Hormone receptor positive breast cancers and others novel developments in management and therapy

1. Hormonal and novel therapy
in metastatic breast cancer
Dr Ajeet Kr Gandhi
MD (AIIMS), DNB, UICCF (MSKCC,USA)
Assistant professor, Radiation oncology
Dr Ram Manohar Lohia Institute of Medical Sciences, Lucknow

2. A constant evolution, several mutations in ESR1 have been
identified
Different sub-clones exist within the primary tumour
An increased level of heterogeneity
From tumour evolution standpoint intuitive concept—prolonged
endocrine therapy will exert selection pressure on the cancer
Resistant Clones present from begining: This hypothesis is based on
the newer insights into tumour heterogeneity and the so-called theory
of ‘branched evolution
Prevalence of the resistant populations
Newer concepts: A continuous Evolution

3. Fulvetrant Anastrozole
TTP 23.4 13.1
OS 54.1 48.4

4. Mehta et al, NEJM,2012

10. Fulvestrant plus anastrozole or placebo versus exemestane alone after
progression on non-steroidal aromatase inhibitors in postmenopausal
patients with hormone-receptor-positive locally advanced or metastatic
breast cancer (SoFEA): a composite, multicentre, phase 3 randomised trial
Aim: assess a maximum double endocrine targeting approach with the steroidal anti-
oestrogen fulvestrant in combination with continued oestrogen deprivation
Post menopausal HR+
NSAI failure
WHO 0-2
CBC/LFT/KFT
R
A
N
D
O
M
I
Z
A
T
I
O
N
Fulvestrant+Anastrozole (243)
Fulvestrant+Placebo (231)
Exemestane (249)

11. Result of SoFEA Trial

12. Result of SoFEA Trial

13. 13
Aim: To eradicate or control resistant clones from the
beginning

14. 14
Upfront use of
mTOR inhibitor
Failed to improve
survival
Response: LET only
:27%
compared to
BOLERO2 0.4%

15. 15
Hormonal Management- At
recurrence ER/PR+/-, Her2neu3+
Trial Regimen n Median PFS (months)
HT alone HT+ Anti Her2
TAnDEM
(2009)
ANA+/- Trastuzumab 208 2.4 4.8
EGF 30008
(2009)
Let+/- Lapatinib 219 3.0 8.2
eLEcTRA Let+/-Trastuzumab 92 3.3 14.1

16. Hormone Resistance
 Intrinsic—resistance occurs de novo at the initial exposure
to endocrine therapy
 Relapse while on the first 2 years of adjuvant
 PD within 6 months of starting first-line endocrine therapy
 Acquired—resistance manifests over time after an initial
response to endocrine therapy
 After the first 2 years,
 Relapse within 12 months of completing such therapy
 PD at ≥6 months after initiating endocrine therapy for MBC
16

17. Resistance to hormonal drugs
17

18. 18
Overcoming hormone resistance

19. Need of targeted Agents
 Survival has reached Plateau with Chemotherapy
 Possibility of reducing toxicity with selectively blocking cell signaling
pathway
 Possibility of modulating the tumor biology and improving the disease
control
Better understanding
of biology
19

20. Targeted signaling
 EGFR pathway
 Ras-Raf-MapK pathway
 PI3K-mTOR pathway
 Met mutation
 BRAF mutation
 Sonic hedgehog pathway
 Wnt pathway
20

21. 21

22. 22
Study design- BoleroII
R
A
N
D
O
M
I
Z
A
T
I
O
N
•multicenter,
•open-label
•phase III study
•N=724
•Randomizatio
n2:1 ratio
Exemestane 25 mg OD
+Placebo 20 mg/d
Exemestane 25 mg OD +
everolimus 10 mg/d.
March 2008 and May 2009,
• The primary end point PFS
• Secondary end points: overall survival, overall
response
rate, clinical benefit rate, time to deterioration
of ECOG performance status, safety, and quality of life
• At least one measurable
lesion or mainly lytic bone
lesions in the absence of
measurable disease
• Exclusion criteria included
a history of brain
metastases and previous
treatment with
exemestane or mTOR
inhibitors

23. BOLERO-2 Met Primary Endpoint: Final PFS Analysis (18-mo)
Based on Local Assessment Demonstrated a 4.6-mo
Prolongation of PFS
1.0
0.8
0.6
Probabilityof
Progression-FreeSurvival
0.4
0.2
0
2826242220181614
Time, months
121086420
0
0
1
0
4
0
10
1
13
1
23
2
42
6
57
9
99
17
147
27
194
42
236
61
318
103
394
146
485
239
EVE+EXE
PBO+EXE
No. at risk
HR = 0.45 (95% CI, 0.38-0.54)
Log-rank P < .0001
Kaplan-Meier medians
EVE+EXE: 7.8 months
PBO+EXE: 3.2 months
Censoring times
EVE+EXE (n/N = 310/485)
PBO+EXE (n/N = 200/239)
Abbreviations: CI, confidence interval; EVE, everolimus; EXE, exemestane; HR, hazard ratio; PBO, placebo; PFS, progression-free survival.
Yardley DA, et al. Adv Ther. 2013;30(10):870-884.

