Sara Hurvitz is an Associate Professor in the Division of Hematology-Oncology, David Geffen School of Medicine at University of California, Los Angeles (UCLA). She also holds several administrative positions at UCLA, including Director of the Breast Oncology Program, Medical Director of the Clinical Research Unit at the Jonsson Comprehensive Cancer Center (JCCC) and Co-director of the Santa Monica Outpatient Oncology Practice. Professor Hurvitz achieved her MD from the University of Southern California School of Medicine in 1999, and carried out a residency and fellowship at UCLA. She has been leading the breast oncology program at UCLA since 2006. She has been a steering committee member for  numerous clinical trials into breast cancer therapies and is a Fellow of the  American College of Physicians and a member of the American Society of Clinical Oncology. In 2011, Professor Hurvitz received the JCCC’s Diana Gordon Jonsson Award for Clinical Excellence. An Associate Editor of Therapeutic Advances in  Medical Oncology, she has authored or co-authored over 60 original research papers and reviews in peer-reviewed journals including Lancet Oncology,  Journal of Clinical Oncology, Clinical Cancer Research, and Cancer Treatment  Reviews, as well as eight book chapters. 
Sara Hurvitz, MD, FACP
Meet the Faculty
Associate Professor of Medicine University of California, Los Angeles Director of the Breast Cancer Program Director, Clinical Research Unit Jonsson Comprehensive Cancer Center Los Angeles, California
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Addressing
Inhibiting Cellular Signaling Pathways 
Endocrine Resistance
in Patients with
Metastatic Breast Cancer
Ref
Palbociclib or ribociclib plus AI
Clinical trials are ongoing to test whether continued use is beneficial
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Continue to Post Test
Fulvestrant plus palbociclib for patients whose disease progressed following endocrine therapy
Current FDA-approved regimens include
Conclusions
Clinical trials are ongoing to evaluate targeting pathways of resistance
There is no evidence to support continued use of CDK4/6 inhibition after disease progression on a CDK4/6 inhibitor
Use of CDK4/6 inhibitors in combination with endocrine therapy has significantly improved PFS for patients with HR+ MBC
P
EGFR/HER2
ERE
 p90RSK
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Mechanism of the Resistance
The PI3K Pathway
ER
Increased upstream signaling through growth factor receptors
Endocrine Resistance:
PI3K Inhibitors in Development
CBP = CREB binding protein; ER = estrogen receptor; ERE = estrogen-responsive element; HER2 = human epidermal growth factor receptor 2; MAPK = mitogen-activated protein kinase; MEK = mitogen-activated protein kinase/extracellular signal–related kinase kinase; mTOR = mammalian target of rapamycin; PI3K = phosphoinositide-3 kinase; SOS = son of sevenless
Targeting the Pathway
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Basal Transcription Machinery
Cell growth
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p160
CBP
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SOS
RAS
E2
RAF
Cytoplasm
Everolimus and exemestane in postmenopausal women with ER-positive, HER2- advanced breast cancer whose disease was refractory to previous letrozole or anastrozole
MTOR
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FGFR1
IGF1R
 
Nucleus
ER Target Gene Transcription
 MEK
CDK4/6
 MAPK
Akt
PI3-K
Increased signaling through PI3-K pathway
ER Signaling
Targets in ER Signaling
Endocrine Trials in 1st-Line MBC
3
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AF1
 Estrogen
   Estrogen Receptor
Estrogen-receptor downregulator (ERD)   • Fulvestrant
4
Selective estrogen-receptor modulators (SERMs)    • Tamoxifen    • Toremifene
Cell growth
1
(starting with number 1) in the ER-signaling pathway
Endocrine Therapy: Hormone Receptors
Aromatase inhibitors (AIs) Nonsteroidal AIs     • Anastrozole     • Letrozole  Steroidal AIs     • Exemestane
Endocrine Therapy
DBD
Gene transcription
2
LBD
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Cofactor complex
Oophorectomy
Growth-factor receptor
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A
E2F
inactivates and releases E2F
Cell-cycle arrest
CDC2
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E
B
Palbociclib
Rb as master regulator of the R-point in the cell cycle
CDK4/6 Inhibitors Video
E2F transcription factors allow the transcription of genes promoting entry into the S phase
CDK2
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Rb loss
E
Receptor tyrosine kinase
Cyclin D1
P
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Phases of the cell cycle
CDK4/6
pRb hyperphosphorylation
DNA synthesis Actual duplication of genome occurs
CDK4/6 inhibitors:
Cyclin-dependent kinases (CDKs) – family of serine-threonine kinases partner with cyclins to regulate cell cycle progression.
