MBC

1. Presentation
Title
DR. R. RAJKUMAR D.M.
CONSULTANT MEDICAL ONCOLOGIST
VELAMMAL MEDICAL COLLEGE &
SPECIALITY HOSPITALS

2. BREAST CANCER: INCIDENCE
1.
Distribution of BC Molecular Subtypes
in United States, 2010
HR+/HER2-
73%
TNBC
12%
HR+/
HER2+
10%
HR-/
HER2+
5%

5. AGE SHIFT – CASES SEEN IN 30’S & 40’S

7. Evolving Treatment Landscape of HR-Positive MBC
 SOC regimens for metastatic HR+/HER2- BC based on endocrine tx
Tamoxifen
(Selective ER
modulator)
1970-80
AIs
Anastrozole
Exemestane
Letrozole
1990s
Fulvestrant
(Selective ER
degrader)
2002
Fulvestrant HD
2010
Everolimus
(mTOR inhibitor)
2012
Palbociclib
(CDK4/6 inhibitor)
2015-17
Ribociclib,
Abemaciclib
(CDK4/6 inhibitors)
2017-18
Targeted Therapy + ET
.
Approvals

8. Initial Treatment of HR+, HER2- Advanced Breast Cancer
 Majority of patients with HR+,
HER2- metastatic BC should be
treated with endocrine therapy–based
regimens often in combination with
targeted therapies
‒ Chemotherapy is not recommended
unless patients have progressed
through multiple lines of endocrine
therapy or display signs of visceral
crisis
 Treatment considerations
‒ Sites and extent of disease
‒ Organ function
‒ Prior systemic therapy
‒ Length of disease-free interval
‒ Rate of disease progression
‒ Presence of gBRCA1/2 mutation

9. TREATMENT GUIDELINES FOR HR+, HER2– ADVANCED
BREAST CANCER
ESMO1 In HR+, HER2– disease, endocrine therapy is the treatment of first choice independent of
metastatic site, unless rapid response is needed. Limited visceral metastases are not a
contraindication for endocrine therapy
ABC2 Endocrine therapy is the preferred option for HR+ disease, even in the presence of visceral
disease, unless there is concern or proof of endocrine resistance or rapidly progressive
disease needing a fast response
ASCO3 Endocrine therapy should be recommended as initial treatment for patients with HR+
metastatic breast cancer except in patients with immediately life-threatening disease or
in those with rapid visceral recurrence on adjuvant endocrine therapy.
NCCN4 Endocrine therapy recommended unless there is visceral crisis, or progression with no
clinical benefit after 3 sequential endocrine therapy regimens.
3

10. CHEMOTHERAPY VERSUS ENDOCRINE THERAPY
Chemotherapy has higher response rate.
1

11. CHEMOTHERAPY VERSUS ENDOCRINE THERAPY
1
Wilcken et al, Cochrane System Database Review 2009
No significant differences in overall survival.

12. Combining Targeted and Antiestrogen Therapies to
Overcome Resistance in HR+ Advanced Breast Cancer
 ~ 50% of advanced HR+
BCs are de novo
resistant to ET, with
most developing
acquired resistance
 Mechanisms of
resistance may include
loss or alteration of
ER expression;
overexpression or
activation of growth
factor receptors; or
activation of
downstream signal
transduction pathways
PI3K
Akt
PTEN
mTOR
RAS
Raf
MEK
MAPK
ER Target Gene
Transcription
P P
EGFR
HER2
E
E
ER
E
ER
E
ER
E
TKI
mTOR Inhibitors
Everolimus
Aromatase Inhibitor
Nonsteroidal AIs:
Anastrozole
Letrozole
Steroidal AI:
Exemestane
Selective ER
Modulators
Tamoxifen
Toremifene
ER Downregulator
Fulvestrant
CDK4/6 Inhibitors
Palbociclib
Abemaciclib
Ribociclib Cell
Cycle
Transcription
Silencing

13. G2
S
M
G1
pRB
The Role of CDK4/6 in Breast Cancer
 Growth of HR+ MBC is
dependent on cyclin D1, a direct
transcriptional target of ER
 Cyclin D1 activates CDK4/6,
resulting in G1-S phase
transition and cell cycle entry[1]
 Some cell-line models of
endocrine resistance show
dependence on cyclin D1 and
CDK4/6[2,3]
ERα Mitogenic
signaling
S phase transcription
program
G1/S transition
P P P
pRB
E2F
E2F
CDK1
Cyclin B
CDK1/2
Cyclin A
CDK2
Cyclin E
CDK4/6
Cyclin D

14. pRB
Cyclin D1 and CDK4/6 Drive Cellular Proliferation
Downstream of Signaling Pathways
Lange. Endocr Relat Cancer. 2011;18:C19. Kundsen. Trends Cancer. 2017;3:39. Otto. Nat Rev Cancer.
2017;17:93. Corona. Drug Des Devel Ther. 2018.12:321. Tripathy. Clin Cancer Res. 2017;23:3251-3262.
Gene
transcription
G2 S
M G1
Inactive
Active tumor
suppressor
E2F
E2F
Restriction point
p16
p21
p53
CDK4/6
Cyclin D
CDK2
Cyclin E
pRB
P P P
G0
Pl3K/Akt
STATs MAPKs
ER/PR/AR Wnt/β-catenin
NF-κB
FGFR