24. BOLERO-2 (39-mo): Final OS Analysis
0
20
40
60
80
100
0 2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 32 34 36 38 40 42 44 46 48 50
ProbabilityofOverallSurvival
Time, months
EVE+EXE (n/N = 267/485)
PBO+EXE (n/N = 143/239)
232
109
248
113
266
120
279
130
292
145
311
153
330
162
347
170
373
182
399
194
414
201
429
211
448
220
471
232
485
239
EVE+EXE
PBO+EXE
No. at risk
HR = 0.89 (95% CI, 0.73-1.10)
Log-rank P = .14
Kaplan-Meier medians
EVE+EXE: 30.98 months
PBO+EXE: 26.55 months
Censoring times
11
5
23
8
39
18
58
28
91
41
118
56
154
77
196
98
216
102
0
0
1
1
• At 39 months’ median follow-up, 410 deaths had occurred (data cutoff date: 03 October 2013)
– 55% deaths (n = 267) in the EVE+EXE arm vs 60% deaths (n = 143) in the PBO+EXE arm
– 13 pts still on treatment

25. BOLERO-2 (39-mo):
Post-study Treatment Anticancer Therapies
Therapy Type
Everolimus + Exemestane
(n = 485), %
Placebo + Exemestane
(n = 239), %
Any posttreatment therapy 84 90
Chemotherapy 53 63
Hormonal therapy 47 44
Targeted therapy 10 11
Radiation therapy 9 11
Surgery 1 1
Immunotherapy <1 0
Other 2 1
10% more patients in placebo arm received chemotherapy compared with the everolimus arm.
Chemotherapy 53 63
Taxane 28 36
Capecitabine 24 28
Anthracyclines 13 15
Cyclophosphamide 9 9
Vinorelbine 7 13
Platinum-based regimens 4 2
Gemcitabine 4 5

26. BOLERO-2 (39-mo): Longer Median Time From
Randomization to First Chemotherapy or Death (Everolimus
Plus Exemestane Arm)
Time From Randomization to
First Chemotherapy or Death
Everolimus +
Exemestane
(n = 485)
Placebo + Exemestane
(n = 239)
Number of events, n (%) 366 (75.5) 192 (80.3)
Chemotherapy 257 (53.0) 150 (62.8)
Death 109 (22.5) 42 (17.6)
Number censored, n (%) 119 (24.5) 47 (19.7)
Discontinued from study 105 (21.6) 45 (18.8)
Ongoing at data cutoffa 14 (2.9) 2 (0.8)
Time from randomization to first chemotherapy or death, months
25th percentile (95% CI) 5.68 (5.03-6.57) 3.06 (2.53-3.48)
Median (95% CI) 11.86 (10.45-13.08) 5.98 (5.09-7.39)
75th percentile (95% CI) 25.10 (22.97-28.06) 14.16 (10.74-18.50)
a Ongoing without any chemotherapy by the cutoff date.

27. BOLERO-2 (39-mo): No New Safety Signals at Final OS
Analysis (Safety Set)
Everolimus +
Exemestane
(n = 482a), %
Placebo +
Exemestane
(n = 238a), %
All deaths 55 60
On-treatment deathsb 5 2
Disease progression as primary cause of death 3 1
AE as primary cause of death 2 <1
Serious AEs 33 16
Suspected to be drug-related 13 2
Grade 3/4 AEs 55 29
Suspected to be drug-related 41 8
AEs leading to discontinuation 29 5
Categories are not mutually exclusive. Patients with multiple events in the same category were counted only once in that category.
Patients with events in more than 1 category were counted once in each of those categories.
aSafety set.
b Deaths occurring >28 days after end of treatment are not included.
Abbreviations: AE, adverse events; OS, overall survival.

28. Overall Survival in Patients With HR+, HER2–
Advanced Breast Cancer—Clinical Evidence
 In patients previously treated with NSAI, the only reports of an OS benefit to date has
been with a small phase 2 trial where OS was an exploratory endpoint
• TAMRAD [N = 111; everolimus + tamoxifen vs tamoxifen alone]
Trial Treatment Arms OS Durations
Post-NSAI population
EFECT (N = 693) FUL 250 mg vs EXE 24.3 mo vs 23.1 mo
SoFEA (N = 723) FUL 250 mg vs EXE vs
FUL+ANA
19.4 mo vs 21.6 mo vs 20.2 mo
BOLERO-2
(N = 724)
EVE+EXE vs PBO+EXE 31.0 mo vs 26.6 mo
Prior AI therapy not required
CONFIRM
(N = 736; post-AI
subset = 42.5% of
total or 313 pts)
FUL 500 mg vs FUL 250 mg 25.1 mo vs 22.8 mo at final PFS analysis; P = .091
26.4 mo vs 22.3 mo at final OS analysis;
nominal P = .016 (not significant as α was fully spent)
28
ANA, anastrozole; EVE, everolimus; EXE, exemestane; FUL, fulvestrant, NSAI, nonsteroidal aromatase inhibitor; OS, overall survival;
PBO, placebo; PFS, progression-free survival.
Longest OS Observed
31 Months .. Clinically
Significant or Statically
Significant???