       CDK4/6
Cellular proliferation
Mitosis Chromosomes are separated and actual cell division occurs
Rb
Cells arrested in G1
Ribociclib
Growth factor
hyperphosphorylation
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Other signaling pathways
Gap 1 Cell accumulates resources needed to duplicate genome
Altered expression and activation of  various regulators of the cyclin D:  CDK4/6:Rb pathway have been  implicated in numerous cancers.
Loss of negative regulators (p16, p27)
Dysregulated Signal
Pathophysiology
  Cyclin D
Abemaciclib
D
Growth-factor signaling (steroid and peptide) and cell-cycle progression
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pRb hypophosphorylation
CDK4/6 Inhibitors MOA
4
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MTOR
Association of above with response to antiestrogens and prognosis
P16
S: key checkpoint
Inactivates Rb and allows cell cycle progression
Induce dephosphorylation of Rb
Estrogen
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pRB
pRb dephosphorylation
Frequent alterations in cyclin D:CDK 4/6:Rb pathway in breast cancer
Regulated by interaction CDKs and cyclin proteins
of Rb protein (pRb)
NUCLEUS
CDK4/6 interact with cyclin D1
MEMBRANE
CDK4/6-mediated phosphorylation of the retinoblastoma protein (pRb)
Amplification of cyclin D1 (11q13) in ER+ breast cancer
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CDK4 amplification/overexpression
Stage of the cell cycle
CYTOPLASM
Alterations in the cyclin D:CDK4/6:Rb pathway have been associated with prognosis, endocrine sensitivity, and growth-factor signaling in breast cancer.
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Gap 2 Proper DNA replication checked and final prep for mitosis phase
R Point
With CDK4/6 Inhibitor
No CDK4/6 Inhibitor
 pRb dephosphorylation
G1
EXTRACELLULAR SPACE
Cell-cycle progression
Cyclin-dependent kinases (CDKs) form complexes with different cyclins to regulate cell cycle
Cyclin D
E2F unable to activate expression of genes favoring cell cycle progression
inactive complex
Rb remains bound to E2F
pRB
Hypophosphorylation
Dephosphorylation
PALOMA-2
MONALEESA-2 Primary Endpoint: PFS
Everolimus plus exemestane is FDA approved for patients with disease that has progressed on or after an aromatase inhibitor, typically in the second- or third-line setting, based on data from the BOLERO-2 study.
Cases
The PALOMA-3 study evaluated fulvestrant plus palbociclib compared with fulvestrant plus placebo in patients with hormone receptor-positive metastatic breast cancer whose disease progressed on endocrine therapy. While it showed a significant improvement in median PFS with palbociclib, it should be noted that this study did not allow patients on study who had previously received a CDK4/6 inhibitor. At this time, there is no data to support the use of CDK4/6 inhibition in patients whose disease progressed on a CDK4/6 inhibitor; thus option B would be inappropriate at this time. Of note, ongoing studies are being conducted to evaluate whether the continued use of CDK4/6 inhibition benefits patients after progression on an CDK4/6 inhibitor. 
PALOMA-3
A Phase III, double-blind, placebo-controlled study of ribociclib + letrozole first-line in ER+, HER2- advanced BC
Age and diagnosis history 63-year-old woman was diagnosed 8 years ago with a stage IIB T2N1 ER+ PR+ HER2– left breast invasive ductal carcinoma treated with surgery, radiation, and 5 years of AI therapy.
Single-agent, first-line AI (exemestane) has been associated with a median PFS of approximately one year.
While fulvestrant plus palbociclib has been evaluated in the phase III PALOMA-3 study in which it was shown to improve PFS compared with fulvestrant plus placebo (9.2 mos vs 3.8 mos palbociclib vs control arm), this study enrolled patients whose disease had progressed on prior endocrine therapy. To date, the use of fulvestrant plus palbociclib has not been evaluated in (nor is it approved in) the first-line setting.
