1. Στρογγυλό Τραπέζι
ΤΟ ΜΕΛΛΟΝ ΣΤΗΝ ΟΓΚΟΛΟΓΙΑ
CDK 4/6 αναστολείς: στοχεύοντας τον κυτταρικό κύκλο
στον ER θετικό / HER2 αρνητικό προχωρημένο καρκίνο μαστού
Ν. Ξενίδης, Δημοκρίτειο Πανεπιστήμιο Θράκης
Με την ευγενική χορηγία της εταιρείας Pfizer
4. For a cell to divide, it must first progress
through a predetermined number of stages
termed the cell cycle
5. Transition from one stage of the cell cycle to the next
is controlled by the actions of cyclin-dependent kinases
(CDKs), which are activated upon interaction
with their partner cyclins
at certain checkpoints
of cell cycle
6. Cyclin dependent kinases (CDKs) activated by Cyclins, control cell cycle processes through
phosphorylation of serine/threonine residues
When a cyclin and CDK form a complex, the complex will bind to a target protein and
modify it via phosphorylation
The phosphorylated target protein will trigger some specific event within the cell cycle
(e.g. centrosome duplication, etc.)
After the event has occurred, the cyclin is degraded and the CDK is rendered inactive again
7. Over the past 20 years, several CDK inhibitors have been developed as potential cancer
therapeutics and tested in numerous trials and in several tumor types
(first and second generation of ‘pan-CDK’ inhibitors)
But… CDKs doesn't regulate only cell cycle…
Theoretically
blocking of CDKs activity prevent over-proliferation of cancer cells
Uzma Asghar Nat Rev Drug Discov. 2015 February ; 14(2): 130–146.
10. RNA Polymerase II-based transcription
epigenetic regulation
Pan-CDK inhibitors target several proteins
that are critical to the proliferation and
survival of normal cells. Their inability
to discriminate between cancerous
and healthy tissues and subsequent
toxicity limits their therapeutic window
Shuhui Lim Development 140, 3079-3093 (2013)
11. What kind of CDK-inhibitor we need ?
- Implicated in certain cellular functions (proliferation or survival)
- Altered (amplified or mutated) in cancer cells
- No critical activity to normal cells
CDK4/6 inhibitors
appear to satisfy
these requirements
Shuhui Lim Development 140, 3079-3093 (2013)
12. Early in the G1 phase,
promitotic signals results in
increased expression of the D-type
cyclins, which complex with, and
activate CDK4/6
13. CDK4/6-CyclinD complex phosphorylates RB1, and
the other RB1-like, ‘pocket’ proteins p130 and p107,
which normally, in its de-phosphorylated state,
represses cell-cycle progression by binding to E2F
transcription factor
Cyclin-Dependent Kinases 4/6
http://www.nature.com/mt/journal/v20/n5/fig_tab/mt20122f1.html
14. Released of RB1-inhibitoring effect, E2F transcription factor promote
transcription of the E-type cyclins, which activate CDK2 and other
proteins that are important
for initiation of S phase
and DNA synthesis
Cyclin E/CDK2
further phosphorylates
RB1, leading to the full
activation of E2F proteins and
the expression of E2F responsive
genes
This genes encodes cell cycle regulators
required for G1/S transition (cyclin E, cyclin A and Cdk1), enzymes involved in nucleotide
biosynthesis (thymidine kinase) and components of the DNA replication machinery (Cdc6 and Orc1)
http://www.nature.com/mt/journal/v20/n5/fig_tab/mt20122f1.html
15. The control of CDK4/6 activity exerted by a family
of proteins known as
inhibitors of CDK4 (INK4 family):
p16INK4A, p15INK4B, p18INK4C and p19INK4D
Other proteins
(CIP/KIP family: p21CIP1,p27KIP1 and p57KIP2)
interfere with D-, E-, A- and B-cyclin-complexes
controlling cell cycle at different points
http://www.nature.com/mt/journal/v20/n5/fig_tab/mt20122f1.html
16. Amplification of cyclin D1 and
CDK4/CDK6 are observed in several
different types of cancer
Uzma Asghar1Nat Rev Drug Discov 2015 February ; 14(2): 130–146
17. - Cyclin D1 gene is amplified in 20% of breast cancers
(mRNA and protein levels are overexpressed in 50%
of breast cancers, primarily ER+ tumors)
- Overexpression of cyclin D1 has been linked to
the development of endocrine resistance
- p16 is downregulated in about 50%
- more than 90% of ER+ breast cancers have
functional RB1 protein (RB-del tumors are resistant
to CDK inhibition)
1. Taneja P, et al. Clin Med Insights 2010;4:15–34; 2. VanArsdale T, et al. Clin Cancer Res 2015;doi:10.1158/1078-0432;
5. Osborne CK, et al. Annu Rev Med 2011;62:233–47; 6. Vicier C, et al. Breast Cancer Res 2014;16(1):203; 7. Baselga J.
Oncologist 2011;16(Suppl. 1):12–9 8. Lange CA, et al. Endocr Relat Cancer 2011;18(4):C19–C24
18. MAPK
IGF-1R
EGFR
PDGFR
PI3K
mTOR
Cyclin D1
+
CDK4/6
Rb
E2F
Cellular proliferation
Estrogen
Receptor
tyrosine
kinase
ER
NUCLEUS
CYTOPLASM
EXTRACELLULAR SPACE
pRb
STAT
Effects of estrogen (and RTKs) on cell cycle progression
are tightly linked to expression of cyclin D1
CDK=cyclin-dependent kinase; E2F=E2 transcription factor; EGFR=epidermal growth factor receptors; ER=estrogen receptor; IGF-1R=insulin-like growth factor-1 receptor;
MAPK=mitogen-activated protein kinase; mTOR=mammalian target of rapamycin; PDGFR=platelet-derived growth factor receptor; PI3K=phosphoinositide 3-kinase;
pRb=phosphorylated retinoblastoma; Rb=retinoblastoma; STAT=signal transducer and activator of transcription.
1. IBRANCE® Prescribing Information. New York, NY: Pfizer Inc; 2016. 2. Milani A, et al. World J Clin Oncol. 2014;5:990-1001. 3. Jung HJ, Suh Y. Front Genet. 2015;5:472. 4.
Osborne CK, et al. Annu Rev Med. 2011;62:233-247. 5. Lange CA, et al. Endocr Relat Cancer. 2011;18:C19-C24.
