cd4/6 inhibitors in HR+ HER2 neu MBC

1. DIFFERENCE IS
MORE LIFE
DR. R. RAJKUMAR D.M.
CONSULTANT MEDICAL ONCOLOGIST
VELAMMAL SPECIALITY HOSPITALS

2. Breast Cancer: Incidence
 BC is the most common cancer in
women in the United States[1]
‒ Estimated 266,120 diagnoses in 2018,
representing 15.3% of all new cancers
 HR+/HER2- BC is most common
molecular subtype[2]
 ~ 6% of patients present with
metastatic disease and up to 50%
with primary BC will later develop
metastatic disease[3]
‒ Currently, metastatic BC is incurable[3]
1. NIH SEER. Cancer stat facts: female breast cancer. 2. Howlader N, et al.
J Natl Cancer Inst. 2014;106. 3. Brufsky AM. Cancer Treat Rev. 2017;59:22-32.
Distribution of BC Molecular Subtypes
in United States, 2010[3]
HR+/HER2-
73%
TNBC
12%
HR+/
HER2+
10%
HR-/
HER2+
5%

4. 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

5. 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

6. 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
References in slidenotes.

7. 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

8. 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
transcriptionG2 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

9. 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

10. CDK4/6 Inhibitors: Comparison of Key Clinical
Characteristics
1. DeMichele A, et al. Clin Cancer Res. 2015;21:995-1001. 2. Hamilton E, et al. Cancer Treatment Rev.
2016;45:129-138. 3. Costa R, et al. Ann Oncol. 2017;28:44-56. 4. Infante JR, et al. Clin Cancer Res.
2016;22:5696-5705. 5. Barroso-Sousa R, et al. Breast Care. 2016;11:167-173. 6. Dickler MN, et al. ASCO
2016. Abstract 510.
Characteristic Palbociclib[1-3] Ribociclib[4,5] Abemaciclib[5,6]
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

11. PALOMA-1[1] PALOMA-2[2] MONALEESA-2[3,4] MONARCH-3[5] MONALEESA-3[6]
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
*ORR includes 1st and 2nd line patients.
1

12. Initial Reports Demonstrated No Improvement in
Overall Survival, But There Were 3 Issues:
1. Survival is prolonged in ER+ MBC and events take time to see
2. The studies were generally underpowered for survival
3. But ultimately, only survival and quality of life matter
‒ All other outcomes are really just surrogates

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

14. MONALEESA-2, -3, and -7: Study Designs
Study Population n Treatment Primary Endpoint
MONALEESA-2 Post-menopausal women
with HR+, HER2- ABC;
treatment naive
668
Ribociclib 600 mg PO QD on Days 1-21 +
Letrozole vs Placebo PO QD on
Days 1-21 + Letrozole
PFS
MONALEESA-3 Post-menopausal men and
women with HR+, HER2-
ABC; treatment naive or 0-
1 prior lines of ET
726
Ribociclib 600 mg PO QD on Days 1-21 +
Fulvestrant vs Placebo PO QD on Days 1-21
+ Fulvestrant
PFS
MONALEESA-7
Pre/peri-menopausal
women with HR+, HER2-
ABC; 0-1 prior lines of CT.
No prior ET
672
Ribociclib 600 mg PO QD on Days 1-21 + AI
+ Goserelin vs Placebo PO QD on Days 1-21
+ AI + Goserelin
PFS
 International, double-blind, randomized phase III trials of ribociclib plus endocrine therapy vs
endocrine therapy alone in advanced breast cancer

15. Primary endpoint: PFS (locally assessed per RECIST v 1.1)
Secondary endpoints:
 Overall survival
 ORR
 CBR
 Time to response
 DoR
 Time to definitive deterioration of ECOG PS
 Patient-reported outcomes
 Safety
 Pharmacokinetics
MONALEESA-3: Study Design
Men and
postmenopausal
women with HR+/HER2-
advanced BC, ≤ 1 line of
endocrine tx for
advanced disease*
(N = 726)
Ribociclib 600 mg PO
QD 3 wks on/1 wk off +
Fulvestrant 500 mg*
(n = 484)
Placebo +
Fulvestrant 500 mg*
(n = 242)
Stratified by presence/absence of liver/lung metastases,
prior endocrine tx for advanced disease
Slamon. J Clin Oncol. 2018; 36:2465. Slamon. ESMO 2019. Abstr LBA7_PR.
Patient Population Definitions
Treatment
naive for ABC
TFI > 12 mo
De novo ABC
≤ 1st-line ET
in ABC
TFI ≤ 12 mo and
no treatment for ABC
TFI > 12 mo + PD on
1L ET for ABC
ABC at diagnosis
with PD on 1L ET for ABC
= Early relapse
*IM on Days 1, 15 of cycle 1, then on Day 1 of 28-day cycles.