29. mTOR Resistance
 The mTOR-activated kinase S6K1 phosphorylates and
destabilizes the insulin-receptor substrate 1 and 2 (IRS1 and
IRS2) proteins in insulin-like growth factor (IGF)-
responsive cells
 mTOR inhibition can block the negative feedback on IGF-
1R signaling interfering on AkT/PI3K signaling.
 The result is an increase in Akt phosphorylation, protein
kinase activity, and downstream signaling, which could
potentially counteract the inhibition of mTOR
29

30. 30
Cell cycle
checkpoints
are
dominated
by CDK

31. 31
PALOMA-1 Trial Finds Palbociclib/Letrozole Doubles Progression-Free
Survival in Metastatic Breast Cancer
Palbociclib is a first-in-class cyclin-dependent kinase (CDK) 4/6 inhibitor
that inhibits cell proliferation and cellular DNA synthesis by preventing cell-
cycle progression.
Progression-free survival was 26.1 months for the
combination of palbociclib plus letrozole vs 5.7
months for letrozole alone (P < .0001)
ASCO,2014

32. 32Turner et al, NEJM, 2015

33. 33Turner et al, NEJM, 2015

34. 34Turner et al, NEJM, 2015

35. PD-L1

36. 36
Possible treatment Plan

37. 37
Possible treatment Plan

38. 38
Optimum outcome,
minimal morbidity
Goal of Treatment
Personalization
of Treatment

39. 39
Hormonal Management- At
recurrence for ER/PR+, Her2neu-
Repeat hormonal profile from metastatic site
If Post menopausal- Tamoxifen pretreated- AI
If progressed in 2nd line HT
3rd /4th line HT- Exemestane/Fulvestrant
(EFFECT/CONFIRM trial)
Progression after 4th line
Exemestane +Everolimus (BLOERO II)
Hormone therapy remains choice of treatment, if not in visceral crisis
Visceral crisis: Brain metastasis, lymph-angitis, Multiple liver metastasis, marrow metastasis

40. Trastuzumab resistance was defined as recurrence during
or within 12 months of adjuvant treatment or progression
during or within 4 weeks of treatment for advanced
disease
SD after treated CNS metastases were eligible treatment
completed 8 weeks before
Exclusion criteria
>3 previous lines of CT,
previous treatment with vinca alkaloids or mTOR
inhibitors,
concomitant immunosuppressive agents or
chronic corticosteroids
RT to >25% bone marrow
Everolimus
+Trastuzumab+Vinorelbin
e
Placebo
+Trastuzumab+Vinorelbin
e
R
A
N
D
O
M
I
Z
A
T
I
O
N
40

41. Progression-free survival
41

42. Forest plot
analysis of
locally
assessed
progressio
n-free
survival
42

43. mTOR Resistance
 The mTOR-activated kinase S6K1 phosphorylates
and destabilizes the insulin-receptor substrate 1 and 2
(IRS1 and IRS2) proteins in insulin-like growth
factor (IGF)-responsive cells
 mTOR inhibition can block the negative feedback on
IGF-1R signaling interfering on AkT/PI3K signaling.
 The result is an increase in Akt phosphorylation,
protein kinase activity, and downstream signaling,
which could potentially counteract the inhibition of
mTOR
43

44. 44
Cell cycle
checkpoints
are
dominated
by CDK

45. • Cleopatra Study -2013, 2015
• Pertuzumab
• Median FU-49.5 mth
• 808 pts
• metastatic breast cancer who had not received previous
chemotherapy or anti-HER2 therapy for their metastatic disease to
receive the pertuzumab combination or the placebo combination

46.  PFS was significantly improved after first-line therapy with pertuzumab,
trastuzumab, and docetaxel, as compared with placebo, trastuzumab, and
docetaxel.
 Overall survival was significantly improved with pertuzumab to 56.5 mth
 First-line therapy with pertuzumab, trastuzumab, and docetaxel significantly
improved overall survival among patients with HER2-positive metastatic
breast cancer

47. Adjuvant therapeutic strategies
 HER 2 Blockade
 Angiogenesis inhibition
 PI3K – mTOR – AKT pathway inhibition
 CDK 4/6 Inhibition
 PARP Inhibition

53. Dual inhibition