15. Pan-CDK Inhibitors: Early
Clinical Trial Experience
Both agents showed low therapeutic index resulting in
toxicities at doses sufficient to inhibit target CDKs
Agent Primary Targets Antitumor Activity Notable Grade 3/4
Toxicities
Alvocidib
(flavopiridol)
CDKs 1, 2, 4, 6, 7, 9 Solid tumors: minimal
CLL (relapsed/
refractory): ORR ≈ 25%
to 50%
Neutropenia,
gastrointestinal/diarrhea,
tumor lysis syndrome,
infections
Seliciclib CDKs 1, 2, 5, 7, 9 Solid tumors: minimal, if
any
Nausea, vomiting, fatigue,
hepatic dysfunction

16. CDK4/6 Inhibitors: Comparison of Key Clinical Characteristics
Characteristic PALBOCICLIB RIBOCICLIB ABEMACICLIB
Target (IC50, nM) CDK4 (11); CDK6 (15) CDK4 (10); CDK6 (39) CDK4 (2); CDK6 (10)
Route PO PO PO
Dose, mg 125 QD 600 QD Monotx: 200 BID
Combo w/ET: 150 BID
Schedule 3 wks on/1 wk off 3 wks on/1 wk off Continuous
Half-life, hr 27 32.6 17-38

17. PALOMA-1 PALOMA-2 MONALEESA-2 MONARCH-3 MONALEESA-3
Study design
Phase II
1st line
Phase III
1st line
Phase III
1st line
Phase III
1st line
Phase III
1st and 2nd line
Endocrine
partner Letrozole Letrozole Letrozole
Letrozole
or anastrozole
Fulvestrant
CDK4/6
inhibitor Palbociclib Palbociclib Ribociclib Abemaciclib Ribociclib
Patients, N 165 666 668 493 367
HR 0.49 0.58 0.56 0.54 0.57
PFS, mos 20.2 vs 10.2 24.8 vs 14.5 25.3 vs 16 NR vs 14.7 NR vs 18.3
ORR, % 56 vs 39 55.3 vs 44.4 52.7 vs 37.1 59 vs 44 40.9 vs 28.7*
Impact of CDK4/6 Inhibition on PFS: First-Line Setting
1

18. 18
PALOMA CLINICAL TRIALS
Footer text here. Arial 7pt font in black.
• Postmenopausal women
with HR+, HER2– ABC
• No prior treatment for
advanced disease
N = 666
PALOMA-2
2:1
PBO + LET
PAL + LET
PALOMA-2 study results
All patients
PAL+LET
(n = 444)
PBO+LET
(n = 222)
Median PFS, mo 24.8 14.5
HR (95% CI); P value
0.58 (0.46, 0.72);
< 0.001
• Pre- or postmenopausal
women with HR+, HER2–
ABC
• Relapsed/progressed
during prior ET
N = 521
PALOMA-32
2:1
PBO + FUL
PAL + FUL PALOMA-3 study results
All patients2 PAL+FUL
(n = 347)
PBO+FUL
(n = 174)
Median PFS, mo 9.5 4.6
HR (95% CI);
P value
0.46 (0.36, 0.59);
< 0.0001

19. 19
MONALEESA CLINICAL TRIALS
Footer text here. Arial 7pt font in black.
ML-2
ML-7
• Postmenopausal women
with HR+, HER2– ABC
• No prior therapy for ABC
N = 668
ML-3 • Men and postmenopausal women
with HR+, HER2– ABC
• No prior CT for ABC
N = 726
• Premenopausal women with HR+,
HER2– ABC
• No prior ET for advanced disease
• ≤ 1L prior CT allowed
N = 672
ML-2 study results
All patients
RIBO+LET
(n = 334)
PBO+LET
(n = 334)
Median PFS, mo 25.3 16.0
HR (95% CI);
P value
0.568 (0.457, 0.704);
9.63×10–8
ML-3 study results
All patients2 RIBO+FUL
(n = 484)
PBO+FUL
(n = 242)
Median PFS, mo 20.5 12.8
HR (95% CI);
P value
0.593 (0.480, 0.732);
<0.001
ML-7 study results
All patients
RIBO+ET+GOS
(n = 335)
PBO+ET+GOS
(n = 337)
Median PFS, mo 23.8 13.0
HR (95% CI);
P value
0.55 (0.44, 0.69);
<0.0001
1:1
RIBO + LET
PBO + LET
2:1
RIBO + FUL
PBO + FUL
1:1
RIBO + ET +
GOS
PBO + ET +
GOS

