1. PALOMA-2: Addition of Palbociclib to Frontline Letrozole Significantly Improves PFS in Postmenopausal ER+/HER2- Advanced Breast Cancer
CCO Independent Conference Coverage* of the 2016 ASCO Annual Meeting, June 3-7, 2016
*CCO is an independent medical education company that provides state-of-the-art medical information to healthcare professionals through conference coverage and other educational programs.
ER, estrogen receptor; HER2, human epidermal growth factor receptor 2.
This activity is supported by educational grants from Amgen, Ariad, Bayer Healthcare Pharmaceuticals, Celgene Corporation, Genentech, Incyte, Merck, and Taiho Pharmaceuticals.

2. PALOMA 2: Background
CDKs: serine/threonine kinases that regulate cell cycle progression via interaction with cyclins[1]
Palbociclib: selective oral CDK-4/6 inhibitor that blocks G1 to S cell cycle progression[2]; currently FDA approved to treat pts with HR+/HER2- MBC in combination with:
Letrozole as initial hormonal-based tx for post-menopausal women
PALOMA-1: open-label, randomized phase II study demonstrated 10-mo PFS improvement (P = .0004) with palbociclib + letrozole vs letrozole alone, leading to accelerated FDA approval for ER+/HER2- advanced breast cancer[3]
Fulvestrant for women with disease progression following hormonal tx
PALOMA-3: double-blind, randomized phase III study showed 5-mo PFS improvement (P < .0001) with palbociclib + fulvestrant vs fulvestrant + placebo in HR+/HER2- advanced breast cancer with PD after endocrine therapy[4]
Current study, PALOMA-2, evaluated first-line palbociclib + letrozole vs placebo + letrozole in pts with ER+/HER2- advanced breast cancer[5]
CDK, cyclin-dependent kinase; ER, estrogen receptor; HER2, human epidermal growth factor receptor 2; HR, hormone receptor; MBC, metastatic breast cancer; PD, progressive disease; tx, treatment.
1. Musgrove EA, et al. Nat Rev Cancer. 2011;11: Fry DW, et al. Mol Cancer Ther. 2004;3: Finn RS, et al. Lancet Oncol. 2015;16: Cristofanilli M, et al. Lancet Oncol. 2016;17: Finn R, et al. ASCO Abstract 507.
Slide credit: clinicaloptions.com
References in slidenotes.

3. Palbociclib 125 mg QD (3/1 schedule)
PALOMA 2: Study Design
Multicenter, international, double-blind, randomized phase III trial
Primary endpoint: PFS by investigator
Secondary endpoints: response, OS, safety, biomarkers, pt-reported outcomes
Stratified by disease site (visceral vs nonvisceral),
disease-free interval (de novo metastatic; ≤ 12 mos vs > 12 mos),
prior neoadjuvant or adjuvant hormonal therapy (yes vs no)
Postmenopausal women with ER+/HER2- advanced breast cancer, no prior treatment for advanced disease, no AI resistance
(N = 666)
Palbociclib 125 mg QD (3/1 schedule)
+ Letrozole 2.5 mg QD
(n = 444)
Placebo (3/1 schedule)
+ Letrozole 2.5 mg QD
(n = 222)
AI, aromatase inhibitor; ER, estrogen receptor; HER2, human epidermal growth factor receptor 2.
Slide credit: clinicaloptions.com
Finn R, et al. ASCO Abstract 507.

4. PALOMA 2: Baseline Characteristics (ITT)
Palbociclib + Letrozole
(n = 444)
Placebo + Letrozole
(n = 222)
Median age, yrs (range)
65 yrs or older, %
62 (30-89) 41
61 (28-88) 36
Race, %
White/Black/Asian/other
77/2/15/6
77/1/14/8
ECOG PS, %
0/1/2
58/40/2
46/53/1
Disease site, %
Visceral
Nonvisceral
Bone only 48 52 23 50 22
Disease-free interval, %
> 12 mos
≤ 12 mos
De novo advanced disease 40 38 42
Prior (neo)adjuvant hormonal therapy, % 56 57
ECOG, Eastern Cooperative Oncology Group; ITT, intent to treat; PS, performance status.
Slide credit: clinicaloptions.com
Finn R, et al. ASCO Abstract 507.