6. Asghar U, et al. Nat Rev Drug Discov. 2015;14:130-146. 7. Baselga J. Oncologist. 2011;16(suppl 1):12-19.
19. Targeting multiple components within the
ER pathway may yield an enhanced effect1-3
- upstream targeting of ER signaling may
decrease mitogenic signaling3
- downstream targeting of CDK4/6
can cause cell cycle arrest4
E2F, E2 transcription factor; G1, growth;
pRb, phosphorylated retinoblastoma protein
1. Osborne CK, et al. Annu Rev Med 2011;62:233–47; 2. Yap TA, et al. J Clin Oncol
2013;31:1592–1605; 3. Finn RS, et al. Breast Cancer Res 2009;11:R77; 4. Finn RS, et al.
Additional file; http://www.biomedcentral.com/content/supplementary/bcr2419-
S5.PPT. Accessed January 31, 2016; 5. Lange CA, et al. Endocr Relat Cancer
2011;18:C19–C24
6. Baselga J. Oncologist 2011;16(Suppl. 1):12–9; 7. Asghar U, et al. Nat Rev Drug Discov
2015;14:130–46; 8. VanArsdale T, et al. Clin Cancer Res 2015;doi:10.1158/1078-0432
21. CDK 4/6 inhibitors
*Investigational drug not approved in Europe for use in breast cancer
EMA, European Medicines Agency
PALOMA
trials
MONALEESA
trials
MONARCH
trials
Abemaciclib* Palbociclib
EMA approved Nov 2016
Ribociclib*
Ben O’Leary, et al. NATURE REVIEWS | CLINICAL ONCOLOGY
VOLUME 13 | JULY 2016 | 417
26. CDK4/6 inhibitors in development
*Investigational drug not approved in Europe for use in breast cancer
EMA, European Medicines Agency
Clinicaltrials.gov;
O’Leary B, et al. Nat Rev Clin Oncol. 2016;13:417–430;
EMA November 2016, EMA/626565/2016
PALOMA
trials
MONALEESA
trials
MONARCH
trials
Abemaciclib*
Palbociclib
EMA approved Nov 2016 Ribociclib*
27. PALOMA trials
Trial
Study
design
Study size
Target population
HR+/HER2– mBC
Partner ET
Primary
endpoint
PALOMA-1
Lancet Oncology
Phase 2
Open label
n = 165
Aromatase Inhibitor
sensitive
Treatment naïve for
mBC
Postmenopausal
Letrozole PFS
PALOMA-2
NEJM
Phase 3
Placebo
control
n = 666
Aromatase Inhibitor
sensitive
Treatment naïve for
mBC
Postmenopausal
Letrozole PFS
PALOMA-3
NEJM
Lancet Oncology
Phase 3
Placebo
control
n = 521
Endocrine resistant
Pre/peri and
postmenopausal
Fulvestrant PFS
AI, aromatase inhibitor; ET, endocrine therapy; HER2, human epidermal growth factor receptor-2;
HR, hormone receptor; mBC, metastatic breast cancer; PFS, progression-free survival
Finn RS, et al. Lancet Oncol. 2015;16:25–35;
Finn RS, et al. N Engl J Med. 2016;375:1925–1936;
Turner NC, et al. N Engl J Med. 2015;373:209–219;
Cristofanilli M, et al. Lancet Oncol. 2016;17:425–439
Palbociclib PALOMA
trials
28. PALOMA-1 – phase II
AI, aromatase inhibitor
Palbociclib is not approved in Europe. Finn RS, et al. Lancet Oncol. 2015;16(1):25–35.
Phase II, PALOMA-1 (1003)
Letrozole
(2.5 mg QD)
Palbociclib (125 mg QD,
3/1 schedule)
+ letrozole
(2.5 mg QD)
Postmenopausal
ER+, HER2− MBC
CCND1 amplification and/or loss of p16 (part
2 only)
No prior treatment for advanced disease
N=165
1:1
RANDOMISATION
Primary endpoint: progression-
free survival
Secondary/exploratory
endpoints:
response, overall survival, safety,
biomarkers,
patient-reported outcomes
Stratification factors: disease
site, disease-free interval
29. Number of patients at risk
PAL+LET 84 67 60 47 36 28 21 13 8 5 1
LET 81 48 36 28 19 14 6 3 3 1
PALOMA-1 primary endpoint PFS
LET, letrozole; PAL, palbociclib; PFS, progression-free survival. Finn RS, et al. Lancet Oncol. 2015;16(1):25–35.
Time (month)
PAL + LET
(n = 84)
LET
(n = 81)
Number of events (%) 41 (49) 59 (73)
Median PFS, months
(95% Cl)
20.2
(13.8–27.5)
10.2
(5.7–12.6)
HR
(95% Cl)
0.488
(0.319–0.748)
P value 0.0004
PAL + LET
LET
Accelerated
approval by FDA
0 4 8 12 16 20 24 28 32 36 40
TIME (MONTHS)
Palbociclib + letrozole
n=84
Letrozole
n=81
90
80
70
60
50
40
30
20
10
0
PFSPROBABILITY(%)
100
30. PALOMA-1: Overall response rate
*1-sided p-value
CR, complete response; ITT, intention to treat; ORR, objective response rate; PR, partial response.
Palbociclib is not approved in Europe. Finn RS, et al. Lancet Oncol. 2015;16(1):25–35.
Measurable
disease
Measurable
disease
ITT
ORR
ITT
CBR
P=0.13
Patients(%)
43%
33%
55%
39%
P=0.047*
Palbociclib + letrozole
Letrozole
PR CR
CRPR
Palbociclib + letrozole resulted in a
statistically significant improvement over
letrozole alone for:
•ORR in patients with measurable disease
(55% vs. 39%)
32. PALOMA-2: Phase III Study Design in Postmenopausal Patients
with ER+, HER2– Advanced Breast Cancer
• Phase III, randomized, double-blind trial at 186 centers in 17 countries
• Treatment continued until objective disease progression, unacceptable toxicity, or withdrawal of consent. Crossover was not allowed
• Palbociclib/placebo dose reductions were allowed per protocol. Letrozole dose reductions were not permitted
aRandomization stratified by disease site (visceral/non-visceral), disease-free interval, and prior (neo)adjuvant hormonal therapy
b3 weeks on/1 week off of a 4-week cycle
ECOG PS, Eastern Cooperative Oncology Group Performance Status; ER+, estrogen receptor-positive; HER2–, human epidermal growth factor receptor 2-negative; NSAI, non-steroidal
aromatase inhibitor; QD, once a day; RECIST, Response Evaluation Criteria In Solid Tumors
clinicaltrials.gov NCT01740427;
Finn RS, et al. N Engl J Med 2016 Nov 17;375(20): 1925–1936
Placebo
(3/1 schedule)
+ letrozole
(2.5 mg QD)
Palbociclib
(125 mg QD, 3/1 scheduleb)
+ letrozole
(2.5 mg QD)
• Postmenopausal
• ER+, HER2– advanced breast cancer
• No prior systemic treatment for advanced disease
• Prior (neo)adjuvant treatment with anastrozole or
letrozole was allowed if the disease-free interval was
≥12 months from completion of therapy
• Measurable disease according to RECIST v1.1 or bone-
only disease
• ECOG PS 0–2
• Adequate organ function
• No advanced, symptomatic visceral spread at risk of
short-term life-threatening complications
RANDOMIZATION
N=666
2:1
33. PALOMA-2: Demographics and Baseline Characteristics (ITT Population)
a“Other” was an option for the site to select on the clinical report form if none of the other available options were applicable;
“data missing” means that the site did not complete that field because the information was not available.
bPatients who received anastrozole or letrozole as a component of their adjuvant or neoadjuvant therapy were excluded
from the study if they had disease progression while receiving the therapy or within 12 months after completing the therapy.
