Role of Newer agent Palbociclib in metastatic breast cancer

1. Management of Metastatic Breast Cancer –
Understanding role of Palbociclib in Indian setting
Dr. Vibhay Pareek
Jupiter Hospital

2. • Disclosure: Few slides taken from Pfizer
• Conflict of Interest: None

9. Recommendations from the ESO-ESMO ABC-2 panel
• “Endocrine therapy is the preferred option for hormone receptor positive
disease, even in the presence of visceral disease, unless there is concern
or proof of endocrine resistance, or there is disease needing a fast
response”
• Level of evidence IA
• Votes: 100% yes, 29 voters (of 43 members)
Cardoso F et al, The Breast 23:489 – 502, 2014, and Ann Oncol 2014

13. Clinical trials comparing
HT vs. HT + biological agent
in ER+ advanced disease.
Focus on: The BOLERO-2 trial

14. EVE 10 mg daily
+
EXE 25 mg daily (n = 485)
Placebo
+
EXE 25 mg daily (n = 239)
R
2:1
N = 724
•Postmenopausal ER+
•Unresectable locally
advanced or metastatic BC
•Recurrence or progression
after letrozole or anastrozole
The BOLERO-2 Phase III trial:
Everolimus in advanced disease
Baselga J, et al. N Engl J Med. 366:520-529, 2012
• 84% of patients sensitive to prior endocrine therapy (i.e. DFI > 24 mos. if relapse
while/after adjuvant AI or clinical benefit to the prior line of endocrine therapy for
advanced disease)
• 84% of patients received the study drugs as ≥ 2° line of therapy for advanced disease

15. The progression free survival improved by 5 months
with addition of everolimus to exemestane and
overall survival improved by 6 months

16. Safety profile everolimus:
most common adverse events
Adverse event Everolimus
N = 482
% G3-G4 (%G1-G4)
Placebo
N = 238
% G3-G4 (%G1-G4)
Stomatitis 8 (56) 1 (11)
Anemia 6 (16) 1 (4)
Dyspnea 4 (18) 1 (9)
Hyperglicemia 4 (13) 1 (2)
Fatigue 4 (33) 1 (26)
Pneumonitis 3 (12) - (-)
Baselga J et al, New Engl J Med 366: 520-9, 2012.

17. The TAMRAD trial
Bachelot T et al, J Clin Oncol 30: 2718-24, 2012
TAM TAM + Everolimus
Clinical benefit
rate at six months
42%
(95% CI: 29-56%)
61%
(95% CI: 47-74%)
• post-menopausal
• ER+/HER-2 neg No. = 111 pts.
• pre-treatment with AI
TAM + Everolimus
TAM

18. Changing paradigms with CDK 4/6
kinase inhibitors in ER+ HER2 – metastatic
breast cancer:
ROLE OF PALBOCICLIB

19. Metastatic Breast Cancer (MBC) Landscape
19
HER2+
Triple negative
~15%5
HER=human epidermal growth factor receptor; HR+=hormone receptor-positive.
1. Early Breast Cancer Trialists’ Collaborative Group, et al. Lancet. 2015;386:1341-1352. 2. O’Shaughnessy J. Oncologist. 2005;10(suppl 3):20-29.
3. National Cancer Institute. SEER cancer statistics review (CSR) 1975-2012. http://seer.cancer.gov/csr/1975_2012/. Accessed April 19, 2016. 4. Mayer M,
Grober SE. Silent voices: women with advanced (metastatic) breast cancer share their needs and preferences for information, support, and practical resources.
https://www.researchgate.net/publication/274510595_Silent_Voices_Women_with_Advanced_Metastatic_ Breast_Cancer_Share_
Their_Needs_and_Preferences_for_Information_Support_and_Practical_Resources. Accessed April 19, 2016.
5. Howlader N, et al. J Natl Cancer Inst. 2014;106(5):dju055.
Women
living with MBC4
HR+
HR+/HER2-
~61%5
HR+/HER2+
~15%5
HR-/HER2+
~9%5
Roughly 20% to 30% of women
who have had early disease will
develop advanced or metastatic
disease1,2
4% to 9% of all women with breast
cancer present with metastatic
disease at the
time of initial diagnosis3

