1. Miquel Àngel Seguí Palmer ¿Ciclinas para todas?
Enfermedad luminal metastásica. Tratamiento de primera línea.
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A favor:

2. Disclosure Information
Consultant or Advisory Role: Pfizer, Novartis
Research Funding: Pfizer, Novartis, Lilly
Speaking: Pfizer, Novartis

3. The majority of deaths from MBC are in patients with HR+/HER2− subtype
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The majority of deaths from MBC are in patients with HR+/HER2− subtype
In the setting of mBC, the goal of treatment is palliative.
According to the most recent national and international recommendations, Endocrine Therapy should be preferred to chemotherapy as upfront treatment for metastatic luminal breast cancer patients without organ dysfunction, for the lack of evidence of any benefit from using chemotherapy prior endocrine therapy.
CASCADE STUDY: Treatment and clinical outcomes of metastatic breast cancer by tumor immunophenotypes

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Forest plot of HRs for PFS in trials of CDKi + ET compared ET alone for endocrine-sensitive disease
One phase II trial (PALOMA-1) and five phase III trials (PALOMA-2, MONALEESA-2, MONARCH-3, MONALEESA-7, MONALEESA-3) assessed the efficacy of CDK inhibitor plus ET versus ET alone in endocrine sensitive setting.
(MONALEESA 3 included women ET naïve or who progressed to one prior line of ET)
A total of 2009 patients were enrolled in the CDKi plus ET arm and 1381 in the ET arm. The addition of CDKi to ET was associated with a statistically significant PFS benefit (HR 0.55, 95% CI 0.50–0.62) for metastatic HR+/HER2− breast cancer patients in endocrine-sensitive setting.
 Messina C et al. Breast Cancer Res Treat 2018

5. Comparison of efficacy as assessed by PFS in the various subsets
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Comparison of efficacy as assessed by PFS in the various subsets
Comparison of efficacy assessed by ORR and CBR of the three trials
A key challenge is the search of patient populations that benefit most from the CDK4/6-ET combination. The selection could be made clinically and/or biologically.
Several potential biomarkers have been investigated and did not show any predictive value for treatment with CDK4/6 inhibitors.
In all trials, the different clinical subgroups including proliferation rate, number of organs involved, HR expression, age and race showed the same relative benefit by the addition of CDK4/6 inhibitors.
The principal factors driving the decision to treat using the various endocrine options available for the treatment of metastatic breast cancer includeds whether the patient was symptomatic or asymptomatic from the metastatic standpoint, whether the metastases were primarily visceral or nonvisceral, menopausal status, and the disease-free interval.
The combination of CDKi plus ET significantly improved the ORR compared to ET alone (ORs: 0.62, 95% CI 052–0.73).
Data from PALOMA-2 [palbociclib], MONALEESA-2 [ribociclib], and MONARCH-3 [abemaciclib].
 Messina C et al. Breast Cancer Res Treat 2018
Laderiana B & Fojoa T. Sem Oncol 2017

6. Non-visceral metastasis
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Forest plot of HRs for PFS in trials of CDKi + ET compared ET alone for endocrine-sensitive disease
Visceral metastasis
Non-visceral metastasis
The combination of a CDK4/6 inhibitor and an AI is efficacious even for women with visceral disease. Between 45% and 60% of patients enrolled across all first-line studies had visceral disease. In subgroup analyses, these patients derived a benefit similar to that seen in the overall study populations. The combination of a CDK4/6 inhibitor and an AI may be considered even when a rapid tumor response is needed, given its robust ORR (50% to 60% in the first line), but chemotherapy should still be used for a true visceral crisis.
 Messina C et al. Breast Cancer Res Treat 2018

7. FDA pooled CDKi Analysis
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FDA pooled CDKi Analysis
Gao JJ et al. ASCO 2018

8. Comparison of adverse events (any adverse event)
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Forest plot of odds ratios for ≥ G3–G4 AE in randomized trials of CDK inhibitors plus ET compared ET alone for endocrine-sensitive population
Comparison of adverse events (any adverse event)
When evaluating risk and benefits of a specific treatment, AEs should be considered for their influence on quality of life (QoL). Neutropenia has been shown to have a minimal impact on QoL and this was confirmed in recent publications, where CDKi plus ET maintained QoL and improved pain scores over ET
While the three agents likely have similar efficacy, the toxicity profiles, dosing schedules, and monitoring required differ.
There is no specific benefit of one toxicity profile over another, and patient comorbidities, preferences, and physician familiarity dictate choice between these agents.
Packaging provided by drug companies also differs between the agents, with the blister packaging of ribociclib potentially allowing for dose reduction in a more timely manner
without the need for a new prescription. Importantly, the financial toxicity of each of these agents can be significant.
Data from PALOMA-2 [palbociclib], MONALEESA-2 [ribociclib], and MONARCH-3 [abemaciclib].
 Messina C et al. Breast Cancer Res Treat 2018
Laderiana B & Fojoa T. Sem Oncol 2017

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Current strategies for slowing cancer progression in women with luminal mBC
The FALCON study established fulvestrant HD as the most efficacious endocrine agent in postmenopausal women luminal mBC not previously treated with endocrine therapy.
Median PFS was 16.6 months with fulvestrant and 13.8 months with anastrozole (hazard ratio 0.797, 95% CI 0.637–0.999; P=0.0486).
The PFS hazard ratio was 0.59 (95% CI 0.42–0.84) in patients with nonvisceral disease (median PFS 22.3 months with fulvestrant versus 13.8 months with anastrozole), and 0.99 (95% CI 0.74–1.33) in patients with visceral disease (median PFS 13.8 months with fulvestrant versus 15.9 months with anastrozole.