Tamoxifen
Exemestane
Sally
Safety
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Exemestane
     Fulvestrant plus palbociclib
Case workup Two years after completing adjuvant AI, she was presented for follow-up complaining of shortness of breath, cough, and left hip pain. Scans revealed multiple lung metastases bilaterally (up to 1 cm), a small left pleural effusion, and a left pubic ramus lytic lesion. Biopsy of the lung confirmed the presence of metastatic breast cancer, ER+ PR+ HER2–. The patient has an excellent performance status.
Exemestane plus everolimus
      Tamoxifen
Efficacy
     Letrozole plus palbocilib
Everolimus plus exemestane
Fulvestrant plus everolimus
PR+, progesterone receptor-positive
The PALOMA-2 study evaluated letrozole plus palbociclib compared with letrozole plus placebo for post menopausal women with hormone receptor-positive, HER2-negative metastatic breast cancer. The median PFS for palbociclib plus letrozole was 24.8 months, just over 10 months longer than that of the control arm. The MONALEESA-2, placebo-controlled, phase 3 trial has shown that in first-line treatment of postmenopausal women with HR+ HER2– advanced or metastatic BC, the duration of progression-free survival was significantly longer with the combination of ribociclib with letrozole versus placebo with letrozole.
Fulvestrant single agent
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        Fulvestrant plus palbociclib
Fulvestrant plus palbociclib
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BOLERO-2
Of the options below, what therapy is associated with the longest progression-free survival for this particular patient (ie, 1st-line metastatic HR+ HER2– MBC)?
     Letrozole plus ribociclib
Age and diagnosis history 56-year-old woman was diagnosed 2 years ago with ER+ PR+ HER2– de novo metastatic breast cancer in the liver and bones and started on first-line letrozole plus palbociclib.
Fulvestrant plus palbociclib
Fulvestrant plus everolimus
Palbociclib Safety
Mary
       Everolimus plus exemestane
Case workup She had an excellent response with disappearance of all liver metastases and stabilization in the bone metastases. At her most recent visit 2 weeks ago, she complained of increasing fatigue and new lower back pain. Scans revealed one new liver metastasis (1.4 cm) and a new lesion in the L4 vertebra without evidence of spinal cord compression. At her request, a liver biopsy is performed for genomic profiling and detects a mutation in ESR1.
Which of the following would be the least appropriate treatment option to offer her?
PALOMA-3: PFS
     Fulvestrant single agent
MONALEESA-2
Letrozole plus ribociclib
     Exemestane plus everolimus
The PALOMA-2 study evaluated letrozole plus palbociclib compared to letrozole plus placebo for post-menopausal women with hormone receptor positive, HER2 negative metastatic breast cancer. The median PFS for palbociclib plus letrozole was 24.8 months, just over 10-months more than that of the control arm. The MONALEESA-2, placebo-controlled, phase 3 trial has shown that in first-line treatment of postmenopausal women with HR+ HER2- advanced or metastatic BC, the duration of progression-free survival was significantly longer with the combination of ribociclib with letrozole versus placebo with letrozole.
     Fulvestrant plus everolimus
Everolimus and exemestane in postmenopausal women with ER-positive, HER2- advanced BC breast cancer whose disease was refractory to previous letrozole or anastrozole
PALOMA-2 Safety
PALOMA-2: Phase III 1st- line in ER+HER- advanced BC
Letrozole plus palbocilib
      Fulvestrant plus palbociclib
FDA approval March 13, 2017
Fulvestrant single agent
MONALEESA-2: Safety
After 18 months, the progression-free survival rate was 63.0% in the ribociclib group and 42% in the placebo group. The progression-free survival benefit in the ribociclib group was observed across all predefined subgroups.
      Everolimus plus exemestane
Single-agent first-line tamoxifen has been associated with a median PFS of less than 10 mos
Use of exemestane plus everolimus, fulvestrant single agent, and fulvestrant plus everolimus are supported by existing data for patients after progression on first-line AI therapy.