20. Cyclin D1 and CDK4/6 Are Critical for Cellular
Proliferation
CDKs are key regulators of sequential progression through the G1, S, G2, and
M phases of the cell cycle
Dickson MA, Schwartz GK. Curr Oncol 2009;16:36–43
Shapiro GI. J Clin Oncol 2006;24:1770–83
M G1
G2 S
CDK4/6
Cyclin
D1/D2/D3
CDK2Cyclin A
CDK2Cyclin E
CDK1 Cyclin A
CDK1 Cyclin B

21. Cyclin D1 and CDK4/6 Are Downstream of Signaling Pathways That Lead
to Cellular Proliferation and regulate the G1-S checkpoint
Lange et al. Endocrine-Related Cancer 2011;18:C19–C24
RB
RB
Gene
transcriptionG2 S
M
G1
G0
P
P P
P
Inactive
Active tumor
suppressor
E2F
E2F
R
CDK4/6Cyclin D
Pl3K/Akt
STATs MAPKs
(ER/PR/AR) Wnt/β-catenin
NF-κB
p16
p21
p53
R = restriction point
RB- retinoblastoma gene product
E2F- transcription factors

22. 22
The Potential of Combined Targeting of ER and CDK4/6
• The complex, interconnected, and redundant
cellular pathways that are co-opted by cancer,
influence the therapeutic vulnerability of tumor
cells1
• 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
1. Osborne CK, et al. Annu Rev Med. 2011;62:233-247; 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):12-19;
7. Asghar U, et al. Nat Rev Drug Discov. 2015;14:130-146;
8. VanArsdale T, et al. Clin Cancer Res. 2015;doi:10.1158/1078-0432.
NUCLEUS
CYTOPLASM
EXTRACELLULAR
SPACE
Growth
factor6
PI3K6
Receptor tyrosine
kinase6
Akt6
mTOR6
Estrogen1
ER1
pRb7
E2F7
Cellular proliferation7
Cyclin D1 +
CDK4/65-8
M
G18
S
G2

23. 23
NN O
N
NH
O
N
N
N
H2
+
S
O
O
O
OH
First-in-class CDK4/6 Inhibitor: Palbociclib
• Orally active selective inhibitor of CDK4 and CDK61,2
• Inhibits cell proliferation and cellular DNA synthesis by preventing
cell-cycle progression from G1 to S phase1
1. Fry DW, et al. Mol Cancer Ther 2004;3:1427–38
2. Menu E, et al. Cancer Res 2008;68:5519–23
3. Sutherland RL, Musgrove EA. Breast Cancer Res 2009;11:112
4. Van Arsdale T, et al. Clin Cancer Res 2015; Epub May 2
• Low nanomolar concentrations block
Rb phosphorylation, inducing specific G1
arrest in sensitive cell lines1-3
• Inhibits proliferation in cultured and
xenografted leukemia, myeloma, breast
cancer, colon cancer, and lung cancer
cells4
Palbociclib
(PD-0332991)

25. 26
• Luminal, ER+ or HER2-amplified breast cancer cell lines most sensitive to CDK4/6 inhibition of
proliferation (non-luminal resistant)
• Synergistic growth inhibitory activity between palbociclib and tamoxifen (ER+) or trastuzumab
(HER2+)
• Palbociclib activity seen in acquired tamoxifen resistance
Palbociclib Preferentially Inhibits Proliferation of Luminal
ER+ Human Breast Cancer Cell Lines In Vitro
Finn RS, et al. Breast Cancer Res 2009;11:R77EMT, epithelial mesenchymal transition 26
0
100
200
300
400
500
600
700
800
900
1000
Luminal
HER2-amplified
Immortalized
Non-luminal/post EMT
Non-luminal

