1. Her-2 negative MBC
10/25/2016

2. Objectives General principles
Endocrine agents for HR+ pts- sequencing/combinations
Addition of biological agents
Clinical scenarios
Triple negative subsets
AR positive disease
PARP inhibitors in BRCA mutations
Immunotherapy

3. General principles ER/PR positive, Her2 negative:
- symptomatic visceral dz/rapidly progressing:
chemo (1-2 drugs) for 4-6 months  change to AET
- asymptomatic, low volume, indolent dz:
AET  if response duration < 6 months  change to chemo
Triple negative: single agent or doublet based on tumor burden and need for rapid response
Triple positive: Her-2 trumps ER, anti-her therapy incorporated with rest of the regimen

4. 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

5. FIRST trial: 1st line Fulvestrant Vs Anastrozole
Phase II trial: N = 205, prior adj endocrine Rx completed 12 months prior to randomization (~25% pts had received AET in both arms), Fulvestrant dosing 500 mg
CBR: 73% vs 67% (p = .386) and ORR: 36 % and 35.5%
Median TTP: 23 vs 13 months (HR = 0.66, P = .01)
Median OS: 54 vs 48 months (HR = 0.70, P = .041), OS data colletion not pre-planned
Serious AEs were similar between fulvestrant (23.8%) and anastrozole (21.4%)
FALCON: phase III trial with similar trial design, completed accrual.
Robertson et al. J Clin Oncol. 2009
Ellis et al. J Clin Oncol. 2015

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 R
Fulvestrant
N =230
Primary endpoints: PFS
Secondary endpoint: OS, RR, CBR, duration of response, safety/QOL

7. FALCON: Results
Patients: Median age 63-64yrs, 87% metastatic disease, about 50% pts with visceral disease in both arms
PFS: 16 mon vs 13 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)
Ellis et al. presented at ESMO 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-1: Phase 2 Study of ER+, HER2– Locally Recurrent or Metastatic Breast Cancer
N=66
1:1
Part 1
Post- menopausal
ER+, HER2– BC status
No prior treatment for advanced disease R A N D O M I Z T
Palbociclib 125 mg QDa + Letrozole 2.5 mg QD
Letrozole 2.5 mg QD
Part 2
N=99
ER+, HER2– BC with CCND1 amplification and/or loss of p16
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
a Schedule is 3 weeks on and 1 week off
- About a third of pts received prior endocrine therapy and half received chemotherapy in adjuvant setting (12 month washout from endocrine therapy required)

14. Dose: 125 mg PO QD x 21 days, every 28 days Response rate: 36% vs 27%
PALOMA-1: Results
Dose: 125 mg PO QD x 21 days, every 28 days
Response rate: 36% vs 27%
Median PFS: 20 vs 10 months (p = )
Median OS: 37.5 vs 33 months (p = 0.42)
Unselected
(PFS 26 vs 6 mo)
Cyclin D amp
and/or P16 loss
(PFS 18 vs 11 mo)
Overall Survival
Finn RS, et al. Lancet Oncology. 2015

15. Palbociclib: Toxicity
Treatment
Palbo + LET
LET alone
Grade
1–2 3 4
Neutropenia
17 (20%)
40 (48%)
5 (6%)
3 (4%)
1 (1%)
Leucopenia
20 (24%)
16 (19%)
2 (3%)
Fatigue
30 (36%)
2 (2%)
17 (22%)
Anemia
24 (29%)
4 (5%)
Nausea
19 (23%)
9 (12%)
Arthralgia
18 (22%)
10 (13%)
Alopecia NA
Diarrhea
14 (17%)
8 (10%)
Hot flush
17 (21%)
Thrombocytopenia
12 (14%)
Decreased appetite
Dyspnea
11 (13%)
Nasopharyngitis
13 (16%)

16. PALOMA-2: Phase III confirmation
Palbociclib 125 mg QDa + Letrozole 2.5 mg QD
2:1 Randomization
HR+, HER2– ABC
Post-menopausal
No prior therapy for ABC
N=666
Stratification:
Disease site
Prior hormonal therapy
DFI from end of neo/adjuvant therapy
Placebo +
Letrozole 2.5 mg QD
Primary endpoints: PFS
Secondary endpoint: OS, RR, CBR, patient reported outcomes and safety
a Schedule is 3 weeks on and 1 week off
Finn et al. ASCO 2016

17. PALOMA-2: Results
Median PFS vs 14.5 months (HR 0.58, p < )
OS data is immature
ORR - 42% vs 35% ( p = 0.031)
CBR - 85% vs 70% (p < )
AEs: Neutropenia (80% vs 6%)
Fatigue (37% vs 27%)
Nausea (35% vs 26%)
Arthralgias (33% both)
Alopecia (33% vs 16%)
Finn et al. ASCO 2016

18. 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
n=174
Post-menopausal patients must have progressed on prior aromatase inhibitor therapy.
†administered on Days 1 and 15 of Cycle 1.
Turner et al. New Engl J Med. 2015