Common grade 3 or 4 events
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Click to review the BOLERO-2 study
Abemaciclib* Preclinical Data
(3 wks on / 1 wk off)
MONARCH-2
Blinded independent central review of efficacy endpoints performed as supportive analysis
Phase III, 2nd/3rd line in ER+ HER2- advanced BC
Response, OS, safety, biomarkers, patient-reported outcomes
Study design
Randomization
+
PALOMA-2 Study Design
a Actual. AI=Aromatase inhibitor; HER2=human epidermal growth factor receptor 2; OS=overall survival; PFS=progression-free survival; QD=once daily
Phase III study in HR+,  HER2- mBC
PALOMA-1: Randomized Open-Label Phase II Trial
Safety
Stratification factors
Phase III study in HR+, HER2- mBC
MONARCH-2: PFS
• Disease site (visceral, non-visceral)
(500 mg IM q4w)
Postmenopausal
Fulvestrant†
Palbociclib
Study Design
(125 mg QD; 3 wks on / 1 wk off)
(3/1 schedule)
Preclinical
PFS (locally assessed per RECIST v1.1)
Phase 2 study in HR+, HER2-mBC (12 month final analysis)
• Two-look Haybittle–Peto stopping criteria: hazard ratio ≤0.56 and P<0.0000129
Ribociclib Preclinical Data
MONARCH 1
Placebo
n=334
The CDK4/6 inhibitor ribociclib is most active in ER+ breast cancer cell lines.
Letrozole (2.5 mg/day)
No prior treatment for advanced disease
Letrozole
Postmenopausal women
AE- adverse event
•Final analysis planned after 302 PFS events
* Novel results from ASCO 2017: 24-month PFS rates: 54.7% vs 35.9%  Hortobagyi GN et al. J Clin Oncol 35, 2017 (suppl; abstr 1038)
N=668
New Text
• 93.5% power to detect a 33% risk reduction (hazard ratio 0.67) with one-sided α=2.5%
Ribociclib (600 mg/day)
Palbociclib is an oral, highly selective inhibitor of CDK4/6 that inhibits cell proliferation by prohibiting cell-cycle progression from G1 to S phase.
CDK4/6 Inhibitors
Phase III 1st-line in ER+, HER2- advanced BC
Primary endpoint
MONALEESA-2 Study Design
*
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IC50s of CDK4/6 Inhibitor Palbociclib in UCLA Breast-Cell Lines
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A phase III, double-blind, placebo-controlled study of ribociclib + letrozole; FDA approval
Palbociclib Preclinical Data
ER+, HER2– advanced breast cancer
Most of the luminal cells were sensitive to inhibition with palbociclib and synergistic inhibition with tamoxifen + palbociclib
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Summary
•Interim analysis planned after ~70% PFS events
•Tumor assessments were performed every 8 weeks for 18 months, then every 12 weeks thereafter
3-weeks-on/1-week-off
(2.5 mg/day)
PALOMA-1
Secondary endpoints
PALOMA-2: Phase III 1st-line in ER+, HER2- advanced BC
• Overall survival (key) • Overall response rate • Clinical benefit rate • Safety
PALOMA-3 Study Design
(125 mg QD, 3/1 schedule)
(2.5 mg QD)
• Disease-free interval (de novo metastatic; ≤12 mo,>12 mo)
• HR+, HER2-ABC • Pre-/peri-* or post-menopausal • Progressed on prior endocrine therapy:       – On or within 12 mo adjuvant       – On therapy for ABC • ≤1 prior chemotherapy regimen     for advanced cancer
• Prior (neo)adjuvant hormonal therapy (yes, no)
*All received goserelin
Post-menopausal patients must have progressed on prior aromatase inhibitor therapy
MONARCH-1
Statistical analysis designed to detect an increase in PFS with a true HR of 0.69 (representing a 31% improvement) with 347 events; 90% power with 1-sided α=0.025
2:1 Randomization N=521
Stratification: • Visceral metastases • Sensitivity to prior    hormonal therapy • Pre-/perimenopausal- vs postmenopausal
Investigator-assessed PFS
Assumptions: Median PFS with placebo plus letrozole = 9 mos vs palbociclib plus letrozole= 13 mos
n=347
Growth adjusted IC50s for abemaciclib in a panel of 47 breast cancer-cell lines, 100 nM cut-off for sensitivity/resistance * Not FDA-approved; 14-fold more potent at inhibiting CDK4 than CDK6 than palbociclib
AI-resistant patients excluded
n=174