Finn RS, et al. N Engl J Med
2016 Nov 17;375(20): 1925–1936
Palbociclib + letrozole
(N=444)
Placebo + letrozole
(N=222)
Disease stage at initial diagnosis, n (%)
I 51 (11.5) 30 (13.5)
II 137 (30.9) 68 (30.6)
III 72 (16.2) 39 (17.6)
IV 138 (31.1) 72 (32.4)
Unknown 36 (8.1) 12 (5.4)
Other or data missinga 10 (2.3) 1 (0.5)
Recurrence type, n (%)
Locoregional 2 (0.5) 2 (0.9)
Local 6 (1.4) 3 (1.4)
Regional 3 (0.7) 1 (0.5)
Distant 294 (66.2) 145 (65.3)
Newly diagnosed 139 (31.3) 71 (32.0)
Prior adjuvant or neoadjuvant therapy, n (%)
Chemotherapy 213 (48.0) 109 (49.1)
Neoadjuvant 54 (12.2) 32 (14.4)
Adjuvant 180 (40.5) 89 (40.1)
Adjuvant hormonal therapyb 249 (56.1) 126 (56.8)
Tamoxifen 209 (47.1) 98 (44.1)
Anastrozole 56 (12.6) 29 (13.1)
Letrozole 36 (8.1) 16 (7.2)
Exemestant 30 (6.8) 13 (5.9)
Goserelin 5 (1.1) 6 (2.7)
Toremifene 7 (1.6) 1 (0.5)
Other 3 (0.7) 4 (1.8)
34. Median (95% CI) PFS
24.8 months
PALOMA-2: Addition of palbociclib improved PFS
in AI-sensitive patients
AI, aromatase inhibitor; HR, hazard ratio; LET, letrozole; NE, not estimable; PAL, palbociclib; PCB,
placebo; PFS, progression-free survival
Finn RS, et al. N Engl J Med. 2016;375:1925–1936
444 395 360 328 295 263 238 154 69 29 10 2
222 171 148 131 116 98 81 54 22 12 4 2
PAL + LET
PCB + LET
Number of patients at risk
PFSprobability(%)
Time from randomization (months)
0 3 6 9 12 15 18 21 24 27 30 33
HR 0.58 (95% CI 0.46, 0.72)
2-sided P<0.001
Median (95% CI) PFS
14.5 months
0
10
20
30
40
50
60
70
80
90
100
Palbociclib + letrozole (n=444)
Placebo + letrozole (n=222)
35. PALOMA-2: PFS by Blinded Independent Central Review
• Blinded independent central review confirmed the PFS advantage for palbociclib + letrozole over placebo
+ letrozole observed by investigator assessment
• CI, confidence interval; HR, hazard ratio; LET, letrozole; NE, not estimable; PAL, palbociclib;
• PCB, placebo; PFS, progression-free survival
444 384 344 319 281 252 228 149 68 31 9 2
222 167 144 131 111 94 76 49 22 12 3 2
PAL + LET
Number of patients at risk
PCB + LET
Palbociclib + letrozole (n=444)
Placebo + letrozole (n=222)
Median (95% CI) PFS
19.3 months (16.4–30.6)
Median (95% CI) PFS
30.5 months (27.4–NE)
PFSprobability(%)
0 3 6 9 12 15 18 21 24 27 30 33
0
10
20
30
40
50
60
70
80
90
100
HR 0.65 (95% CI 0.51, 0.84)
2-sided P=0.001
Time from randomization (months)
Finn RS, et al. N Engl J Med. 2016;375:1925–1936
36. The PFS advantage for palbociclib + letrozole over letrozole alone was consistent across subgroups
aVisceral disease was defined as: any lung (including pleura) and/or liver involvement
CI, confidence interval; ECOG PS, Eastern Cooperative Oncology Group
Performance Status; HR, hazard ratio; ITT, intention to treat; LET, letrozole;
PAL, palbociclib; PCB, placebo; PFS, progression-free survival
Finn RS, et al. N Engl J Med 2016 Nov 17;375(20): 1925–1936
Subgroup
Palbociclib–Letrozole,
n (%)
Placebo–Letrozole,
n (%)
HR (95% CI)
All randomized patients 444 (100) 222 (100) 0.58 (0.46–0.72)
Age
<65 years
≥65 years
263 (59.2)
181 (40.8)
141 (63.5)
81 (36.5)
0.57 (0.43–0.74)
0.57 (0.39–0.84)
Race
White
Asian
344 (77.5)
65 (14.6)
172 (77.5)
30 (13.5)
0.58 (0.45–0.74)
0.48 (0.27–0.87)
Site of metastatic disease at
baseline
Viscerala
Non-visceral
214 (48.2)
230 (51.8)
110 (49.5)
112 (50.5)
0.63 (0.47–0.85)
0.50 (0.36–0.70)
Prior hormonal therapy
Yes
No
249 (56.1)
195 (43.9)
126 (56.8)
96 (43.2)
0.53 (0.40–0.70)
0.63 (0.44–0.90)
Disease-free interval
Newly metastatic disease
≤12 months
>12 months
167 (37.6)
99 (22.3)
178 (40.1)
81 (36.5)
48 (21.6)
93 (41.9)
0.67 (0.46–0.99)
0.50 (0.33–0.76)
0.52 (0.37–0.73)
Region
North America
Europe
Asia/Pacific
168 (37.8)
212 (47.7)
64 (14.4)
99 (44.6)
95 (42.8)
28 (12.6)
0.61 (0.43–0.85)
0.57 (0.41–0.80)
0.49 (0.27–0.87)
ECOG performance status
0
1/2
257 (57.9)
187 (42.1)
102 (45.9)
120 (54.1)
0.65 (0.47–0.90)
0.53 (0.39–0.72)
Bone-only disease at baseline
Yes
No
103 (23.2)
341 (76.8)
48 (21.6)
174 (78.4)
0.36 (0.22–0.59)
0.65 (0.51–0.84)
Measurable disease
Yes
No
338 (76.1)
106 (23.9)
171 (77.0)
51 (23.0)
0.66 (0.52–0.85)
0.35 (0.22–0.57)
Prior chemotherapy
Yes
No
213 (48.0)
231 (52.0)
109 (49.1)
113 (50.9)
0.53 (0.40–0.72)
0.61 (0.44–0.84)
Most recent therapy
Aromatase inhibitor
Antiestrogen
91 (20.5)
154 (34.7)
44 (19.8)
75 (33.8)
0.55 (0.34–0.88)
0.56 (0.39–0.80)
Number of disease sites
1
≥2
138 (31.1)
306 (68.9)
66 (29.7)
156 (70.3)