26. Combination Palbociclib and an Endocrine Therapy in
Preclinical Models
• In these preclinical analyses, treatment of breast cancer cell lines with the combination of palbociclib and an
endocrine therapy led to increased growth arrest compared to treatment with each drug alone2
CIm=mean combination index; ER=estrogen receptor; ET=endocrine therapy; nM=nanomolar; PAL=palbociclib.
1. Finn RS, et al. Breast Cancer Res. 2009;11(5):R77. 2. IBRANCE® Prescribing Information. New York, NY: Pfizer Inc; 2016.
0
80
60
40
20
100
T47D1
CIm=0.1 ± 0.01
6255000ET
PAL
Concentration (nM)
2500 1250 312
25 12.5 3.1256.2550
EFM191
0
80
60
40
20
100
6255000ET
PAL
Concentration (nM)
2500 1250 312
25 12.5 3.1256.2550
CIm=0.45 ± 0.09
0
80
60
40
20
100
62510,000ET
PAL
Concentration (nM)
2500 12505000 312
25 12.550 3.1256.25100
CIm=0.37 ± 0.04
MCF71
%Inhibition
Endocrine Therapy Alone Palbociclib + Endocrine Therapy CombinationPalbociclib Alone
27
• Preclinical analyses contributed to the rationale to combine IBRANCE with letrozole or fulvestrant in the PALOMA-1 and PALOMA-3 trials
• MCF7, EFM19, and T47D are ER+, estrogen-sensitive breast cancer cell lines that were treated with endocrine therapy alone, palbociclib
alone, or palbociclib + endocrine therapy over a range of concentrations; growth of the cell lines was measured1

27. 28
Dose ranging study: 3/1 Schedule Associated With
Prolonged SD vs 2/1 Schedule but Both Well Tolerated
1. Flaherty KT, et al. Clin Cancer Res 2012;18:568–76
2. Schwartz GK, et al. Br J Cancer 2011;104:1862–8
•Both schedules generally well tolerated
•2/1: 18% of patients had DLTs
•3/1: 12% of patients had DLTs
•Hematologic AEs: neutropenia/other cytopenias
•Most common non-hematologic AE: fatigue
•No treatment-related, grade 4/5 adverse events were reported
Primary endpoint:
safety1,2
•Prolonged SD with 3/1 schedule
•2/1: 6 patients (19%) achieved SD for ≥4 cycles, 3 (10%) for ≥10
cycles
•3/1: 10 patients (27%) achieved SD for ≥4 cycles, 6 (16%) for
≥10 cycles
Secondary
endpoint:
preliminary
antitumor efficacy1,2
•Dose-proportional exposure
•Slow absorption and elimination
•Large volume of distribution
Secondary
endpoint: PK of
palbociclib1,2

28. Once-Daily Oral Dosing With Palbociclib
29
Palbociclib® Prescribing Information
Palbociclib should be taken with food. Patients should be encouraged to take their dose at
approximately the same time each day
If the patient vomits or misses a dose, an additional dose should not be taken that day. The next
prescribed dose should be taken at the usual time
Palbociclib capsules should be swallowed whole (patients should not chew, crush, or open them prior to
swallowing). Capsules should not be ingested if they are broken, cracked, or otherwise not intact
Letrozole
2.5 mg
CONTINUOUS
ONCE-DAILY
DOSINGPO
Palbociclib
125 mg
3 WEEKS ON
1 WEEK OFFonce
daily

29. PALOMA 1/TRIO 18: Phase II Study Design in Patients with ER+,
HER2– Locally Recurrent or Metastatic Breast Cancer
Finn RS, et al. Lancet Oncol. 2015; 16(1): 25–35.
*Patients receiving letrozole alone did not cross over to the combination at the time of progression.
Adapted from Finn RS, et al. 2015.1
• Randomized phase II open-
label trial at 50 centers in 12
countries (NCT00721409)
• Key eligibility criteria:
inoperable locally recurrent
disease, postmenopausal
status, no prior therapy for
advanced breast cancer, no
prior CDK inhibitors, no
letrozole within 12 months,
no prior/current brain
metastases, measurable
disease (RECIST 1.0) or bone-
only disease, ECOG PS ≤1,
adequate bone marrow and
renal function