19. PALOMA-3: Fulvestrant +/- palbociclib
Turner et al. New Engl J Med. 2015

20. Monaleesa-2: Ribociclib
Ribociclib 600 mg QDa + Letrozole 2.5 mg QD
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=223
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

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

22. 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

23. 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

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

25. Abemaciclib: 150mg or 200mg orally Q12H Days 1-28 of a 28-day cycle

26. Differences between CDK4/6 inhibitors
Neutropenia (%)
Fatigue
(%)
Nausea
Diarrhea
QTc prolongation (%)
G3/4
All
Palbociclib 54 73 2 24 16 4 21 NR
Abemaciclib 19 40 43 57 6 68
Ribociclib 29 46 3 22 8%
Abemaciclib has CNS penetration
Abemaciclib had higher monotherapy response rate
Abemaciclib is continuous daily dosing, others are 3wks on/1 wk off

27. 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: 7.8 months vs 3.2 months, ORR 9.5 vs 0.4 percent
OS data: 31 months vs 26.6 months (HR= 0.89; p= 0.14)
Poststudy 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%), and elevated liver enzymes (3 %)
Baselga et al. New Engl J Med. 2012

28. Future Directions: HR+ subset
PI3K inhibitors:
- Belle-2 trial: N = 1147, progressed on AI, Fulvestrant +/- Buparlisib
- PFS 6.9 vs 5 mo(HR 0.78, p< 0.001)
- PI3K mutation by ctDNA- PFS 7 vs 3.2 mo (HR 0.56, p< 0.001)
- AEs: deranged LFTs, fatigue, rash, diarrhea, hyperglcemia (gr 3/4 events in 77%)
- Phase III trials with more specific PI3K inhibitor alpelisib with fuvestrant ongoing
Selective estrogen receptor degraders:
- Phase I trials with RAD1901 which can bind to ER and degrade it (ESR mutations)
HDAC inhibitiors:
- Exemestane +/- Entinostat ongoing in HR+ MBC who have progressed on NSAI
CDK 4/6 inhibitors:
- being tested in Her-2 positive MBC & in adjuvant as well as neoadjuvant settings
- combinations with PI3K inhibitors and mTOR inhibitors being studied

29. Clinical cases

30. TNBC: Molecularly Heterogeneous
Name
Characteristic gene expression
“LAR”, luminal AR
AR, ER (no ER by IHC), prolactin, HER4
“MES”, mesenchymal
Cell cycle, damage response, growth factor
“BLIS”, basal-like immunosuppressed
Basal-like, ↓T-, B-, NK-cell and cytokine pathways
“BLIA”, basal-like immune activated
Basal-like, ↑immunoregulatory pathways, STAT
Overlap with PAM50
Some overlap with “TNBCtype”
All characterized by basal, immune, and stromal signatures
Burstein MD et al. Clin Cancer Res 2015

31. Sequencing chemotherapy in TNBC
Anthracyclines
Taxanes: nab-paclitaxel
Platinum based (single agent or combo with gem/taxane)
Eribulin
Capecitabine +/- Ixabepilone
Oral Cytoxan + MTX
Irinotecan
Others- vinorelbine, pemetrexed

32. Targeting AR in TNBC MDV3100-11 Background
Phase II study of bicalutamide in 26 patients with AR+ TNBC: CBR 19%, mPFS 12 weeks
Enzalutamide > bicalutamide in mCRPC
Endpoints:
1°:
2°:
PFS, OS etc
AR biomarker
MDV
AR+ mTNBC
Any prior Rx
Enzalutamide 160 mg/d po
165 screened patients
89 AR > 10%
75 evaluable
61% 1st /2nd line
Endpoint
CBR16
35% (24-46%)
CBR24
29% (20-41%) RR 8%
Median PFS
14 wks (8-19)
Traina et al. ASCO 2015 32

33. PREDICT AR− PREDICT AR+
Biomarker to predict sensitivity to Enzalutamide in TNBC: multigene RNA based assay 64
PREDICT AR− 8 16 24 32 40 52
Time (weeks)
PREDICT AR+
Total, n (%)
62 (53%)
56 (47%)
CBR16, %
(95% CI) n
11%
(5, 21)
n = 7
39%
(27, 53)
n = 22
CBR24, % 6%
(2, 16)
n = 4
36%
(24, 49)
n = 20
0–1 Prior Lines
2+ Prior Lines
Active
Confirmed RR
PREDICT AR+ 8 16 24 32 40 52 64
Time (weeks)
Parker JS et al. ASCO 2015

34. PARP Inhibitors
Phase II trial in metastatic triple negative patients - Iniparib
N = 123, carbo+gem +/- inaparib
CBR 34% to 56% (P=0.01) , ORR 32% to 52% (P=0.02)
PFS 3.6 months to 5.9 months (HR 0.59; P=0.01)
OS 7.7 months to 12.3 months (HR 0.57; P=0.01)
No significant difference was seen between the two groups in the rate of adverse events
Phase III trial with 519 pts, no improvement in PFS or OS, exploratory analysis showed PFS and OS benefit in 2nd/3rd line settings which need to be explored further
Olaparib and Veliparib investigated in BRCA mutated patients
Shaughnessy et al. New Eng J Med. 2011
Shaughnessy et al. J Clin Oncol. 2014

