1. HR positive, Her-2 negative MBC
4/10/2018

2. General Principles Rx is palliative, maintain QOL
Re-biopsy at the time of mets- bx results altered Rx in 15% pts
Prognostic factors: time to relapse, no. of metastatic sites, visceral dz particularly liver, lymphangitic lung, marrow, meningeal
Management overview: less toxic to more toxic therapy
- symptomatic visceral dz/rapidly progressing:
chemo (1-2 drugs) for 4-6 months  change to AET after control
- asymptomatic, low volume, indolent dz:
AET  if response duration < 6 months  change to chemo

3. Monitoring response Physical exam: breast mass, LN, superficial lumps
Tumor markers: CEA, Ca 27.29, Ca 15-3
Imaging: PET not recommended routinely
Bone scan once or twice yearly
CT scans 3-4 months
CTCs- insufficient data from trials on CTCs to help tailor therapy, not used outside of clinical trials

4. Letrozole + ribociclib
Examples of Hormonal Therapies for ER+ Breast Cancer (and Year of FDA Approval)
AI + palbociclib
Letrozole + ribociclib
Fulvestrant +
abemaciclib
Abemaciclib monotherapy (2017)
Tamoxifen (1977)
Anastrozole (1995)
Letrozole (1997)
Toremifene (1997)
Fulvestrant (2002)
Exemestane (1999)
Exemestane + everolimus (2012)
Letrozole + palbociclib
(2015)
Fulvestrant + palbociclib
(2016)
1980
1995
2000
2010
2015
2017
2016
AI, aromatase inhibitor; ER+, estrogen receptor positive.
US Food and Drug Administration.

5. Endocrine therapy Estrogen depletion:
Oophorectomy for premenopausal women
LHRH agonist- Leuprolide and goserelin: onset 2-4 weeks, monthly shots preferable, estradiol monitoring needed
Aromatase inhibitors- inhibits peripheral conversion, all 3 agents similar in efficacy and side effect profiles
Estrogen receptor blockade:
SERMs- Tamoxifen 2nd line(Raloxifene for prevention only)
SERDs- Fulvestrant (500 mg improved efficacy compared to 250 mg dosing)

6. FALCON: Phase III trial of Fulvestrant vs Anastrozole
Eligibility:
Postmenopausal women
Locally advanced or metastatic
ER/PR pos, Her-2 neg
No prior endocrine therapy
One prior chemo allowed
N = 462 R
Fulvestrant
N =230
Primary endpoints: PFS
Secondary endpoint: OS, RR, CBR, duration of response, safety/QOL
Robertson et al. Lancet 2016

7. FALCON: Results
Patients: Median age 63-64yrs, 87% metastatic disease, about 50% pts with visceral disease in both arms
PFS: 16.6 mon vs 13.8 mon (HR 0.8, p = )
RR and CBR did not differ, duration of response favored fulvestrant at 20 mon vs 13 mon
Sub-group visceral vs non-visceral disease: fulvestrant better for non-visceral disease PFS 22.3 months vs 13.8 months
AEs- Fulvestrant vs Anastrozole: Arthralgias (17% vs 10%)
Hot flashes (11% vs 10%)
Nausea (10% for both)
Robertson et al. Lancet 2016

8. Fulvestrant + Anastrozole: FACT
Open-label, randomized, phase III study, 1st line, N = 514, adjuvant tamoxifen use in 68% patients
TTP 11 vs 10 months (HR= 0.99; P = .91)
Median OS was 38 months for both (HR = 1.0; P = 1.00)
Combination offered no clinical efficacy advantage over anastrozole monotherapy
Caveats: Fulvestrant was 250 mg dosing (CONFIRM) & significant number of pts with prior exposure to endocrine therapy
Bergh et al. J Clin Oncol. 2012