30. 31
PALOMA 1/TRIO 18: Progression-Free Survival (ITTP)
PAL + LET
(N=84)
LET
(N=81)
Number of Events (%) 41 (49) 59 (73)
Median PFS, months
(95% CI)
20.2
(13.8, 27.5)
10.2
(5.7, 12.6)
Hazard Ratio
(95% CI)
0.488
(0.319, 0.748)
P value 0.0004
90
80
70
60
50
40
30
20
10
0
Progressionfreesurvivalprobability(%)
0 4 8 12 16 20 24 28 32 36 40
Time (months)
84 67 60 47 36 28 21 13 8 5 1
81 48 36 28 19 14 6 3 3 1
PAL + LET
LET
Number of patients at risk
100
Palbociclib plus letrozole
Letrozole
Finn RS, et al. Lancet Oncol 2015;16:25-35
Reduction in the risk of
disease progression
with first-line
Palbociclib + letrozole
vs letrozole alone
51%

31. 32
PALOMA 1/TRIO 18: Best Overall Response
Finn RS, et al. Lancet Oncol 2015;16:25-35
Characteristic Combined Cohorts
PAL + LET LET
All randomized patients, n 84 81
Objective response rate, % (95% CI) 43 (32−54) 33 (23−45)
Complete response, n (%) 1 (1) 1 (1)
Partial response, n (%) 35 (42) 26 (32)
Stable disease, n (%) 37 (44) 30 (37)
Stable disease ≥24 weeks, n (%) 32 (38) 20 (25)
Stable disease <24 weeks, n (%) 5 (6) 10 (12)
Progressive disease, n (%) 3 (4) 18 (22)
Indeterminate, n (%) 8 (10) 6 (7)
Patients with measurable disease, n 65 66
Objective response rate, % (95% CI) 55 (43−68) 39 (28−52)
Complete response, n (%) 1 (2) 0
Partial response, n (%) 35 (54) 26 (39)
Stable disease, n (%) 20 (31) 22 (33)
Progressive disease, n (%) 2 (3) 15 (23)
Indeterminate, n (%) 7 (11) 3 (5)

32. PALOMA-1: Adverse Reactions Reported in
≥10% of Patients1
1
11
5 4
13
15
7
1
10
3†
22‡ 25
18
7
23
3
5
13
4
16 17
21
7
13
25
31
43
35
41
75
0
10
20
30
40
50
60
70
80
Percentage
33
Grading according to Common Terminology Criteria for Adverse Events 3.0.
*Peripheral neuropathy includes: neuropathy peripheral and peripheral sensory neuropathy.
†Grade 1 events: 3%.
‡Grade 1 events: 21%; Grade 2 events: 1%.
§Stomatitis includes: aphthous stomatitis, cheilitis, glossitis, glossodynia, mouth ulceration, mucosal inflammation, oral pain, oral discomfort, oropharyngeal pain, and
stomatitis.
‖URI includes influenza, influenza-like illness, laryngitis, nasopharyngitis, pharyngitis, rhinitis, sinusitis, and upper respiratory tract infection.
URI=upper respiratory infection.
Palbociclib Prescribing Information.
Grade 4
Grade 3
Grades 1/2
Grade 3
Grades 1/2
IPalbociclib + LetrozoleLetrozole Alone
All Grade, %

33. 34
PALOMA 1/TRIO 18: Conclusions
• PALOMA-1 demonstrated the activity and safety of CDK 4/6 inhibition in the first-line setting in
patients with ER+/HER2- advanced breast cancer1
– Palbociclib + letrozole significantly prolonged PFS, irrespective of cyclin D1 and p16 alterations
– ORR and CBR were also substantially improved, confirming the clinical benefit
– OS data is immature at this time; a final OS analysis will be conducted following additional events
• Palbociclib + letrozole had a clinically manageable toxicity profile1
– The most common adverse event was uncomplicated neutropenia
• For patients with disease progression after study treatment, addition of palbociclib to letrozole did
not compromise the ability to receive further endocrine therapy or chemotherapy, and delayed the
start of subsequent therapy2
1. Finn RS, et al. Lancet Oncol 2015;16:25-35; 2. Finn RS et al.
Presented at SABCS 2015; San Antonio, Texas, USA (Poster 4-13-02)

34. 35
PALOMA-2: Phase III Study Design in Postmenopausal Patients with ER+, HER2–
Advanced Breast Cancer
clinicaltrials.gov NCT01740427;
Finn RS, et al. N Engl J Med 2016 Nov 17;375(20): 1925–1936