0.51 (0.34–0.77)
0.61 (0.47–0.79)
Histopathological classification
Ductal carcinoma
Lobular carcinoma
356 (80.2)
68 (15.3)
184 (82.9)
30 (13.5)
0.59 (0.46–0.75)
0.46 (0.27–0.78)
In favor of PAL + LET In favor of PCB + LET
0.15 0.2 0.4 0.6 0.8 1.00 2.00
PALOMA-2: PFS Subgroup Analysis (ITT, Investigator Assessment)
37. PALOMA-2: Overall Response (ITT population)
• As initial therapy for postmenopausal ER+/HER2– advanced breast cancer, palbociclib + letrozole
improves ORR and CBR over letrozole alone
aConfirmed complete response + partial response
bConfirmed complete response + partial response + stable disease ≥24 weeks
cOne patient with bone-only disease at baseline was included; all other patients had measurable disease at baseline
CI, confidence interval; CBR, clinical benefit rate; DoR, duration of response; ER+, estrogen receptor-positive;
HER2–, human epidermal growth factor receptor 2-negative; ITT, intention to treat; NR, not reported;
NS, not significant; ORR, overall response rate
Finn RS, et al. N Engl J Med
2016 Nov 17;375(20): 1925–1936
Palbociclib + letrozole
(N=444)
Placebo + letrozole
(N=222)
Odds ratio
(95% CI)
2-sided P value
(exact)
All randomized patients,
n
444 222
ORR,a % (95% CI) 42.1 34.7 1.40 0.06
CBR,b % (95% CI)
84.9
(81.2–88.1)
70.3
(63.8–76.2)
2.39
(1.58–3.59)
<0.0001
Median DoR, mo
22.5
(19.8–28.0)
16.8c
(14.2–28.5)
NR NR
Patients with
measurable disease
338 171
ORR,a % (95% CI)
55.3
(49.9–60.7)
44.4
(36.9–52.2)
1.55
(1.05–2.28)
0.03
CBR,b % (95% CI)
84.3
(80.0–88.0)
70.8
(63.3–77.5)
2.23
(1.39–3.56)
<0.001
Median DoR,
months
22.5
(19.8–28.0)
16.8
(15.4–28.5)
NR NR
39. PALOMA-2: All-causality Hematological AEs Occurring in ≥15% of Patients in Either
Arm (As-treated Population)
• Grade 3/4 febrile neutropenia was reported in 1.8% of patients in the palbociclib + letrozole arm vs. 0% in the
placebo + letrozole arm
aIncludes clustered Medical Dictionary for Regulatory Activity (MedDRA) preferred terms
AE, adverse event Finn RS, et al. N Engl J Med 2016 Nov 17;375(20): 1925–1936
Palbociclib + letrozole
(N=444)
Placebo + letrozole
(N=222)
Any grade Grade 3 Grade 4 Any grade Grade 3 Grade 4
Any AE, % 98.9 62.2 13.5 95.5 22.1 2.3
Neutropeniaa 79.5 56.1 10.4 6.3 0.9 0.5
Leukopeniaa 39.0 24.1 0.7 2.3 0 0
Anemiaa 24.1 5.2 0.2 9.0 1.8 0
Thrombocytopenia
a
15.5 1.4 0.2 1.4 0 0
40. PALOMA-2: Summary
Palbociclib combined with letrozole significantly improved median PFS compared with placebo +
letrozole as first-line therapy in women with ER+/HER2– advanced breast cancer
– >10 month improvement in median PFS was observed (24.8 vs. 14.5 months)
– HR=0.58 (95% CI: 0.46–0.72; 2-sided P<0.001)
Clinical benefit from palbociclib was also demonstrated across all prespecified subgroup
SAEs
• Overall incidence of SAEs was higher in patients receiving palbociclib + letrozole vs. placebo + letrozole
(20% vs. 13%)
• SAEs were reported for <1% of patients in either treatment arm except febrile neutropenia (1.6%
palbociclib + letrozole arm vs. 0% placebo + letrozole arm) and pulmonary embolism (0.9% palbociclib
arm vs. 1.4% placebo arm)
Permanent treatment discontinuations of palbociclib or placebo associated with AEs
• 7% of patients in the palbociclib arm vs. 5% in the placebo arm
AE, adverse event; SAE, serious adverse event Finn RS, et al. N Engl J Med 2016 Nov 17;375(20): 1925–1936
41. Higher response rate in combination arm probably reflects the effect of palbociclib in primary resistance
to aromatase inhibitors (resistant to estrogen deprivation tumors become sensitive due to CDK inhibition)
Longer PFS reflects the delay of onset of acquired resistance to aromatase inhibitors
(sensitive cells remain longer sensitive due to CDK inhibition)
What about after aromatase inhibitors failure ?
42. We know that exemestane or fulvestrant are reasonable
options for second line endocrine therapy
Alone…
Chia S, et al. J Clin Oncol. 2008 Apr 1;26(10):1664-70
43. … or in combinations, as a strategy to overcome hormone therapy resistance
HDAC inhibitors mTOR inhibitors
PI3K inhibitors
45. Hormonal therapies function partly through
suppression of CDK4 and CDK6 activity,
and reactivation of these kinases has been
implicated in endocrine resistance
Endocrine-resistant luminal breast cancer cell
lines are sensitive to direct inhibition of CDK4
and CDK6 and show synergy when combined with
hormonal therapy
Cynthia X. Ma, et al.