9. Fulvestrant + Anastrozole: SWOG S0226
Phase III, N = 707 post-menopausal, no prior Rx for metastatic disease
Fulvestrant dosing 250 mg (higher dose allowed later), 41% crossover from AI to fulvestrant at the time of progression, 40% de novo metastatic disease
Pts stratified according to prior receipt of adjuvant tamoxifen (40% pts were exposed to tamoxifen), adjuvant AI allowed if completed >12 months prior
Median TTP: 13.5 vs 15 months (HR 0.80; P=0.007), Median OS: 41 vs 48 months (HR 0.81; P=0.05)
No prior tamoxifen: PFS 12.6 vs 17 months (HR 0.74; p = 0.006)
Prior tamoxifen exposure: PFS 14.1 vs 13.5 months, (HR 0.89; p = 0.37)
Similar difference observed for OS as well for pts with and w/o tamoxifen exposure
Mehta et al. N Engl J Med. 2012

10. CDK 4/6 Complex Regulates Proliferation

11. CDK 4/6 Inhibition Preferentially Inhibits Luminal Estrogen
Receptor-Positive Breast Cancer Cell Lines in Vitro
IC50, nM
Subtype
Luminal
Non-luminal/post EMT
HER2 amplified
Non-luminal
Immortalized
Finn RS, et al. Breast Cancer Res. 2009;11(5):R77 11

12. Preclinical Activity of Combination Therapy: AI and CDK4/6i
Infante JR et al. TAT 2014; abstr O4.4;
Munster PN et al. J Clin Oncol 2014;32:5s:abstr 533.

13. Palbociclib 125 mg QDa + Letrozole 2.5 mg QD
PALOMA-2: Phase 3 Study of ER+, HER2– Locally Recurrent or Metastatic Breast Cancer
N=666
2:1
Post-menopausal
ER+, HER2- breast cancer
No prior treatment for advanced disease
Stratification by- sites of disease, disease-free interval and prior endocrine therapy
Cross over not allowed
Patients with advanced, symptomatic visceral spread excluded R A N D O M I Z T
Palbociclib 125 mg QDa + Letrozole 2.5 mg QD
Letrozole 2.5 mg QD
Key Eligibility Criteria
Measurable disease (RECIST 1.0) or bone-only disease
ECOG PS of 0 or 1
Adequate blood counts and organ function
No prior/current brain metastases
Prior AI allowed if >= 12 months since last therapy
a Schedule is 3 weeks on and 1 week off
Primary end-pt: PFS
Secondary end-pt: OS, RR, duration of response, CBR, patient outcomes, pk and safety
About half of pts received prior endocrine therapy and
half received chemotherapy in adjuvant/neo-adj setting
Finn RS, et al. New Eng J Med. 2016

14. PFS 24.8 vs 14.5 months PALOMA-2: Results
Finn RS, et al. New Eng J Med. 2016

15. PALOMA-2: Results
Finn RS, et al. New Eng J Med. 2016

16. PALOMA-2: Side effects
Finn RS, et al. New Eng J Med. 2016

17. PALOMA-2: Side effects
Finn RS, et al. New Eng J Med. 2016

18. Palbociclib dose modifications
Toxicity 
Dose to Restart Palbociclib or Placebo Treatment
Uncomplicated grade 3 neutropenia (ANC <1000) 
Same dose level*
Grade 3 neutropenia (ANC <1000) associated with  documented infection or fever ≥38.5oC 
Reduce by 1 dose level 
Grade 4 neutropenia (ANC <500)
Grade 4 thrombocytopenia (plt count <25,000)
Grade ≥3 nonhematologic toxicity†
*Day 1: Withhold palbociclib therapy, repeat CBCD in 1 week, when improved to ≤ grade 2, initiate the next cycle at the same dose.
Day 15: If grade 3, continue palbociclib therapy at current dose to complete the cycle. Repeat CBCD on day 22. If at grade 4 then resume at next lower dose.
Consider dose reduction in future cycles- if recovery from grade 3 neutropenia is >1 week or recurrent grade 3 neutropenia on day 1 of subsequent cycles
†Includes nausea, vomiting, diarrhea, and hypertension only if persisting despite optimal medical  treatment.