16. MONALEESA-3: Overall Survival
 Reduction in relative risk of death with ribociclib: 28%
FUL, fulvestrant; HR, hazard ratio; KM, Kaplan-Meier; NR, not reached; OS, overall survival; PBO, placebo; RIB, ribociclib.
16
RIBO + FULV PBO + FULV
Events/N 167/484 108/242
Median OS, Mos (95% CI) NR (42.5-NR) 40.0 (37.0-NR)
Landmark Analyses
KM
Est., %
RIBO +
FULV
PBO +
FULV
36 mos 67.0 58.2
42 mos 57.8 45.9
OS,%
RIBO + FULV
PBO + FULV
0
20
40
60
80
100
484 470 454 444 436 428 414 402 397 389 374 365 348 334 326 309 300 287 237 159 92 41 14 2
0242 233 227 223 218 213 207 199 194 187 184 174 169 159 155 147 141 134 107 64 37 14 3 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
Slamon. ESMO 2019. Abstr LBA7_PR.
Patients
At risk, n
PBO
RIBO
HR: 0.724 (95% CI: 0.568-0.924; P = .00455)
 P = .00455 crossed prespecified boundary for superior efficacy of P < .01129

17. 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 06 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

18. MONALEESA-7: Background
 Among women with breast cancer, younger patients generally have more aggressive disease and
poor prognoses vs older patients[1]
‒ Premenopausal women underrepresented in clinical trial populations
 Ribociclib: CDK4/6 inhibitor FDA approved for HR+/HER2- advanced or metastatic breast cancer
with letrozole or another aromatase inhibitor as initial ET for pre/peri/postmenopausal women, or
with fulvestrant as initial ET or following PD on ET for postmenopausal women[2,3]
 Unknown whether CDK4/6 inhibition + ET significantly prolongs OS in breast cancer; challenging to
assess in trials due to potential crossover between arms, variable treatment histories[4,5]
 Phase III MONALEESA-7 trial showed significantly prolonged PFS with ribociclib + ET vs placebo + ET
as initial ET in pre/perimenopausal women with HR+/HER2- advanced breast cancer[6]
 Current report presents protocol-specified interim analysis of OS in MONALEESA-7 trial[7,8]
1. Bardia. Clin Cancer Res. 2018;24:5206. 2. Ribociclib and letrozole PI. 3. Ribociclib PI. 4. Turner. NEJM. 2018;379:1926. 5. Hurvitz.
Cancer Treat Rev. 2011;37:495. 6. Tripathy. Lancet Oncol. 2018;19:904. 7. Hurvitz. ASCO 2019. Abstr LBA1008. 8. Im. NEJM. 2019;[Epub].

19. MONALEESA-7: Baseline Patient Characteristics
Hurvitz. ASCO 2019. Abstr LBA1008.
Characteristic Ribociclib + ET (n = 335) Placebo + ET (n = 337)
Age, yrs (range) 43 (25-58) 45 (29-58)
Race, n (%)
 White
 Asian
 Black
 Other/unknown
187 (56)
99 (30)
10 (3)
39 (12)
201 (60)
99 (29)
9 (3)
28 (8)
ECOG PS,* n (%)
 0
 1
 2
245 (73)
87 (26)
0
255 (76)
78 (23)
1 (< 1)
Prior (neo)adjuvant ET, n (%) 127 (38) 141 (42)
Prior CT for advanced disease, n (%) 47 (14) 47 (14)