35. Parp Inhibitors

36. Phase II single arm trial Eligible: gBRCA carriers, heavily pretreated
4th+ line breast
Platinum-refractory ovarian
Gemcitabine-resistant pancreatic
Hormone refractory, 2nd+ line prostate
Olaparib 400 mg bid
N=298 evaluable for 1° (RR) - Mostly ovarian
62 breast cancer patients
60% BRCA1
30 ER+, 32 ER-
Kaufman B et al. J Clin Oncol. 2015

37. Olaparib in gBRCA+ Tumors: Results
Ovarian
(n=193)
Breast
(n=62)
Pancreas
(n=23)
Prostate
(n=8)
Other
(n=12)
Total
(n=298) RR
31%
13%
22%
50% 8%
26%
Prior platinum -
4 (9%)
3 (20%)
1 (25%)
1 (11%) NR
Naive
4 (20%)
2 (25%)
3 (75%)
0 (0%)
No difference BRCA1, 2
Gr3+ AE > 5%:
Fatigue (6%), anemia (17%), Abd pain (6%)
Breast cancer:
RR: ER + 12%, ER- 13%
6month PFS 29%
Median PFS 3.7 months, OS 11 months
Kaufman B et al. J Clin Oncol. 2015

38. Immunotherapy
SABCS 2014
A Phase Ib Study of Pembrolizumab (MK-3475) in Patients With Advanced Triple-Negative Breast Cancer
SABCS 2015
Avelumab (MSB C), an anti-PD-L1 antibody, in patients with locally advanced or metastatic breast cancer: a phase Ib JAVELIN Solid Tumor trial
ASCO 2016
Phase Ib trial of atezolizumab in combination with nab-paclitaxel in patients with metastatic triple-negative breast cancer
Nanda R et al. SABCS 2014
Dirix L et al. SABCS 2015
Adams et al. ASCO 2016

39. Keynote-012: Pembrolizumab in TNBC
Phase Ib trial: N= 32, 65/111 (58.6%) had PD-L1+ tumors
ORR in 5/27 evaluable = 18.5%, 3 responders remain on Rx for ≥ 1 yr
Median time to response 18 weeks, median duration of SD was 17 weeks (7-32 wks), median PFS 1.9 months
Any AE = 56%, grade 3+ = 16%
Nanda et al, JCO; 34: 2016

40. Keynote-012: Pembrolizumab in TNBC
Nanda et al. J Clin Oncol. 2016

41. Keynote-012: Take home points
Pembrolizumab is effective and relatively tolerable, time to response was long ~4 months but responding pts had durability
RR may have been affected by heavily pre-treated population and pts with high proliferative index as evidenced by LDH
Higher dosing may have caused more toxicity and the more conventional dosing at 200 mg every 3 weeks may be better tolerated
Small sample size limits definitive conclusions about efficacy
Phase II and III trials are underway

42. Avelumab Phase Ib (10mg/kg q2wk)
Endpoint
All (n=168)
TNBC (n=58)
ORR
5% (2-9%)
9% (3-19%)
RR + SD
28%
31%
Grade 3+ AE
14% (all grade AE 68.5%)
Any AE ≥ 10%
Fatigue (19%), infusion rxn (14%), nausea (13%), immune (10%)
Time to response 11wks (6-18)
Duration of response 28 wks (6-NE)
33% RR in PDL1+
> 10% immune cell hotspots
Dirix L et al. SABCS 2015

43. Atezolizumab in TNBC Toxicity Overall well tolerated
Phase Ib expansion trial
21 PD-L1 positive enrolled, 19% ORR
24 week PFS 27%
Toxicity
Overall well tolerated
Toxicities- thyroid disorders, colitis, hepatitis, aseptic meningitis, DIC
Emens L, et al. AACR 2015 Abstract 2859

44. Atezolizumab + nab-Paclitaxel in TNBC: Phase Ib Trial
Nab-paclitaxel 125 mg/m2 weekly, 3 weeks on, one week off with atezolizumab every 2 weeks; < 3 prior lines of Rx
32 evaluable patients; response independent of PD-L1+
Adams et al, J Clin Oncol 34, 2016 (suppl; abstr 1009)

45. Case
52 y/o female with stage IIB TNBC, BRCA neg, underwent neo-adjuvant chemotherapy with AC->T, mastectomy, AND, adjuvant radiation therapy.
She was found to have chest wall nodules at the time of reconstruction a year later, scan suggested mets to nodal station in chest/abd and bones. She underwent therapy with carbo-gem with response lasting 8 months.
She refused immunotherapy clinical trial participation. She has decent PS and wants to continue therapy, would you send multiplex genomic assay?

46. Summary TNBC molecular heterogeneity is a challenge.
Unlike ER+ and HER2+, “TNBC” does not describe anything targetable.
Promising non-chemotherapy options- Immune checkpoint inhibitors, AR-targeted drugs, and PARP inhibition.
However in all cases only a subset benefit.
Good predictive biomarkers will be as important as good drugs.