Nature Reviews Cancer 15, 261–275 (2015)
46. PALOMA-3: Study Design
Phase III, double-blind study involving 144 centers in 17 countries
aAll received goserelin; bMust have progressed on adjuvant tamoxifen or other prior endocrine therapy (pre-/perimenopausal) or AI
therapy (postmenopausal); cPatients randomised; dAdministered on days 1 and 15 of Cycle 1, then every 28 days
Data cutoff December 5 2014 used for interim analysis; median follow-up 5.6 months
Data cutoff March 16 2015 used for final analysis; median follow-up 8.9 months
HR, hormone receptor
1. Turner NC, et al. N Engl J Med 2015;373:209–19
2. Cristofanilli M, et al. Lancet Oncol 2016 2016 Apr;17(4):425–39
3. Harbeck N, et al. Annals Oncol 2016;6:1047−54
4. Verma S, et al. The Oncologist 2016;0097
• Visceral metastases
• Sensitivity to prior
hormonal therapy
• Pre-/peri- vs.
postmenopausal
2:1 Randomization
N=521c
Stratification:
n=347
n=174
•HR+, HER2– MBC
•Pre/perimenopausala,b or
postmenopausalb
•Progressed on prior endocrine therapy:
– on or within 12 months of completion of
adjuvant treatment
– on or within 1 month after treatment for
MBC
• ≤1 prior chemotherapy regimen for
advanced cancer
Palbociclib
(125 mg QD;
3 weeks on/1 week off)
+
fulvestrantd
(500 mg IM Q4W)
Placebo
(3 weeks on/1 week off)
+
fulvestrantd
(500 mg IM Q4W)
47. PALOMA-3 Final Analysis: ITT Population Clinical and Pathological
Characteristics
aPer protocol, visceral refers to lung, liver, brain, pleural and
peritoneal involvement, and was a study stratification factor Cristofanilli M, et al. Lancet Oncol 2016 2016 Apr;17(4):425–39
Characteristic
ITT population
Palbociclib + fulvestrant (n=347)
Placebo + fulvestrant
(n=174)
Median age, years (range) 57 (30−88) 56 (29−80)
Self-reported race, n (%)
White 252 (73) 133 (76)
Asian 74 (21) 31 (18)
Black or other 21 (6) 10 (6)
ECOG PS, n (%)
0 206 (59) 116 (67)
1 141 (41) 58 (33)
Menopausal status, n (%)
Pre- or perimenopausal 72 (21) 36 (21)
Postmenopausal 275 (79) 138 (79)
Non-measurable disease, n (%)
Bone 75 (22) 36 (21)
Others 4 (1) 0
Measurable disease, n (%)
Any measurable disease 268 (77) 138 (79)
Visceral diseasea
206 (59) 105 (60)
Lung involvement 100 (29) 45 (26)
Liver involvement 127 (37) 81 (47)
Peritoneal involvement 2 (1) 1 (1)
Brain or pleural involvement, or both 4 (1) 2 (1)
48. Median PFS
11.2 months
PALOMA-3: Addition of palbociclib improved PFS in ET-resistant patients
*Stratified by the presence of visceral disease and sensitivity to prior hormone therapy.
CI, confidence interval; ET, endocrine therapy; FUL, fulvestrant; HR, hazard ratio;
PAL, palbociclib; PCB, placebo; PFS, progression-free survival Turner NC, et al. Poster presented at SABCS 2016 (Abstract P4-22-06)
PAL + FUL
PCB + FUL
Number of patients at risk
Median PFS
4.6 months
1 3 5 7 9 11 15 17 19 21 23
20
40
60
80
100
2 4 6 8 10 13 16 18 20 221412
347
174
324
162
271
105
242
80
214
61
188
50
162
40
45
11
15
4
9
3
1
0
0276
112
245
83
215
62
189
51
168
43
119
29
38
11
12
4
2
1
169
15
137
29
0
0
Progression-freesurvival(%)
Time (months)
Palbociclib + fulvestrant (n=374)
Placebo + fulvestrant (n=174)
HR 0.50 (95% CI: 0.40, 0.62)
1-sided P<0.0001*
49. PALOMA-3 Final Analysis: PFS by Patient Subgroup
Palbociclib +
fulvestrant
median PFS (95% CI)
Placebo + fulvestrant
median PFS (95% CI)
HR
(95% CI) Pinteraction
Menopausal status at study entry 0.89
Premenopausal or
perimenopausal
9.5 (7.4–NE) 5.6 (1.8–7.6) 0.50 (0.29–0.87)
Postmenopausal 9.9 (8.5–11.0) 3.9 (3.5–5.5) 0.45 (0.34–0.59)
Site of metastatic disease 0.82
Visceral 8.0 (7.5–9.5) 3.5 (2.0–5.3) 0.47 (0.34–0.63)
Non-visceral 11.2 (9.9–NE) 5.6 (4.6–10.9) 0.43 (0.28–0.67)
No. of disease sites 0.43
1 11.2 (9.9–NE) 9.3 (5.5–NE) 0.55 (0.34–0.90)
2 11.0 (7.5–NE) 3.6 (1.9–5.6) 0.37 (0.24–0.59)
≥3 7.6 (7.4–9.5) 3.4 (1.9–3.7) 0.40 (0.28–0.59)
Disease-free interval 0.16
≤24 months 7.2 (2.5–9.2) 5.4 (1.8–9.3) 0.83 (0.43–1.59)
>24 months 9.9 (9.3–11.2) 5.5 (3.5–7.3) 0.48 (0.35–0.68)
Previous lines of endocrine
therapy
0.75
1 9.5 (7.6–NE) 4.6 (3.4–5.6) 0.42 (0.29–0.60)
2 9.9 (7.5–13.9) 5.1 (2.8–7.2) 0.46 (0.31–0.69)
≥3 9.4 (7.5–NE) 3.9 (1.8–NE) 0.61 (0.30–1.24)
Previous endocrine therapy 0.63
AI only 9.5 (7.6–13.9) 3.7 (2.1–5.5) 0.39 (0.27–0.57)
Tamoxifen only 9.5 (7.5–NE) NE (1.7–NE) 0.61 (0.28–1.33)
AI and tamoxifen 9.5 (7.6–11.2) 4.2 (3.5–7.2) 0.50 (0.35–0.71)
Favors palbociclib +
fulvestrant
Favors placebo +
fulvestrant
0.125 0.25 0.5 1 2 4 8
Cristofanilli M, et al. Lancet Oncol 2016 2016 Apr;17(4):425–39
50. Palbociclib +
fulvestrant
median PFS
(95% CI)
Placebo +
fulvestrant
median PFS
(95% CI)
HR
(95% CI) Pinteraction
Sensitivity to previous
hormonal therapy
0.13
Yes 10.2 (9.4–11.2) 4.2 (3.5–5.6) 0.42 (0.32–0.56)
No 7.4 (5.6–9.2) 5.4 (1.9–7.4) 0.64 (0.39–1.07)
The purpose of most recent
therapy
0.39
Neoadjuvant or adjuvant
treatment
