Clinical considerations of the role of palbociclib in the management of advanced breast cancer patients with and without visceral metastases

Turner, Nicholas C.; Finn, Richard S.; Martín, Miguel; Im, Seock Ah; DeMichele, Angela; Ettl, Johannes; Dièras, Véronique; Moulder, Stacy L.; Lipatov, Oleg; Colleoni, Marco; Cristofanilli, Massimo; Lu, Dongrui R.; Mori, Alessia; Giorgetti, C.; Iyer, Shrividya; Bartlett, C Huang; Gelmon, Karen A.

doi:10.1093/annonc/mdx797

Cited by 82 publications

(76 citation statements)

References 21 publications

(39 reference statements)

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“…Evidence from registrative trials confirms that palbociclib had similar had efficacy in nearly all prespecified subgroups (Finn, Crown, Ettl et al, ; Turner et al, ). Conversely, in our patient population, both ORR and CB rate were significantly higher in patients without visceral metastases.…”

Section: Discussionmentioning

confidence: 90%

Palbociclib plus endocrine therapy in HER2 negative, hormonal receptor‐positive, advanced breast cancer: A real‐world experience

Pizzuti

Giordano

Michelotti

et al. 2018

Journal Cellular Physiology

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Data from 423 human epidermal growth factor receptor 2‐negative (HER2−), hormone receptor‐positive (HR+) advanced breast cancer (aBC) patients treated with palbociclib and endocrine therapy (ET) were provided by 35 Italian cancer centers and analyzed for treatment outcomes. Overall, 158 patients were treated in first line and 265 in second/later lines. We observed 19 complete responses and 112 partial responses. The overall response rate (ORR) was 31% (95% confidence interval [CI], 26.6–35.4) and clinical benefit was 52.7% (95% CI, 48–57.5). ORR was negatively affected by prior exposure to everolimus/exemestane ( p = 0.002) and favorably influenced by early line‐treatment ( p < 0.0001). At 6 months, median progression‐free survival was 12 months (95% CI, 8–16) and median overall survival was 24 months (95% CI, 17–30). More favorable outcomes were associated with palbociclib in early lines, no visceral metastases and no prior everolimus/exemestane. The main toxicity reported was neutropenia. Our results provide further support to the use of palbociclib with ET in HER2−, HR+ aBC. Differences in outcomes across patients subsets remain largely unexplained.

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Section: Discussionmentioning

confidence: 90%

Palbociclib plus endocrine therapy in HER2 negative, hormonal receptor‐positive, advanced breast cancer: A real‐world experience

Pizzuti

Giordano

Michelotti

et al. 2018

Journal Cellular Physiology

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“…PALOMA-3 was a prospective, randomised, multicentre, placebo-controlled study evaluating palbociclib plus fulvestrant versus placebo plus fulvestrant in patients with HRþ/HER2e MBC that had progressed on prior ET [7]. The study demonstrated improved PFS and objective response rates at predetermined time points with the combination; subgroup analyses have shown that the observed benefit was independent of menopausal status, previous ET, number of disease sites, previous lines of ET, sensitivity to previous hormonal therapy, previous chemotherapy [5,7] and presence of visceral metastases at baseline [19]. Furthermore, patients receiving the combined regimen experienced an improvement in the quality of life and a favourable toxicity profile [20e22].…”

Section: Discussionmentioning

confidence: 96%

Predictors of prolonged benefit from palbociclib plus fulvestrant in women with endocrine-resistant hormone receptor–positive/human epidermal growth factor receptor 2–negative metastatic breast cancer in PALOMA-3

Cristofanilli¹,

DeMichele

Giorgetti

et al. 2018

European Journal of Cancer

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Background: The addition of palbociclib to fulvestrant improved clinical outcomes over placebo-fulvestrant in endocrine-pretreated metastatic breast cancer (MBC) patients in PALOMA-3. Here, we examined factors predictive of long-term benefit. Methods: Premenopausal-peri/postmenopausal patients with endocrine-resistant, hormone receptorepositive (HRþ)/human epidermal growth factor receptor 2enegative MBC were randomised 2:1 to fulvestrant (500 mg) and either palbociclib (125 mg/d; 3/1 schedule; n Z 347) or placebo (n Z 174). Baseline characteristics, mutation status and HR expression levels were compared in patients with and without prolonged benefit (treatment duration !18 months). Results: By August 2016, 100 patients (29%) on palbociclib-fulvestrant and 26 (15%) on placebo-fulvestrant demonstrated prolonged benefit, with long-term responders in both arms sharing common clinical characteristics. They usually had less disease burden at baseline versus those treated <18 months, such as having one disease site (40% vs 29% on palbociclib-fulvestrant and 69% vs 29% on placebo-fulvestrant), bone-only disease (32% vs 22% and 46% vs 17%) and were less heavily pretreated (69% vs 56% and 73% vs 60% had 2 prior therapies). Baseline tumour ESR1 and PIK3CA mutation rates were lower among long-term responders in both arms; median oestrogen receptor H-scores were similar, whereas progesterone receptor H-scores were higher among long-term responders. Conclusions: This exploratory analysis demonstrates that some patients with endocrineresistant MBC derive significant and prolonged benefit when treated with palbociclibfulvestrant, with fewer patients experiencing similar efficacy with placebo-fulvestrant. The current analysis did not identify specific molecular or clinical factors prognostic of long-term benefit with palbociclib-fulvestrant (ClinicalTrials.gov, NCT01942135).