19. Are CDK4/6 inhibitors associated with a OS benefit?
PALOMA-1
Palbociclib + Letrozole= 37.5 mo
Letrozole=33.3 mo
P=0.813
n=66
Palbociclib 125 mg/d* + letrozole 2.5 mg/d
1:1
ER+, HER2− BC
RANDOMIZATION
Letrozole 2.5 mg/d
No OS benefit seen in this small phase 2 trial, but need to await longer term follow-up data from the pivotal phase 3 studies
Finn RS et al, ASCO 2017

20. Placebo (3 wks on/ 1wk off)
PALOMA-3: Study Design
Palbociclib
(125 mg QD; 3 wks on/1 wk off)
+ Fulvestrant† (500 mg IM q4w)
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
*All received goserelin.
n=347
2:1 Randomization
N=521
Stratification:
Placebo (3 wks on/ 1wk off)
+ Fulvestrant† (500 mg IM q4w)
Visceral metastases
Sensitivity to prior hormonal therapy
Pre-/peri- vs Post- menopausal
PIK3CA mutation
n=174
Post-menopausal patients must have progressed on prior aromatase inhibitor therapy.
†administered on Days 1 and 15 of Cycle 1.
Cristofanilli et al. Lancet 2016

21. PALOMA-3: Fulvestrant +/- palbociclib
Cristofanilli et al. Lancet 2016

22. Monaleesa-2: Ribociclib
Ribociclib 600 mg QDa + Letrozole 2.5 mg QD
Phase III, HR+, HER2– ABC
Post-menopausal
No prior therapy for ABC
Previous neo/adjuvant NSAI not allowed unless DFI > 12 months
Exclusion: Inflammatory cancer, brain mets and cardiac disease including increased QTc
N=668
Stratification:
Disease site- liver or lung mets
Placebo +
Letrozole 2.5 mg QD
Primary endpoints: PFS
Secondary endpoint: OS, RR, CBR, QOL assessments and safety
a Schedule is 3 weeks on and 1 week off
Hortobaygi et al. New Engl J Med 2016

23. Monaleesa-2: Patient characteristics
Hortobaygi et al. New Engl J Med 2016

24. Kaplan–Meier Analysis of Progression-free Survival.
After 18 months, the PFS was 63% in the ribociclib group and 42% in the placebo
The median PFS not reached in the ribociclib group, 14.7 mon in the placebo group
Hortobaygi et al. New Engl J Med 2016

25. Subgroup Analysis of Progression-free Survival.
Figure 2. Subgroup Analysis of Progression-free Survival. The progression-free survival benefit in the ribociclib group (as assessed by investigators) was observed across all predefined subgroups (overall hazard ratio, 0.56; 95% CI, 0.43 to 0.72; P<3.29×10−6 for superiority) (dashed line). Among the patients who had received previous endocrine therapy, those taking nonsteroidal aromatase inhibitors (NSAIs) or other therapies not listed here had not received tamoxifen. Previous endocrine therapy and chemotherapy include neoadjuvant and adjuvant treatment. The size of the data points is proportional to the number of patients included in the subgroup analysis. ECOG denotes Eastern Cooperative Oncology Group.
Hortobaygi et al. New Engl J Med 2016

26. Adverse Events.
Monaleesa-2: AEs
Hortobaygi et al. New Engl J Med 2016

27. Monaleesa-2: AEs Adverse Events. Hortobaygi et al. New Engl J Med 2016
11 patients (3.3%) had at least one average QTcF interval of more than 480 msec after baseline, most were able to continue at the 600-mg dose of ribociclib without interruption.
Hortobaygi et al. New Engl J Med 2016