20. MONALEESA-7: OS in All Patients
(Key Secondary Endpoint)
 29% relative reduction in
risk of death
 P value crossed the
prespecified boundary
for superior efficacy
 Exploratory analyses observed generally consistent OS benefit across subgroups
Patients at Risk, n
Ribociclib 335 330 325 320 316 309 304 292 287 279 274 266 249 236 193 155 110 68 43 25 7 3 0
Placebo 337 330 325 321 314 309 301 295 288 280 272 258 251 235 210 166 122 92 62 33 19 7 2 0
Events/N
Median OS, mos
Ribociclib + ET
83/335
NR
Placebo + ET
109/337
40.9
HR: 0.712 (95% CI: 0.535-0.948); P = .00973
Landmark
Analysis, %
Ribociclib
+ ET
Placebo +
ET
36-mo OS 71.9 64.9
42-mo OS 70.2 46.0
Ribociclib + ET
Placebo + ET
Mos
OS
100
80
60
40
20
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

21. Patients Who Received an NSAI
MONALEESA-7: Prespecified Analysis of OS by
Endocrine Therapy
Patients Who Received Tamoxifen
Mos
Patients at Risk, n
Ribociclib + ET
Placebo + ET
OS
100
80
60
40
20
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
Ribociclib 248 245 241 326 233 230 226 216 213 206 201 196 192 184 174 142 113 80 49 29 16 5 2 0
Placebo 247 240 236 232 225 221 215 209 204 199 193 183 179 165 145 116 87 67 46 24 12 4 2 0
Median OS, Mos
Ribociclib + ET (n = 248)
Placebo + ET (n = 247)
NE
40.7
HR for death: 0.70 (95% CI: 0.50-0.98)
Mos
Patients at Risk, n
Ribociclib + ET
Placebo + ET
OS
100
80
60
40
20
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
Median OS,
Mos
Ribociclib + ET (n = 87)
Placebo + ET (n = 90)
NE
NE
HR for death: 0.79 (95% CI: 0.45-1.38)
Ribociclib 87 85 84 84 83 79 78 76 74 73 73 70 66 65 62 51 42 30 19 14 9 2 1 0
Placebo 90 90 89 89 89 88 86 86 84 81 79 75 72 70 65 50 35 25 16 9 7 3 0 0

22. MONALEESA-7: Subsequent Anticancer Therapies and
Time to First Subsequent Chemotherapy
Im. NEJM. 2019;[Epub].
First Subsequent Therapy
Ribociclib + ET
(n = 335)
Placebo + ET
(n = 337)
Patients discontinuing
study tx, n
219 280
 Received any
subsequent tx, n (%)
151 (68.9) 205 (73.2)
– CT alone, n (%) 49 (22.4) 80 (28.6)
– CT + hormone
therapy/other, n (%)
18 (8.2) 22 (7.9)
– Hormone therapy
alone, n (%)
49 (22.4) 57 (20.4)
– Hormone therapy +
other (no CT), n (%)
31 (14.2) 41 (14.6)
– Other, n (%) 4 (1.8) 5 (1.8)
– CDK4/6 inhibitor(s),
n (%)
22 (10.0) 52 (18.6)
Time to First Subsequent Chemotherapy
Patients at Risk, n
Events,
n
Median Time to
Subsequent CT, Mos
Ribociclib + ET
Placebo + ET
Patients,
n
335 95 NR
337 139 36.9
HR for death: 0.596 (95% CI: 0.459-0.774)
Ribociclib335 324307 299 288275 267 255247240231225216 206195 158125 90 54 35 21 5 2 0
Placebo 337 315 288 277261246232 223212204194181174 161147 119 86 67 42 20 11 6 1 0
Mos
Ribociclib + ET
Placebo + ET
OS
100
80
60
40
20
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

23. MONALEESA-7: Conclusions
 In this protocol-specified interim analysis of the phase III MONALEESA-7 trial for
pre/perimenopausal women with HR+/HER2- advanced breast cancer, the key secondary
endpoint of OS was significantly prolonged with ribociclib + ET vs placebo + ET alone
‒ Median OS: NE vs 40.9 mos (HR: 0.71; 95% CI: 0.54-0.95; P = .00973)
‒ Median OS with an NSAI: NE vs 40.7 mos (HR: 0.70; 95% CI: 0.50-0.98)
 Patients still receiving study treatment: ribociclib arm, 35%; placebo arm, 17%
 Ribociclib + ET was associated with benefit that continued beyond initial treatment, as
shown in prolonged time to subsequent CT and PFS during subsequent therapy or death
from any cause
 According to study investigators, this is the first report of significantly prolonged OS with a
CDK4/6 inhibitor + ET in patients with HR+/HER2 advanced breast cancer
‒ MONALEESA-7 the only trial to date to assess CDK4/6 inhibitors in only premenopausal women
Hurvitz. ASCO 2019. Abstr LBA1008. Im. NEJM. 2019;[Epub].