9.5 (7.4–NE) 5.4 (2.1–10.9) 0.55 (0.32–0.92)
Metastatic treatment 9.9 (9.2–11.2) 3.9 (3.5–5.6) 0.43 (0.32–0.57)
Previous chemotherapy 0.22
Neoadjuvant or adjuvant
treatment only
11.0 (7.6–NE) 5.6 (3.5–9.3) 0.60 (0.40–0.88)
Metastatic treatment 7.7 (5.7–9.5) 3.5 (1.9–5.4) 0.43 (0.29–0.64)
None 10.8 (9.5–NE) 5.4 (3.4–7.3) 0.31 (0.18–0.53)
PIK3CA status 0.83
Positive 9.5 (5.7–11.2) 3.6 (1.9–5.6) 0.48 (0.30–0.78)
Negative 9.9 (9.2–13.9) 4.6 (3.4–7.3) 0.45 (0.31–0.64)
Overall 9.5 (9.2–11.0) 4.6 (3.5–5.6) 0.46 (0.36–0.59)
Favors palbociclib +
fulvestrant
Favors placebo +
fulvestrant
0.125 0.25 0.5 1 2 4 8
PALOMA-3 Final Analysis: PFS by Patient Subgroup (cont’d)
Cristofanilli M, et al. Lancet Oncol 2016 2016 Apr;17(4):425–39
51. 11%9%
PALOMA-3 Final Analysis: Response Rates
*2-sided exact tests stratified by the presence of visceral metastases and sensitivity to previous hormonal therapy as per
randomization were used to calculate p values
CBR, clinical benefit rate; CR, complete response; OR, odds ratio; ORR, objective response rate; PR, partial response; SD, stable
disease Cristofanilli M, et al. Lancet Oncol 2016 2016 Apr;17(4):425–39
Palbociclib + fulvestrant resulted in a
statistically significant improvement
over fulvestrant alone for:
•ORR in ITT (19% vs. 9%,
respectively) and in patients with
measurable disease (25% vs. 11%)
•Clinical benefit in ITT (67% vs. 40%)
and in patients with measurable
disease (64% vs. 36%)
Palbociclib + fulvestrant
Placebo + fulvestrant
Population: ITT Measurable disease ITT Measurable disease
OR
(95% CI)
2.47
(1.36–4.91)
2.69
(1.43–5.26)
3.05
(2.07–4.61)
3.10
(1.99–4.92)
60
50
40
30
20
10
0 Measurable
disease
Measurable
disease
ITT
P<0.0001*
P=0.0019*
P=0.0012*
ORR
ITT
CBR
P<0.0001*
Patients(%)
70
19%
25%
67%
40%
64%
36%
PR CR SD
PR CR SD
52. Palbociclib + fulvestrant:
Effect on subsequent treatment
• Exploratory analysis of post-progression
treatment
• Most common post-progression treatment
regimens in both arms were everolimus,
capecitabine, paclitaxel and exemestane
(with or without everolimus)
• Data suggest that treatment effect of
palbociclib + fulvestrant is retained through
immediate next line of post-progression
therapy
• Progression after palbociclib treatment
does not seem to affect clinical benefit of
subsequent therapies
aDetermined using the Kaplan-Meier method
CI, confidence interval; ET, endocrine therapy; FUL, fulvestrant; PAL, palbociclib; PCB, placebo Turner NC, et al. Poster presented at SABCS 2016 (Abstract P4-22-06)
Median time (95% CI), months
Time from first dose to end
of study treatmenta
n=142
PAL + FUL
6.9 (5.4–7.8)
All therapies
4.3 (3.5–5.6)
n=107
PCB + FUL
3.7 (2.8–4.6)
All therapies
5.7 (4.1–8.9)
n=124
PAL + FUL
6.1 (4.6–7.5)
Chemotherapy
4.8 (3.7–6.0)
n=88
PCB + FUL
3.7 (2.3–4.0)
Chemotherapy
5.9 (3.9–8.9)
n=57
PAL + FUL
7.6 (4.2–9.9)
ET
3.4 (2.4–6.1)
n=47
PCB + FUL
4.2 (2.8–5.6)
ET
4.4 (2.8–6.2)
n=44
PAL + FUL
7.1 (3.6–9.9)
Targeted therapy
3.4 (2.4–6.8)
n=42
PCB + FUL
4.0 (3.5–5.6)
Targeted therapy
5.0 (2.8–13.1)
Time from start to end of the
immediate follow-up therapya
Median time (95% CI), months
54. PALOMA-3: Summary of Hematologic Toxicity
aPalbociclib + fulvestrant arm only; bBy episode by grade analysis. Percentages are based on number of episodes in each subgroup. For
multiple time to recovery periods within a subject, average was taken prior to summarizing across subjects
Data cutoff March 16 2015 used for final analysis; median follow-up 8.9 months Verma S, et al. The Oncologist 2016;0097
Time to onset of hematologic toxicitya Duration of each episode (days)
Grade ≥3 Grade 4
0 402010 50 6030
Thrombocytopenia
Anemia
Neutropenia
Median (range) time to onset from
first dose of palbociclib to first episode (days)
0.0
16.0
17.0
39.5
26.5
15.0
0 861 9 107
Median (range) duration of each episode (days)
2 3 4 5
Thrombocytopenia
Anemia
Neutropenia
0.0
7.0
8.0
7.0
7.0
7.0
55. Palbociclib-induced neutropenia differs from that seen with Chemotherapy
Palbociclib-induced neutropenia1,2 CT-induced neutropenia2-4
Mechanism
Cell-cycle arrest but no death of
proliferating neutrophil precursors
DNA damage and apoptosis of
proliferating neutrophil precursors
Reversibility Rapid recovery Delayed recovery
CT = chemotherapy.
1. Johnson SM, et al. J Clin Invest. 2010;120:2528-2536. 2. Hu W, et al. Clin Cancer Res. 2015;22(8):2000-2008. 3. Helleday T, et al. Nat Rev Cancer. 2008;8:193−204.
4. Curtin NJ. Nat Rev Cancer. 2012;12:801-817.
56. Example 1:
A patient with Grade ≤2 neutropenia
= CBC
= Off IBRANCE
= On IBRANCE No dose adjustment is required for Grade 1
or Grade 2 neutropenia
2
1500/mm3
3
1000/mm3
1
LLN
4
500/mm3
Cycle 2 Cycle 3 onwardCycle 1
D1 D7 D14 D21D1 D7 D14 D21D1 D7 D14 D21
Continue 125 mg
Next CBC Cycle 4, Day 1
(Unless clinically indicated)
125 mg
starting
dose
ANCGrade*
*Grading according to CTCAE 4.0.