20. 20
MONARCH CLINICAL TRIALS
Footer text here. Arial 7pt font in black.
MONARCH-2
MONARCH-3
• Pre- and postmenopausal
women with HR+,
HER2– ABC
• Progression on ET
([neo]adjuvant or 1L
advanced)
N = 669
1:1
ABE + FUL
PBO + FUL
MONARCH-2 study results
All patients
ABE+FUL
n = 446
PBO+FUL
n = 223
Median PFS, mo 16.4 9.3
HR (95% CI);
P value
0.553 (0.449, 0.681);
<0.001
N = 493
1:1
ABE + NSAI
PBO + NSAI
MONARCH-3 study results
All patients
ABE+NSAI
n = 328
PBO+NSAI
n = 165
Median PFS, mo NR 14.7
HR (95% CI);
P value
0.54 (0.41, 0.72);
0.000021
N = 493
• Postmenopausal women
with HR+, HER2– ABC
• No prior systemic therapy
in the advanced setting

21. Do CDK4/6 inhibitors result in an
improvement in overall survival?
YES

22. MONALEESA-3: OVERALL SURVIVAL BY LINE OF THERAPY
 OS by line of therapy was consistent with overall population
Slamon. ESMO 2019. Abstr LBA7_PR.
RIBO + FULV PBO + FULV
Events/N 102/237 60/109
Median OS, Mos 40.2 32.5
RIBO + FULV PBO + FULV
Events/N 63/237 47/128
Median OS, Mos NR 45.1
RIBO + FULV
PBO + FULV
RIBO + FULV
PBO + FULV
237231222218213210199188184179172167158152145135
109103 98 97 93 90 88 83 81 78 77 72 69 63 61 59 54 49 35 23 15 6
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
129122 94 63 36 17 7 1 0
1 0 0
0
20
40
60
80
100
Mos
237229222217214210207206205202194190182174173166163157138 92 54 22 0
6 1
128126 122121119116113110106104 99 97 93 91 85 84 82 70 40 21 8 2 0 0
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
Mos
0
20
40
60
80
100 First line Early relapse + Second line
OS,
%
Patients
Atrisk,n
PBO
RIBO
Patients
Atrisk,n
PBO
RIBO
HR: 0.700 (95% CI: 0.479-1.021) HR: 0.730 (95% CI: 0.530-1.004)
125

23. Approach to Therapy for HR+/HER2- MBC:
Move to Personalization
1L[1-4] 2L[1] 3L
AI + CDK4/6i Fulvestrant ±
everolimus
Exemestane +
everolimus[8]
Fulvestrant + CDK4/6i
Exemestane +
everolimus
4L/5L[1]
Taxane or
capecitabine
4L+[1]
Eribulin
PIK3CAm:
fulvestrant +
alpelisib[5]
BRCAm: olaparib or
talazoparib[9,10]
Sacituzumab
govitecan
(IMMU-132)[13]
ESR1m: SERD (+ CDK4/6i)[6,7]
HER2 low: trastuzumab
deruxtecan
(DS8201a)[11]
HER2m: neratinib[12]

24. *De novo stage IV disease appears to be enriched in relative endocrine resistant disease.
†No data comparing CDK4/6i combined with AI vs fulvestrant in first line setting.
HR+/HER2- Advanced BC: Changing Paradigms
CT
Poor Endocrine Sensitivity
Progression within 2 yrs
from start of adj ET
Fulvestrant +
CDK4/6i
High Endocrine Sensitivity
NSAI + CDK4/6i
ET naive*
Progression > 1 yr after adj ET
Fulvestrant†
(bone only, no
prior ET)
EXE + EVE
PIK3CA WT
FULV
(± EVE)
FULV +
Alpelisib
PIK3CA MUT
FULV +
CDK4/6i
EXE + EVE
Progression between 2-3 yrs from
start of or < 1 yr from end of adj ET
Moderate Endocrine Sensitivity
AI +
Alpelisib
PIK3CA WT PIK3CA MUT
EXE + EVE AI +
alpelisib
PIK3CA WT
PIK3CA MUT

25. THERAPEUTIC OPTIONS FOR HR+, HER2– ABC ARE
EVOLVING
• ET-based therapy remains the basis
of treatment for HR+, HER2– ABC1
• CDK4/6 inhibitors in combination with ET have
resulted in a paradigm shift for treating HR+,
HER2– ABC2
─ A meta analysis of 50,029 patients with HR+, HER2–
MBC across 140 phase 2 and 3 studies found that the
combination of CDK4/6 inhibitors plus hormone therapies
is associated with better PFS than standard hormone
therapies as first- or second-line treatments for
postmenopausal patients3
Oestrogen
ER
SRC
Me/Ac
EGFR/HER2/HER3
Inhibitors
FGFR
Inhibitors
IGFR
Inhibitors
EGFR/HER3 FGFR IGFR MET
E2F
CDK
Cyclin D
p21WAF1/CIP1
SRC Inhibitor
SRC
STAT3
RAF
MEK
ERK
CDK
Inhibitors
MAPK/MEK
Inhibitors
RAS PI3K
PIP2
PI3K Inhibitors
mTOR Inhibitors
PIP3
mTORC2
AKT
TSC
p53
Rheb
Rheb
mTORC1
P
AKT
Inhibitors
HDAC Inhibitors
MDM2
ER
SERDs/
SERMs
25