35. PALOMA-2: Demographics and Baseline Characteristics
aVisceral disease was defined as: any lung (including pleura) and/or liver involvement bTime since completion of (neo)adjuvant therapy and onset of recurrence; percentage calculated based on number of
patients who received (neo)adjuvant therapy Patients who progressed while receiving or ≤12 months from completion of prior anastrozole or letrozole were excluded cPatients 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
therapyHormonal therapy included tamoxifen, anastrozole, letrozole, exemestane, goserelin, toremifene, other agents
Palbociclib + letrozole (N=444) Placebo + letrozole (N=222)
Age, n (%)
Median (range) 62 (30–89) 61 (28–88)
<65 years 263 (59.2) 141 (63.5)
65 years 181 (40.8) 81 (36.5)
ECOG PS, n (%)
0 257 (57.9) 102 (45.9)
1 178 (40.1) 117 (52.7)
2 9 (2.0) 3 (1.4)
Disease site, n (%)
Viscerala 214 (48.2) 110 (49.5)
Non-visceral 230 (51.8) 112 (50.5)
Bone-only 103 (23.2) 48 (21.6)
No. of disease sites
1 138 (31.1) 66 (29.7)
2 117 (26.4) 52 (23.4)
3 112 (25.2) 61 (27.5)
≥4 77 (17.3) 43 (19.4)
Disease-free interval,b n (%)
Newly metastatic disease 167 (37.6) 81 (36.5)
12 months 99 (22.3) 48 (21.6)
>12 months 178 (40.1) 93 (41.9)
Recurrence type, n (%)
Locoregional 2 (0.5) 2 (0.9)
Loca 6 (1.4) 3 (1.4)
Regional 3 (0.7) 1 (0.5)
Distant 294 (66.2) 145 (65.3)
Newly diasgnosed 139 (31.3) 71 (32.0)
Prior neoadjuvant therapy, n (%)
Chemotherapy 213 (48.0) 109 (49.1)
Adjuvant hormonal therapyc 249 (56.1) 126 (56.8)

36. 37
PALOMA-2: Investigator-assessed PFS (ITT Population)
• As initial therapy for postmenopausal ER+/HER2– advanced breast cancer, palbociclib + letrozole significantly
improved PFS compared with placebo + letrozole
CI, confidence interval; ER+, estrogen receptor;-positive HER2–, human epidermal growth factor receptor 2-
negative; HR, hazard ratio; ITT, intention to treat; LET, letrozole; NE, not estimable; PAL, palbociclib; PCB,
placebo; PFS, progression-free survival
PFSprobability(%)
Time from randomization (months)
0 3 6 9 12 15 18 21 24 27 30 33
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
HR 0.58 (95% CI 0.46, 0.72)
2-sided P<0.001
Palbociclib + letrozole (n=444)
Placebo + letrozole (n=222)
Median (95% CI) PFS
14.5 months (12.9–17.1)
Median (95% CI) PFS
24.8 months (22.1–NE)
Finn RS, et al. N Engl J Med 2016 Nov 17;375(20): 1925–1936
0
10
20
30
40
50
60
70
80
90
100

37. PALOMA-2: PFS Subgroup Analysis
• 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 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
0.2 0.4 0.6 0.8 1.00 2.00

38. 39
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
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
(37.5–46.9)
34.7
(28.4–41.3)
1.40
(0.98–2.01)
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, mo
22.5
(19.8–28.0)
16.8
(15.4–28.5)
NR NR
Finn RS, et al. N Engl J Med 2016 Nov 17;375(20): 1925–1936

39. 40
PALOMA-2: All-causality Hematological AEs occurring in ≥15% of patients in either arm
(as-treated population)
aIncludes clustered Medical Dictionary for Regulatory Activity (MedDRA) preferred terms.
AE, adverse event
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
Thrombocytopeniaa 15.5 1.4 0.2 1.4 0 0
• Grade 3/4 febrile neutropenia was reported in 1.8% of patients in the palbociclib + letrozole arm vs. 0% in the
placebo + letrozole arm
Finn RS, et al. N Engl J Med 2016 Nov 17;375(20): 1925–1936