28. MONARCH 1: A Phase II Study of Abemaciclib in Refractory HR+/HER2- Metastatic Breast Cancer
Patients: N= 132, median 3 lines of Rx
90% visceral dz, 50% >3 mets
Results: ORR = 20%, CBR 42%
PFS 6 mon, OS 18 mon
A. The best percentage of change in
tumor size from baseline is plotted
for each patient who had an available
assessment
B. Time on treatment with abemaciclib
is plotted for each patient treated in
the MONARCH 1 study (N = 132).
A, The best percentage of change in tumor size from baseline is plotted for each patient who had an available assessment B. Time on treatment with abemaciclib is plotted for each patient treated in the MONARCH 1 study (N = 132). The colors in A and B represent response status per RECIST v1.1 and each bar in A and B represents one patient.
Maura N. Dickler et al. Clin Cancer Res 2017;23:

29. Monarch-3: Abemaciclib
Abemaciclib 150 mg BID + Letrozole 2.5 mg QD
Phase III, HR+, HER2– ABC
Post-menopausal
No prior therapy for ABC
Previous neo/adjuvant ET allowed if DFI > 12 months
Exclusion: Inflammatory cancer, brain mets and
2:1 Randomization
N=493
Stratification:
Disease site and prior endocrine therapy
Placebo +
Letrozole 2.5 mg QD
Primary endpoints: PFS
Secondary endpoint: OS, RR, CBR, duration of response, tolerability and safety
Goetz et al. J Clin Oncol 2017

30. Monarch-3: Results
Goetz et al. J Clin Oncol 2017

31. Abemaciclib: Side effects

32. MONARCH 2: Abemaciclib/Fulvestrant
J Clin Oncol 2017;35(25):

33. MONARCH 2: PFS with Abemaciclib/Fulvestrant After Disease Progression on Prior ET
Objective response rate: Abemaciclib arm 48.1%; placebo arm 21.3%
Sledge G et al. J Clin Oncol 2017

34. Impact of CDK 4/6 inhibition on PFS
1st Line Trials
2nd Line Trials
PALOMA-1
PALOMA-2
MONALEESA-2
MONARCH 3
PALOMA-3
MONARCH 2
Design
Ph 2
1st Line
Ph 3
2nd Line
Endocrine partner
Letrozole
Letrozole or Anastrozole
Fulvestrant
CDK 4/6 inhibitor
Palbociclib
Ribociclib
Abemaciclib
Patients on study, n
165
666
668
493
521
669 HR
0.49
0.58
0.56
0.54
0.46
0.55
PFS (months)
20.2 vs 10.2
24.8 vs 14.5
25.3 vs 16
NR vs 14.7
9.5 vs 4.6
16.4 vs 9.3
ORR
56% vs 39%
55.3% vs 44.4%
52.7% vs 37.1%
59% vs 44%
25% vs 11%
48.1% vs 21.3%
Finn RS et al, Lancet Oncology 2015
Finn RS et al, NEJM 2016
Hortobagyi GN et al, NEJM 2016
Goetz MP et al, J Clin Oncol 2017
Cristofanelli M et al, The Lancet 2016
Sledge GW et al, J Clin Oncol 2017
Very Different Patient Populations
Any # prior endocrine tx
1 prior chemo allowed
Only 1 prior endocrine tx
No prior chemo allowed

35. Differences among the three CDK 4/6 Inhibitors
Palbociclib
Abemaciclib
Ribociclib
IC50
CDK 4: 9-11 mM
CDK 6: 15 mM
CDK 4: 2 mM
CDK 6: 5 mM
CDK 4: 11 mM
CDK 6: 39 mM
Dosing
125 mg daily
(3 weeks on, 1 week off)
150 mg twice daily
(continuous) with endocrine therapy
OR 200 mg po bid
600 mg daily
ORR in monotherapy* 6%
9.5%/20% 3%
CNS penetration No
Yes
Common adverse events (%)*
All grades
Grade 3/4
Neutropenia 95 54 88 27 46 29
Thrombocytopenia 76 19 42 2 37 10
Fatigue 68 65 13 3
Diarrhea 16 90 20 22
Nausea 23 5
Vomiting 35 25
QTc prolongation NR 8
CDK, cyclin-dependent kinase; HR, hormone receptor; IC50, half-maximal inhibitory concentration; NR, not reported; ORR, objective response rate; QTc, corrected QT interval.
*The single-agent activity and common adverse events shown in this table are those reported n [23, 29, 14] for palbociclib, abemaciclib, and ribociclib, respectively.
Adapted from: Barroso-Sousa et al, Breast Care 2016;11:

36. Is there a role for continuing CDK4/6 inhibition beyond progression?
TRINITI-1
PACE Trial
n = 180 R A N D O M I Z T
MBC HR+/HER2−
Progression on aromatase inhibitor + CDK4/6 inhibitor
0-1 prior chemo
1:2:1 randomization
Arm C: Fulvestrant + avelumab + palbociclib
Arm A: Fulvestrant -> palbociclib alone at time of progressive disease
Arm B: Fulvestrant + up-front palbociclib
Randomization 1:1
Ribociclib + Everolimus + Exemestane
Everolimus + Exemestane
Men and premenopausal and postmenopausal women with
HR+ HER2− ABC
Refractory to either AI, tamoxifen or fulvestrant
BYLieve Trial
Alpelisib 300 mg + fulvestrant 500 mg (n≈80)
Patients received prior CDK4/6i + AI†
Men or postmenopausal women with HR+, HER2– ABC (N=160)
PIK3CA mutation in tumor tissue*
Last line of prior therapy: CDK4/6i + an AI or fulvestrant in the first- or second-line metastatic setting
Alpelisib 300 mg + letrozole 2.5 mg (n≈80)
Patients received prior CDK4/6i + fulvestrant

37. TREnd: Phase II Trial Design
Palbociclib 125 mg/d 3 wk on/1 wk off (n = 57)
Eligibility
Postmenopausal ER+, HER2- mBC
Pretreatement with 1 or 2 lines of ET for mBC
1 prior line of chemotherapy for mBC permitted R
Palbociclib 125 mg/d 3 wk on/1 wk off +
Same ET as preprogression (aromatase inhibitor or fulvestrant) (n = 58)
N = 115
67% of pts had the study treatment as second-line ET, 33% as third line, and 1/3 of pts received 1 prior line of chemotherapy for mBC.
Primary endpoint: Clinical benefit rate (CBR). The inactivity cutoff was CBR ≤20%; the activity cutoff was CBR ≥40%.
Secondary endpoints include PFS, safety
Malorni L et al. Proc ASCO 2017;Abstract 1002.

38. TREnd: Primary Endpoint CBR
Response
P + ET (n = 57)
P (n = 58)
CBR
31 (54%)
35 (60%)
Complete response
0 (0%)
Partial response
6 (10%)
4 (7%)
Stable disease ≥24 weeks
25 (44%)
31 (53%)
Malorni L et al. Proc ASCO 2017;Abstract 1002.

39. TREnd: Median PFS Patient group P + ET P HR, p-value All patients
10.8 mo
6.5 mo
0.69, p = 0.12
Prior ET ≤ 6 months
(n = 10, 20)
3.2 mo
6 mo
1.6, p = 0.33
Prior ET > 6 months
(n = 46, 38)
11.5 mo
0.53, p = 0.02
Malorni L et al. Proc ASCO 2017;Abstract 1002.

40. Exemestane + Everolimus: BOLERO-2
Phase III, randomized, double blind, international trial, N = 724
Patients that recurred or progressed during/after nonsteroidal aromatase inhibitors  exemestane +/- everolimus
PFS: 6.9 months vs 2.8 months (HR= 0.48; p< 0.001) , ORR 9.5 vs 0.4 percent
OS data: 31 months vs 26.6 months (HR= 0.89; p= 0.14)
Post-study therapies were balanced across arms, except for chemotherapy (53% vs 63% in placebo arm)
AEs, grade 3/4: stomatitis (8%), dyspnea (4 %), noninfectious pneumonitis (3%), hyperglycemia (4%) & elevated liver enzymes (3 %)
Baselga et al. New Engl J Med. 2012
Piccart et al. Ann Oncol. 2014

41. Swish trial: Single arm, phase II
10 mL of alcohol-free dexamethasone 0·5 mg per 5 mL oral solution to swish for 2 min and spit four times daily for 8 weeks.
Rugo et al. Lancet 2017.