24. Analysis of Post- vs Pre-CDK4/6i Breast Cancer Tumors
 210 paired pre- and post-CDK4/6i samples (105 patients)
 Total of 1059 tumors from 845 patients in the MSK Breast Cancer
Genomic Initiative
‒ 838 Pretreatment tumors (765 patients)
‒ 221 post-treatment tumors (185 patients)
‒ Post CDK4/6i + AI: n = 112
‒ Post CDK4/6i + SERD: n = 61
‒ Post multiple CDK4/6i: n = 48
24Razavi. ASCO 2019. Abstract 1009.

25. Comparison of Paired Post- vs Pre-CDK4/6i Breast
Cancer Tumors
Razavi. ASCO 2019. Abstract 1009.

26. Landscape of Resistance to CDK4/6 Inhibitors
Wander. doi.org/10.1101/857839

27. Turner. J Clin Oncol. 2019;37:1169.
Pretreatment Cyclin E1 Gene Expression Predictive in
PALOMA-3
 Palbociclib + FULV
vs FULV (N = 302)
 Pretreatment
mRNA gene
expression
profiling on FFPE
and HTG EdgeSeq
 Effect most
pronounced in
metastatic vs
primary tissue
PFS with PALB + FULV:
Low Cyclin E1, 14.1 mos vs High Cyclin E1, 7.6 mos
(Interaction P = .0028)
CCNE1 Expression Below Median
0
20
40
60
80
100
0 5 10 15 20
Mos
PFS(%)
HR: 0.32 (95% CI: 0.20-0.50)
CCNE1 Expression Above Median
0
20
40
60
80
100
0 5 10 15 20
PFS(%)
HR: 0.85 (95% CI: 0.58-1.26)
Mos
Median
PFS, Mos
14.1
4.8
PALB + FULV
PBO + FULV
Patients,
n
103
48
Median
PFS, Mos
7.6
4.0
Patients,
n
91
60
PALB + FULV
PBO + FULV

28. KRYXANA Is the Only CDK4/6 Inhibitor Twice Proven to Help
Women With HR+/HER2− mBC Live Longer1,2
28
 KRYXANA significantly improved overall survival ~30% reduction in risk of death1
‒ MONALEESA-3: HR=0.72, (95% CI, 0.568-0.924), P = 0.004552
 Treatment with KRYXANA consistently delayed time to chemotherapy and improved or maintained QoL1-4
 Predictable: Adverse events typically appeared early and resolved with appropriate management5
 Once-daily oral dose of 600 mg (3 x 200-mg tablets) that can be taken with or without food5
CDK, cyclin-dependent kinase; HER2, human epidermal growth factor receptor 2; HR, hazard ratio; HR+, hormone receptor positive; mBC, metastatic breast cancer; QoL, quality of life.
1.Im SA, Lu YS, Bardia A, et al. N Engl J Med. 2019: DOI: 10.1056/NEJMoa1903765. | 2. Data on File. Novartis Pharma AG. | 3. Fasching PA, Esteva FJ, Pivot X, et al. Patient-reported outcomes in advanced breast cancer treated with ribociclib +
fulvestrant: results from MONALEESA-3. Paper presented at: European Society for Medical Oncology Congress; October 19-23, 2018; Munich, Germany. | 4. Harbeck N, Villanueva Vazquez R, Franke F, et al. Ribociclib + tamoxifen or a nonsteroidal al
aromatase inhibitor in premenopausal patients with hormone receptor-positive, HER2-negative advanced breast cancer: MONALEESA-7 patient-reported outcomes. Oral presentation at: European Society for Medical Oncology Congress; October 19-23,
2018; Munich, Germany. | 5. KRYXANA India package insert dtd 27 Feb 2020 based on EU SmPC dated 13 Feb 2020

29. Thank You!
Dr. RAJKUMAR , R. M.D. , D.M.
Phone
9677722024
Email
drraj12319@gmail.com