40. 41
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
Fatigue 37.4 1.8 0 27.5 0.5 0
Nausea 35.1 0.2 0 26.1 1.8 0
Arthralgia 33.3 0.2 0 33.8 0.5 0
Alopeciaa 32.9 0 0 15.8 0 0
Diarrhea 26.1 1.4 0 19.4 1.4 0
Cough 25.0 0 0 18.9 0 0
Back pain 21.6 1.4 0 21.6 0 0
Headache 21.4 0.2 0 26.1 1.8 0
Hot flush 20.9 0 0 30.6 0 0
Constipation 19.4 0.5 0 15.3 0.5 0
Rashb 17.8 0.9 0 11.7 0.5 0
Asthenia 16.9 2.3 0 11.7 0 0
Vomiting 15.5 0.5 0 16.7 1.4 0
Pain in extremity 15.3 0.2 0 17.6 1.4 0
Stomatitis 15.3 0.2 0 5.9 0 0
PALOMA-2: All-causality Non-Hematological AEs Occurring in
≥15% of Patients
Finn RS, et al. N Engl J Med 2016 Nov 17;375(20): 1925–1936
aIn the palbociclib + letrozole group, 30% patients had grade 1 alopecia and 3% had grade 2 alopecia. In the placebo +
letrozole group, 15% patients had grade 1 alopecia and 1% had grade 2 alopecia. bincludes MedRA preferred terms for
Rash. AE, adverse event

41. 42
PALOMA-2: Summary of AEs
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
Deaths due to AEs
• 2.3% of patients in the palbociclib + letrozole arm vs. 1.8% in the placebo + letrozole arm
• One on-study death (secondary to lower respiratory tract infection and pulmonary embolism) in
the placebo + letrozole arm was considered treatment-related by the investigator
AE, adverse event; SAE, serious adverse event
Finn RS, et al. N Engl J Med 2016 Nov 17;375(20): 1925–1936

42. 43
PALOMA-2: Conclusions
• 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 subgroups
• Palbociclib was well tolerated with the most common AEs being neutropenia and leukopenia; however, the overall
incidence of neutropenic fever was low (1.6%)
• PALOMA-2, a double-blind, placebo-controlled phase 3 trial confirmed the safety and efficacy of palbociclib +
letrozole demonstrated in the open-label phase 2 PALOMA-1 trial and builds on the efficacy and safety profile of
CDK 4/6 inhibition in the first-line treatment of advanced ER+/HER2– breast cancer
AE, adverse event; CI, confidence interval; ER+, estrogen receptor-positive;
HER2–, human epidermal growth factor receptor 2-negative; HR, hazard ratio;
PFS, progression-free survival
Finn RS, et al. N Engl J Med 2016 Nov 17;375(20): 1925–1936

47. Frequency of
neutropenia in
PALOMA 1
Finn RS. Breast Cancer Res. 2016 Jun 28;18(1):67

48. 49
Chemotherapy-induced Neutropenia (CIN) Is Common,
Severe, and Associated with Fever, Infection, and Death
1. Crawford J, et al. Cancer. 2004;100:228−37
2. Eskander RN, Tewari KS. J Hematol Malig. 2012;2:63−73
3. Lalami Y, et al. Ann Oncol. 2006;17:507−14
4. Lyman GH, et al. Crit Rev Oncol Hematol. 2014;90:190−9
5. Pettengell R, et al. Support Care Cancer. 2008;16:1299−309
6. Kurkjian C, Ozer H. Chapter 157. In: DeVita V, et al, eds. Cancer. 9th ed. Philadelphia, PA: Lippincott Williams & Wilkins; 2011:2300−13
7. Caggiano V, et al. Cancer. 2005;103:1916−24
8. Freifeld AG, et al. Clin Infect Dis. 2011;52:e56−e93
9. Kuderer N, et al. Cancer. 2006;106:2258−66
Characteristic Grade 3/4 Chemotherapy-induced Neutropenia (CIN)
Incidence Common
16-90% of adjuvant breast cancer patients;
>70% in advanced breast cancer patients1,2
Severity Severe to life-threatening
64% grade 3/4, 34% grade 4
in adjuvant/neo-adjuvant breast cancer patients5
Nadir Usually early, may be late ~1-2 weeks, delayed with some regimens6
Duration May be prolonged ~7-10 days, extended with some regimens6,7
FN incidence Common 10-50% of solid tumor patients1,3,8
Documented
infections
Common 20-30% of febrile neutropenia episodes8
FN mortality Common ~9% in solid tumor patients3,5,9
FN = febrile neutropenia