ANC = absolute neutrophil count; CBC = complete blood count; LLN = lower limit of normal.
57. Example 2:
A patient with recurrent uncomplicated Grade 3 neutropenia without prolonged
recovery (<1week)
Consider dose reduction in cases of recurrent Grade 3
neutropenia in subsequent cycles
= CBC
= Off IBRANCE
= On IBRANCE
*Grading according to CTCAE 4.0.
ANC = absolute neutrophil count; CBC = complete blood count; LLN = lower limit of normal.
In many cases, as in
this scenario, patients can
be monitored and neutropenia allowed
to persist throughout treatment without
a dose reduction
Continue at same dose;
repeat CBC on Day 21
125 mg starting
dose
Continue 125 mg
Next CBC Cycle 4, Day 1
(Unless clinically indicated)
ANCGrade*
Cycle 2 Cycle 3 onwardCycle 1
D1 D7 D14 D21D1 D7 D14 D21D1 D7 D14 D21
2
1500/mm3
3
1000/mm3
1
LLN
4
500/mm3
58. D1 D7 D14D D7 D14 D21D1 D7 D14 D21 D1D
Oncologist decided
to decrease
dose to 100 mg Continue on 100 mg
Next CBC Cycle 4, Day 1
(Unless clinically indicated)
Would be Day 1 of
Cycle 2
2-week
treatment
break before
recovery
of ANC ≤2
125 mg
starting dose
Continue at same dose;
repeat CBC on Day 21
Consider dose reduction in cases of prolonged
(>1 week) recovery from Grade 3 neutropenia
= CBC
= Off IBRANCE
= On IBRANCE
= On lower dose IBRANCE
Example 3:
A patient with uncomplicated Grade 3 neutropenia and prolonged recovery
to Grade 2
*Grading according to CTCAE 4.0.
ANC = absolute neutrophil count; CBC = complete blood count; CTCAE = Common Terminology Criteria for Adverse Events; LLN = lower limit of normal.
Cycle 2 Cycle 3 onwardCycle 1ANCGrade*
2
1500/mm3
3
1000/mm3
1
LLN
4
500/mm3
59. In cases of febrile neutropenia, withhold
therapy until recovery to Grade ≤2, resume
at the next lower dose
= CBC
= Off IBRANCE
= On IBRANCE
= On lower dose IBRANCE
Example 4:
A patient with Grade 3 febrile neutropenia
*Grading according to CTCAE 4.0.
ANC = absolute neutrophil count; CBC = complete blood count; CTCAE = Common Terminology Criteria for Adverse Events; LLN = lower limit of normal.
Fever resolved
Reduce dose to 100 mg
Day 17 patient presented
with fever, CBC revealed
Grade 3 neutropenia
Withhold IBRANCE
until recovery to Grade ≤2
Continue
at same dose
Continue on 100 mg
Next CBC Cycle 4, Day 1
(Unless clinically indicated)
125 mg starting
dose
ANCGrade*
Cycle 2 Cycle 3 onwardCycle 1
D1 D7 D14 D21D1 D7 D14 D21D1 D7 D14 D21
2
1500/mm3
3
1000/mm3
1
LLN
4
500/mm3
60. In cases of Grade 4 neutropenia, withhold therapy
until recovery to Grade ≤2, and then resume at the
next lower dose
= CBC
= Off IBRANCE
= On IBRANCE
= On lower dose IBRANCE
Reduce dose
to 100 mg
Withhold IBRANCE until
recovery
to Grade ≤2
Continue
at same dose
Continue on 100 mg
Next CBC Cycle 4, Day 1
(Unless clinically indicated)
125 mg
starting dose
Example 5:
A patient with Grade 4 neutropenia
Cycle 2 Cycle 3 onwardCycle 1
D1 D7 D14 D21D1 D7 D14 D21D1 D7 D14 D21
ANCGrade*
2
1500/mm3
3
1000/mm3
1
LLN
4
500/mm3
*Grading according to CTCAE 4.0.
ANC = absolute neutrophil count; CBC = complete blood count; CTCAE = Common Terminology Criteria for Adverse Events; LLN = lower limit of normal.
61. Cumulative incidence of hematologic AEs during the first 3 years of palbociclib treatment
• No evidence of specific cumulative or delayed toxicity resulting from prolonged treatment with palbociclib
and ET for HR+/HER2– mBC
aClustered preferred terms as defined in primary papers
AEs, adverse events; ET, endocrine therapy; HER2, human epidermal growth factor receptor-2;
HR, hormone therapy; mBC, metastatic breast cancer Diéras V, et al. Poster presented at SABCS 2016 (Abstract P4-22-07)
All grades Grades 3/4
Patients(%)
First year
0
10
20
30
40
90
50
60
80
70
First 2 years First 3 years
Palbociclib treatment
Neutropeniaa (n=690)
Leukopeniaa (n=377)
Anaemiaa (n=212)
Patients(%)
First year
0
20
30
40
70
50
60
First 2 years First 3 years
Palbociclib treatment
10
62. Palbociclib combination therapy: Efficacy AI sensitive & ET resistant
ET, endocrine therapy; ITT, intention to treat; PFS, progression-free survival
1. Finn RS, et al. N Engl J Med 2016;375:1925–1936;
2. Turner NC, et al. Poster presented at SABCS 2016 (Abstract P4-22-06).
3. IBRANCE EU SmPC
Median PFS
AI sensitive (PALOMA-2)1
ET resistant (PALOMA-3)2
Months
Objective response rate (ITT population)
0 5 10 15 20 25
14.5 24.8
4.6 11.2
42.1%
21,0%
34.7%
8.6%
Palbociclib + ET
ET + placebo
AI sensitive (PALOMA-2)1 ET resistant (PALOMA-3)2,3
For PALOMA-2, ET was letrozole
For PALOMA-3, ET was fulvestrant
In Summary…
63.
64.