42. BELLE-3 Trial Schema R Primary endpoint: PFS
Postmenopausal women with HR+/HER2-, AI-pretreated, locally advanced or metastatic breast cancer
Progression on or after an mTOR inhibitor as last line of treatment
N = 432
Buparlisib (100 mg/day) + fulvestrant (500 mg) n = 289
2:1 R
Placebo + fulvestrant (500 mg) n = 143
Stratified by visceral disease status
Primary endpoint: PFS
Di Leo A et al. Lancet Oncol 2018.

43. BELLE-3: Progression-Free Survival by PIK3CA Status
PIK3CA status assessed in primary tumor tissue by PCR (n = 321)
Mutant
Wild type
Tissue (mutant)
Buparlisib + fulvestrant
Placebo + fulvestrant
Median PFS, months
4.7
1.4
HR 0.39; p < 0.001
Tissue (WT)
Buparlisib + fulvestrant
Placebo + fulvestrant
Median PFS, months
2.8
2.7
HR 0.83; p = 0.117
Probability of PFS, %
Di Leo A et al. Lancet Oncol 2018. .

44. BELLE-3: Adverse Events
Buparlisib + fulvestrant (n = 288)
Placebo + fulvestrant (n = 140)
Adverse event, %
All grades
Grade 3/4
Total 98 62 91 34
ALT increased 39 22 7 3
AST increased 37 18 10
Hyperglycemia 36 12
Nausea 1 2
Diarrhea 26 9
Fatigue 23 4 19
Depression 21 8
Anxiety
Di Leo A et al. Lancet Oncol 2018

45. Parp Inhibitors

46. OlympiAD: Phase III Trial Design
Olaparib 300 mg tablets BID
HER2-negative mBC
ER+ and/or PR+ or triple-negative
Deleterious or suspected deleterious germline BRCA mutation
Prior anthracycline and taxane
≤2 prior chemotherapy lines in metastatic setting
HR+ disease progression on ≥1 endocrine therapy, or not suitable for ET
If prior platinum use:
No evidence of progression during treatment in the advanced setting
≥12 months since (neo)adjuvant treatment
2:1 randomization R
Standard therapy
Capecitabine
Eribulin
Vinorelbine
Primary endpoint: Progression-free survival (PFS) by blinded independent central review (BICR)
Secondary endpoints include time to second disease progression or death (PFS2), overall survival, objective response rate (ORR)
Robson M et al. N Engl J Med 2017

47. OlympiAD: PFS with Olaparib vs Standard Therapy
Median overall survival: No significant difference between arms (HR 0.9, p = 0.57)
ORR: olaparib (n = 167): 59.9%, standard therapy (n = 66): 28.8%
Robson M et al. N Engl J Med 2017;377(6):
Delaloge S et al. Proc ESMO 2017;Abstract 243PD.

48. OlympiAD: Grade ≥3 Adverse Events
Olaparib
(n = 205)
Standard therapy
(n = 91)
Anemia
16% 4%
Neutropenia 9%
26%
Decreased white blood cells 3%
10%
Fatigue 1%
Leukopenia 2%
Decreased platelet count
Increased AST
Dyspnea
Headache
Hand-foot syndrome
Robson M et al. N Engl J Med 2017.

49. ABRAZO: Phase II Trial Design
Cohort 1
Partial or complete response to last platinum-containing regimen for metastatic disease, with disease progression >8 weeks after last dose of platinum
Eligibility
Measurable advanced breast cancer with BRCA1/2 mutation
CNS metastases allowed if stable after local therapy
HER2-positive breast cancer permitted if refractory to HER2-targeted therapy
Cohort 2
≥3 prior cytotoxic regimens for metastatic disease; no prior platinum for metastatic disease
Stage 1
Patients in both cohorts (n = 35 in each) received TALA 1 mg/day orally
Median number of prior cytotoxic regimens administered for advanced disease was 2 in cohort 1 and 4 in cohort 2
Primary endpoint: Objective response rate (ORR) by central independent radiology facility (IRF)
Secondary endpoints include duration of response, progression-free survival (PFS), overall survival (OS), safety
Turner NC et al. Proc ASCO 2017;Abstract 1007.

