ©2016 AACR.See commentary Lim et al., p. 697This article is highlighted In Issue feature, 681.

Language: Английский

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Plasma ESR1 Mutations and the Treatment of Estrogen Receptor–Positive Advanced Breast Cancer

Journal of Clinical Oncology, Journal Year: 2016, Volume and Issue: 34(25), P. 2961 - 2968

Published: June 7, 2016

ESR1 mutations are selected by prior aromatase inhibitor (AI) therapy in advanced breast cancer. We assessed the impact of on sensitivity to standard therapies two phase III randomized trials that represent development current for estrogen receptor-positive cancer.In a prospective-retrospective analysis, we available archived baseline plasma from SoFEA (Study Faslodex Versus Exemestane With or Without Arimidex) trial, which compared exemestane with fulvestrant-containing regimens patients nonsteroidal AI and PALOMA3 (Palbociclib Combined Fulvestrant Hormone Receptor-Positive HER2-Negative Metastatic Breast Cancer After Endocrine Failure) fulvestrant plus placebo palbociclib progression after receiving endocrine therapy. were analyzed multiplex digital polymerase chain reaction.In SoFEA, found 39.1% (63 161), whom 49.1% (27 55) polyclonal, rates mutation detection unaffected delays processing archival plasma. Patients had improved progression-free survival (PFS) taking (n = 45) 18; hazard ratio [HR], 0.52; 95% CI, 0.30 0.92; P .02), whereas wild-type similar PFS either treatment (HR, 1.07; 0.68 1.67; .77). In PALOMA3, 25.3% (91 360), 28.6% (26 91) associated acquired resistance AI. both mutant 0.43; 0.25 0.74; .002) 0.49; 0.35 0.70; < .001).ESR1 analysis may help direct choice further endocrine-based Additional confirmatory studies required.

Language: Английский

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Early Adaptation and Acquired Resistance to CDK4/6 Inhibition in Estrogen Receptor–Positive Breast Cancer

Cancer Research, Journal Year: 2016, Volume and Issue: 76(8), P. 2301 - 2313

Published: March 29, 2016

Small-molecule inhibitors of the CDK4/6 cell-cycle kinases have shown clinical efficacy in estrogen receptor (ER)-positive metastatic breast cancer, although their cytostatic effects are limited by primary and acquired resistance. Here we report that ER-positive cancer cells can adapt quickly to inhibition evade cytostasis, part, via noncanonical cyclin D1-CDK2-mediated S-phase entry. This adaptation was prevented cotreatment with hormone therapies or PI3K inhibitors, which reduced levels D1 (CCND1) other G1-S cyclins, abolished pRb phosphorylation, inhibited activation transcriptional programs. Combined targeting both triggered cell apoptosis vitro patient-derived tumor xenograft (PDX) models, resulting regression improved disease control. Furthermore, a triple combination endocrine therapy, CDK4/6, more effective than paired combinations, provoking rapid regressions PDX model. Mechanistic investigations showed resistance resulted from bypass D1-CDK4/6 dependency through selection CCNE1 amplification RB1 loss. Notably, could prevent they failed resensitize once had been acquired. However, found acquiring due be resensitized CDK2. Overall, our results illustrate convergent mechanisms early enable alternate means entry, highlighting strategies acquisition therapeutic these agents. Cancer Res; 76(8); 2301-13. ©2016 AACR.

Language: Английский

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