65. CDK4/6 inhibitors in development
*Investigational drug not approved in Europe for use in breast cancer
EMA, European Medicines Agency
Clinicaltrials.gov;
O’Leary B, et al. Nat Rev Clin Oncol. 2016;13:417–430;
EMA November 2016, EMA/626565/2016
PALOMA
trials
MONALEESA
trials
MONARCH
trials
Abemaciclib*
Palbociclib
EMA approved Nov 2016 Ribociclib*
66. Abemaciclib*: Phase II MONARCH-1 study
*Abemaciclib is not approved for use in mBC
aAssessments based on independent review were comparable
ECOG performance status, Eastern Cooperative Oncology Group Performance Status; ER, oestrogen receptor;
ET, endocrine therapy; HER2, human epidermal growth factor receptor-2; mBC, metastatic breast cancer; OS,
overall survival; PFS, progression-free survival; Q12H, every 12 hours www.clinicaltrials.gov NCT02102490
Abemaciclib
(200 mg orally Q12H)
• ER+, HER2– mBC
• 1 or 2 chemotherapy
regimens in the metastatic
setting, at least 1 regimen
containing a taxane
• Progression on/after prior ET
• ECOG PS 0 or 1
n=132
Primary endpoint:
Investigator-assessed
objective response ratea
Secondary endpoints:
Duration of response,
PFS, OS, clinical benefit
rate, safety
67. MONARCH-1: Anti-tumour activity
ER+/HER2– patients with 1–2 prior chemotherapy regimens for advanced cancer
*Abemaciclib is not approved for use in mBC
aAssessments based on independent review were comparable
CR, complete response; ER, oestrogen receptor; HER2, human epidermal growth factor receptor-2;
mBC, metastatic breast cancer; PR, partial response; SD, stable disease Dickler MN, et al. Presented at ASCO 2016. Abstract 510
100
50
20
0
–30
–50
–100
Changefrombaseline(%)
Investigator-assessed responsea
Abemaciclib* 200mg
(n=132)
Confirmed objective response rate (ORR = CR + PR) 19.7%
Clinical benefit rate (CBR = ORR + SD ≥ 6 mos) 42.4%
68. Ribociclib*: Phase III MONALEESA-2 study
*Ribociclib is not approved in Europe for use in ABC
ABC, advanced breast cancer; ER, oestrogen receptor; HER2, human epidermal growth factor
receptor-2; OS, overall survival; PFS, progression-free survival; QD, once daily Hortobagyi GN, et al. N Engl J Med 2016;375:1738–1748
Primary endpoint:
Investigator-assessed
PFS
Secondary endpoints:
OS, objective response
rate, clinical benefit rate,
safety
Stratification factors:
Presence/absence of lung
and liver metastases
Placebo
(3/1 schedule)
+ letrozole
(2.5 mg QD)
Ribociclib (600 mg QD,
3/1 schedule)
+ letrozole
(2.5 mg QD)
Postmenopausal
ER+, HER2– ABC
No prior treatment for advanced
disease
RANDOMISATION
N=668
1:1
69. MONALEESA-2: Longer PFS with addition of ribociclib* to ET
*Ribociclib is not approved in Europe for use in ABC
ABC, advanced breast cancer; CI, confidence interval; HR, hazard ratio
PFS, progression-free survival Hortobagyi GN, et al. N Engl J Med 2016;375:1738–1748
0 2 4 6 8 10 12 14 16 18 20 22 24
1.0
0.9
0.8
0.7
0.6
0.5
0.4
0.3
0.2
0.1
0
Time (months)
PFSprobability(%)
HR 0.56 (95% CI, 0.43-0.72)
P=3.29 x 10-6 for superiority
Ribociclib + letrozole
Placebo + letrozole
334 294 277 257 240 226 164 119 68 20 6 1 0
334 279 264 237 217 192 143 88 44 23 5 0 0
Ribociclib
Placebo
No. at risk
Median PFS:
not reached
Median PFS:
14.7 months
71. More data to come for CDK4/6 inhibitors
in HR+/HER2– breast cancer
*Ribociclib and abemaciclib are not approved in Europe for use in breast cancer
HER2, human epidermal growth factor receptor-2; HR, hormone receptor www.clinicaltrials.gov
MONALEESA-7
NCT02278120
PALOMA trials
further analysis
NCT00721409
NCT01740427
NCT01942135
PEARL
NCT02028507
MONALEESA-2
NCT01958021
MONALEESA-3
NCT02422615
MONARCH-2
NCT02107703
MONARCH-3
NCT02246621
PALOMA-4
NCT02297438
Asian
population
PARSIFAL
NCT02491983Palbociclib
Ribociclib*
Abemaciclib*
72. RTK signaling activates CDK4/6
signaling, but might also promote
CDK4/6 inhibitor resistance,
potentially through promotion of
cyclin E or through inhibition of
CDK inhibitor 1/CDK inhibitor 1B.
Possible combination therapies CDK4/6 inhibitors
Ben O’Leary, et al. NATURE REVIEWS | CLINICAL ONCOLOGY
VOLUME 13 | JULY 2016 | 417
73. Promising strategies:
CDK4/6 inhibition with
- PI3K-pathway blockade with
PI3K inhibitors
- mTOR inhibition with
rapamycin analogues
- MAPK pathway blockade with
BRAF and MEK inhibitors
Ben O’Leary, et al. NATURE REVIEWS | CLINICAL ONCOLOGY
VOLUME 13 | JULY 2016 | 417
74. Early Adaptation and Acquired Resistance to CDK4/6 Inhibition in Estrogen Receptor–Positive Breast Cancer
Maria Teresa Herrera-Abreu, Cancer Res April 2016
Triple combination of endocrine therapy, CDK4/6,
and PI3K inhibition was more effective than paired
combinations
76. And what about HER2(+) disease ?
Overcoming Therapeutic Resistance in HER2-Positive Breast Cancers
With CDK4/6 Inhibitors Shom Goel Cancer Cell. 2017
Inhibition of CDK4/6 not only suppresses Rb phosphorylation, but also reduces TSC2 phosphorylation and
thus partially decrease mTORC1 activity. Dual inhibition of EGFR/HER2 and CDK4/6 invokes a more potent
suppression of TSC2 phosphorylation and hence mTORC1/S6K/S6RP activity enhancing G1 arrest
77. Conclusions
• Guidelines for HR+/HER2– mBC have recently been revised to include the
CKD4/6 inhibitor palbociclib, providing a new standard of care
– Additional CDK4/6 inhibitors in development comprise ribociclib* and abemaciclib*
• Palbociclib + ET extends PFS over ET alone, in both the AI-sensitive (10.3-month
improvement) and ET-resistant (6.6-month improvement) HR+/HER2– mBC
setting
• Haematologic toxicities are common, but manageable
• The use of combination palbociclib + ET does not seem to compromise time on
subsequent treatment
• Further clinical trials in mBC and other breast cancer settings are underway
with palbociclib,† ribociclib* and abemaciclib*
*Investigational drug not approved in Europe for use in breast cancer
†Palbociclib is only approved for use in mBC
AI, aromatase inhibitor; CDK, cyclin-dependent kinase; HR, hormone receptor; HER2, human epidermal growth factor
receptor-2; ET, endocrine therapy; mBC, metastatic breast cancer; PFS, progression-free survival