50. ABRAZO: Primary Endpoint ORR
Cohort 1 Prior platinum (n = 48)
Cohort 2 ≥3 prior lines, no prior platinum (n = 35)
Total (n = 83)
Objective response rate, % 21 37 28
Best overall response, % (no.)
Complete response
4 (2)
2 (2)
Partial response
17 (8)
37 (13)
25 (21)
Stable disease
38 (18)
51 (18)
43 (36)
Progressive disease
11 (4)
27 (22)
Not evaluable
Turner NC et al. Proc ASCO 2017;Abstract 1007.

51. ≥3 prior lines, no prior platinum
ABRAZO: PFS and OS
Cohort 1
Prior platinum
(n = 49)
Cohort 2
≥3 prior lines, no prior platinum
(n = 35)
Median PFS
4.0 mo
5.6 mo
Median OS
12.7 mo
14.7 mo
Turner NC et al. Proc ASCO 2017;Abstract 1007.

52. ABRAZO: Grade ≥3 Adverse Events
Cohort 1
Prior platinum
(n = 48)
Cohort 2
≥3 prior lines, no prior platinum
(n = 35) G3 G4
Anemia
33.3
37.1
Thrombocytopenia
16.7
4.2
11.4
5.7
Neutropenia
12.5
17.1
Leukopenia
2.1
Platelet count decrease
6.3
2.9
Fatigue
Nausea
Diarrhea
Dyspnea
Pleural effusion
Turner NC et al. Proc ASCO 2017;Abstract 1007.

53. Future Directions: HR+ subset
PI3K inhibitors:
- Phase III trials with specific PI3K inhibitor alpelisib with fuvestrant ongoing
Selective estrogen receptor degraders:
- Phase I trials with RAD1901 (ESR mutations)
- GDC-0810, novel SERD that degrades ESR mutant receptors
HDAC inhibitiors:
- Exemestane +/- Entinostat ongoing in HR+ MBC who have progressed on NSAI
CDK 4/6 inhibitors:
- being tested in Her-2 pos MBC & in (neo)adjuvant settings
- combinations with PI3K inhibitors, PD-1 inhibitors and mTOR inhibitors

54. Phase II Trial Schema of ET +/- Radium-223 Dichloride
Trial Identifier: NCT
Target Accrual: 227
Eligibility
Confirmed ER+/HER2- bone- dominant MBC (soft tissue metastases allowed)
≥2 bone metastases
1-2 prior SREs
≥1 prior hormonal tx for MBC
Eligible for hormonal tx
Study treatment
Active follow-up
Radium kBq/kg IV q4wk x 6 + best standard of care hormonal tx + BP or denosumab
With clinic visits
q4wk ± 7 d*
q12wk ± 7 d† R
Placebo (saline) q4wk x 6 + best standard of care hormonal tx + BP or denosumab
Without clinic visits
Phone calls q4wk ± 7 d*
Phone calls q12wk ± 7 d†
1:1
SREs = skeletal-related events; BP = bisphosphonate
* For patients not experiencing symptomatic skeletal event
† For patients who have experienced a symptomatic skeletal event
Primary endpoint: Symptomatic skeletal event-free survival
Coleman RE et al. San Antonio Breast Cancer Symposium 2016;Abstract OT

55. Role of breast surgery in MBC
About 3-4% pts present with metastatic disease
Stage IV pts: 5-10% have 5 year survival or longer and 2-5 % are long term survivors
Breast tumor resection indicated for palliation
Retrospective studies show survival benefit: surgery vs no surgery, 3-year OS 40% vs 22% (selection bias??)
Turkish and Indian trials presented at SABCS 2014 showed no survival benefit with resection of primary tumor
RCT: ECOG 2108 currently underway to address this question