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“…For instance, in a randomized phase III clinical trial called PALOMA-3, made of 521 patients with HR-positive HER2-negative breast cancer randomly assigned to receive either palbociclib with fulvestrant or placebo with fulvestrant, the median overall survival (OS) improved by 6.9 months in the palbociclib arm versus the control arm, at a median follow-up duration of 44.8 months (HR 0.81, 95% CI 0.64-1.03, p= 0.09) 50 Although these improvements in OS were not statistically significant, they support the notion that the addition of palbociclib to fulvestrant improves mPFS by 4.9 months previously reported in 2016 51 . Moreover, the data proved that there was an even higher improvement in those patients who previously showed a sensitivity to the endocrine therapy and in those patients without visceral disease 52 . In fact, Turner et al showed that there is an improvement of 6.4 months in patients who were sensitive to endocrine therapy and had visceral disease.…”

Section: Fda-approved Cdk4/6 Inhibitors In Advanced or Metastatic Er-mentioning

confidence: 73%

“…Furthermore they also showed that there is a mPFS improvement of 9.3 months in patients without visceral disease. The mPFS was 16.6 months in patients who received palbociclib plus fulvestrant vs 7.3 months in patients who received placebo plus fulvestrant 52 .…”

Section: Fda-approved Cdk4/6 Inhibitors In Advanced or Metastatic Er-mentioning

confidence: 94%

Updates on the CDK4/6 Inhibitory Strategy and Combinations in Breast Cancer

Sobhani¹,

D’Angelo²,

Pittacolo³

et al. 2019

Preprint

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Breast Cancer (BC) is the second most common type of cancer worldwide and displays the highest cancer-related mortality among women worldwide. Targeted therapies have revolutionized the way BC has been treated in the last decades improving life expectancies of millions of women. Among the different molecular pathways that have been of interest for the development of targeted therapies are the Cyclin-Dependent Kinases (CDK). CDK inhibitors are a class of molecules that already exist in nature and those belonging to the INK4 protein family specifically inhibit the CDK4/6 proteins. CDK4/6 inhibitors specifically block the transition from the G1 to the S phase of the cell cycle by dephosphorylation of the retinoblastoma tumor suppressor protein. In the past four years CDK4/6 inhibitors palbociclib, ribociclib, and abemaciclib received their first FDA approval for the treatment of Hormone Receptor (HR)-positive and Human Epidermal growth factor Receptor 2 (HER2)-negative breast cancer after showing significant improvements in progression-free survival in the PALOMA-1, MONALEESA-2 and the MONARCH-2 randomized clinical trials, respectively. After the encouraging results from these clinical trials, CDK4/6 inhibitors have also been investigated in the other BC subtypes. In HER2-positive BC, combination of CDK4/6 inhibitors with HER2-targeted therapies showed promise in preclinical studies and their clinical evaluation is ongoing. Moreover, in triple-negative BC, CDK4/6 inhibitors efficacy has been investigated in combination with other targeted therapies or immunotherapies. This review summarizes the molecular background and clinical efficacy of CDK4/6 inhibitors as single agents or in combination with other targeted therapies for the treatment of BC. Future directions of ongoing clinical trials and predictive biomarkers will be further debated.

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Clinical considerations of the role of palbociclib in the management of advanced breast cancer patients with and without visceral metastases

Cited by 82 publications

References 21 publications

Palbociclib plus endocrine therapy in HER2 negative, hormonal receptor‐positive, advanced breast cancer: A real‐world experience

Palbociclib plus endocrine therapy in HER2 negative, hormonal receptor‐positive, advanced breast cancer: A real‐world experience

Predictors of prolonged benefit from palbociclib plus fulvestrant in women with endocrine-resistant hormone receptor–positive/human epidermal growth factor receptor 2–negative metastatic breast cancer in PALOMA-3

Updates on the CDK4/6 Inhibitory Strategy and Combinations in Breast Cancer

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