5. Palbociclib + Letrozole
PALOMA 2: PFS
Outcome
Palbociclib + Letrozole
(n = 444)
Placebo + Letrozole
(n = 222) HR
(95% CI);
P Value
Investigator-assessed
Number of events, n (%)
Median PFS, mos (95% CI)
194 (44)
24.8 (22.1-NR)
137 (62)
14.7 ( )
0.58
( );
<
Blinded independent central review
152 (34)
30.5 (27.4-NR)
96 (43)
19.3 ( )
0.65
( );
.0005
Blinded independent central review confirmed investigator- assessed PFS advantage
Benefit with palbociclib + letrozole evident across all subgroups
NR, not reached.
Slide credit: clinicaloptions.com
Finn R, et al. ASCO Abstract 507.

6. PALOMA 2: Secondary Endpoints
Outcome[1]
Palbociclib + Letrozole
Placebo + Letrozole
OR (95% CI)
P Value
ITT population
ORR,* % (95% CI)
CBR,† % (95% CI)
n = 444
42 ( )
85 ( )
n = 222
35 ( )
70 ( )
1.40 ( )
2.39 ( )
.0310
< .0001
Pts with measurable disease
n = 338
55 ( )
84 ( )
n = 171
44 ( )
71 ( )
1.55 ( )
2.23 ( )
.0132
.0003
*Confirmed CR + PR. †Confirmed CR + PR + SD ≥ 24 wks.
Clinical benefit consistent with phase II open-label PALOMA-1 study[2]
CBR, clinical benefit rate; ITT, intent to treat; OR, odds ratio; SD, stable disease.
1. Finn R, et al. ASCO Abstract 507.
2. Finn RS, et al. Lancet Oncol. 2015;16:25-35.
Slide credit: clinicaloptions.com

7. Palbociclib + Letrozole (n = 444) Placebo + Letrozole (n = 222)
PALOMA 2: Safety
AEs (All Causality), %
Palbociclib + Letrozole (n = 444)
Placebo + Letrozole (n = 222)
Any Grade
Grade 3
Grade 4
Any AE 99 62 14 95 22 2
Hematologic AE in ≥ 15% of pts in either arm
Neutropenia* 80 56 10 6 1
< 1
Leukopenia* 39 24
Anemia* 5 9
Thrombocytopenia* 16
Nonhematologic AE in ≥ 25% of pts in either arm
Fatigue 37 28
Nausea 35 26
Arthralgia 33 34
Alopecia
Diarrhea 19
Cough 25
Headache 21
Hot flush 31
AE, adverse event; MedDRA, Medical Dictionary for Regulatory Activity.
*Includes clustered MedDRA-preferred terms.
Slide credit: clinicaloptions.com
Finn R, et al. ASCO Abstract 507.

8. Palbociclib + Letrozole (n = 444) Placebo + Letrozole (n = 222)
PALOMA 2: AE Summary
Outcome, %
Palbociclib + Letrozole (n = 444)
Placebo + Letrozole (n = 222)
Serious AE
19.6
12.6
Serious AE occurring in ≥ 1% of pts
Febrile neutropenia
Pulmonary embolism
1.6
0.9
1.4
AE-related discontinuation
9.7
5.9
AE-related death
2.3
1.8
AE, adverse event; d/c, discontinuation.
Most AEs resulting in d/c reported as single events, most commonly neutropenia with palbociclib (1.6%) or fatigue with placebo (0.9%)
One on-study, treatment-related death because of pulmonary embolism/respiratory failure in placebo arm
Slide credit: clinicaloptions.com
Finn R, et al. ASCO Abstract 507.

9. PALOMA 2: Conclusions
First-line palbociclib + letrozole significantly improved median PFS vs placebo + letrozole in women with ER+/HER2- advanced breast cancer
Median PFS improved by > 10 mos compared to placebo
24.8 mos vs 14.5 mos, HR: 0.58 (95% CI: ; P < .0001)
Palbociclib clinical benefit observed in all prespecified subgroups
Palbociclib well tolerated with neutropenia, leukopenia the most frequently reported AEs
PALOMA-2[1] data confirm PALOMA-1[2] results and constitute the longest median PFS improvement to date in the front-line setting in advanced ER+ breast cancer
AE, adverse event; ER, estrogen receptor; HER2, human epidermal growth factor receptor 2.
1. Finn R, et al. ASCO Abstract 507.
2. Finn RS, et al. Lancet Oncol. 2015;16:25-35.
Slide credit: clinicaloptions.com

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