49. Palbociclib-induced Neutropenia (PIN) is Rapidly Reversible
1. Finn RS, et al. ESMO 2014 (Abstract 368P); 2. Finn RS, et al.
Lancet Oncol. 2015;16:25-35; 3. DeMichele A, et al. ASCO 2014 (Abstract 2547);
4. Turner N, et al. N Engl J Med 2015;373:209-19; 5. Cristofanilli M, et al. Lancet Oncol 2016
[Published online 2 March 2016; http://dx.doi.org/10.1016/S1470-2045(15)00613-0].
Incidence of neutropenia in patients on palbociclib in 3 phase II trials and 1 phase III trial
Incidence: Frequent1-3
Severity: Grade 3 common, grade 4 uncommon1-3
Nadir: Weeks 3-41,3
Duration: 7 days1
Febrile
neutropenia:
In PALOMA-1, no cases of febrile neutropenia were observed;1 in PALOMA-3, incidence with
palbociclib + fulvestrant (1.0%) was the same as placebo + fulvestrant (1.0%)5
Infections:
PALOMA-3 had more cases of neutropenia than PALOMA-1;2,4,5 incidence of infections in
PALOMA-3 was greater with palbociclib + fulvestrant than with placebo + fulvestrant, but most
were grade 1 or 2 severity4,5
Reversibility: Rapidly reversible with dose reduction, interruption, delay1
50
*All-causality events; patients received letrozole in addition to palbociclib †Causality of events not specified ‡All-causality events; patients received
fulvestrant in addition to palbociclib
Study
Number of
patients
All grades
(%)
Grade 3 (%) Grade 4 (%)
Grade 3/4
(%)
Finn et al1,2* 83 74 48 6 54
DeMichele et al3† 143 82 37.1 3.5 41
Turner et al.4‡ 347 78.8 53.3 8.7 62.0
Cristofanilli et al.5‡ 347 81 55 10 65

51. Proactively Monitor Patients to Help Manage Potential
Side Effects
52
Monitor CBC prior to the start of Palbociclib therapy and at the beginning of each cycle, as
well as on Day 14 of the first 2 cycles, and as clinically indicated.
When scheduling Day 14 monitoring and subsequent follow-up visits, remember to consider when the patient actually
receives her medication and initiates each cycle.
Detecting and Managing Neutropenia
• Neutropenia was the most frequently reported adverse event in both PALOMA-1 (75%) .
Grade ≥3 neutropenia was reported in 48% of patients receiving Palbociclib + letrozole in
PALOMA-1
• Dose interruption, dose reduction, or delay in starting treatment cycles is recommended
for patients who develop Grade 3 or 4 neutropenia1
• Advise patients to immediately report any signs or symptoms of myelosuppression or
infection, such as fever, chills, dizziness, shortness of breath, weakness, or any increased
tendency to bleed and/or to bruise1
• Primary prophylactic use of granulocyte-colony stimulating factors was not permitted in
PALOMA-1 , but they could be used to treat treatmentemergent neutropenia, as
indicated by the current American Society of Clinical Oncology guidelines2,3
CBC=complete blood count.
1. Palbociclib Prescribing Information.. 2. Data on file. Clinical Study Report: Protocol A5481003. New York, NY: Pfizer Inc; 2014. 3. Data on file. Clinical Study
Report: Protocol A5481023. New York, NY: Pfizer Inc; 2015.

52. Modify the Dose If Needed Based on Individual Safety
and Tolerability1
53
Recommended dose modifications for Palbociclib
Starting dose First reduction Second reduction
125 mg/day 100 mg/day 75 mg/day
If dose reduction below 75 mg/day is required, discontinue
1. IBRANCE® Prescribing Information. New York, NY: Pfizer Inc; 2016.
• Dose modifications may help manage hematologic and nonhematologic toxicities,
if they occur

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Thank You !