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Current strategies for slowing cancer progression in women with luminal mBC
The FALCON study established fulvestrant HD as the most efficacious endocrine agent in postmenopausal women luminal mBC not previously treated with endocrine therapy.
Median PFS was 16.6 months with fulvestrant and 13.8 months with anastrozole (hazard ratio 0.797, 95% CI 0.637–0.999; P=0.0486).
The PFS hazard ratio was 0.59 (95% CI 0.42–0.84) in patients with nonvisceral disease (median PFS 22.3 months with fulvestrant versus 13.8 months with anastrozole), and 0.99 (95% CI 0.74–1.33) in patients with visceral disease (median PFS 13.8 months with fulvestrant versus 15.9 months with anastrozole.
Network meta-analysis to indirectly compare the CDK4/6 inhibitors as well as fulvestrant in the first-line treatment of metastatic luminal breast cancer
El Rassy E et al. Fut Oncol 2018

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Network meta-analysis to indirectly compare the CDKi as well as fulvestrant in the first-line treatment of metastatic luminal breast cancer  .
The results of the present NMA highlight the superiority of CDK4/ 6 inhibitors over fulvestrant and suggest that palbociclib may be the safest drug among CDK4/ 6 inhibitors in the first-line treatment of metastatic luminal breast cancer.
El Rassy E et al. Fut Oncol 2018

12. MONALEESA-3: PFS in first line endocrine therapy
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MONALEESA-3: PFS in first line endocrine therapy
Slamon DJ et al. ASCO 2018

13. CDK4/6 inhibitors and overall survival:
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CDK4/6 inhibitors and overall survival:
Power of first-line trials in metastatic breast cancer
Whilst OS data represent a clinically relevant endpoint in the first-line management of luminal mBC, they are arguably not the most sensitive or accurate measure of benefit derived from upfront treatment, given that postprogression survival may be largely reflective of lines of therapy subsequently received off study.
Unfortunately, these clinical trials were not powered to detect an OS advantage and indeed the majority of survival results are still pending; and as such, pooling/meta-analysis of trial data, as well as further follow up, may be needed to adequately evaluate this endpoint.
However, the observed PFS benefit is consistent across the six trials and is clinically relevant; even in the absence of mature data, the magnitude of PFS benefit is likely to translate in a significant improvement in OS.

14. Reporting and Grading Financial Toxicity
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Reporting and Grading Financial Toxicity

15. Baricorcho Toxicity Grading Criteria
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Reporting and Grading Financial Toxicity
Baricorcho Toxicity Grading Criteria
Grade 1
Grade 2
Grade 3
Grade 4
Tamoxifen X IA
Fulvestrant
Capecitabine
CDKi
Tax + Beva

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MONARCH-3
Goetz MP et al. ASCO 2018

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Should all metastatic luminal patients receive a CDK 4/6 inhibitor in the first-line setting?
Level 1 evidence now supports use of a CDK 4/6 inhibitor in combination with endocrine therapy for patients with luminal mBC as first-line treatment.
Based on forest plots presented in the major clinical trials, all subgroups of patients with luminal mBC benefit, with manageable toxicity, and there is not at present a clinical feature or biomarker for use of these agents, nor is there a clinical outlier whom one could reliably predict would, or would not benefit from the use of a CDK 4/6 inhibitor with endocrine therapy.
However, benefits should be balanced with longer treatment duration, toxicities, and costs.
Mature OS data are awaited. Head-to-head trials are warranted to compare the efficacy of CDKi plus ET or chemotherapy especially for women with high tumour burden and visceral metastases in order to improve patient’s selection and maximize the benefit from the combined approach.
Without clear biomarkers, selection of ET in the first line metastatic setting depends on clinician/patient preferences, disease burden, and disease biology. While endocrine therapy alone, including aromatase inhibitors, tamoxifen, or fulvestrant, may be appropriate for select patients, the consistent benefits of CDK4/6 inhibitors across multiple subgroups, including those with longer disease free intervals, support their use
in the first line for most patients while we await overall survival data.
And even without an OS benefit, a prolonged PFS may delay the onset of more severe disease symptoms and have other benefits.

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Should all metastatic luminal patients receive a CDK 4/6 inhibitor in the first-line setting?
Certain clinical scenarios likely exist where absolute benefit of CDK 4/6 inhibitors may be small.
Newly diagnosed (or prior history with long TFI) with bone-only, highly ER+/PR+ mBC). In these scenarios, fulvestrant as momotherapy could be considered.
While it is possible that they would do even better with the addition of a CDK4/6 inhibitor, patients should be counseled regarding the treatment schedule for the agents being considered, the need for laboratory and other monitoring, and safety profiles.

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Should all metastatic luminal patients receive a CDK 4/6 inhibitor in the first-line setting?
Sequential trials are needed for better patient selection with the primary end point after two lines of treatment, particularly regarding the missing data about cross over after progression in the mono-endocrine arms.
At present, use in the upfront setting is better than waiting for a later line of therapy or adding after endocrine therapy has started.

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21. Título de la diapositiva en dos líneas
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Título de la diapositiva
en dos líneas

22. Título de la diapositiva en dos líneas
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Título de la diapositiva
en dos líneas

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Most commonly reported grade 3 or 4 toxicities

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