Articles

The cyclin-dependent kinase 4/6 inhibitor palbociclib in

combination with letrozole versus letrozole alone as
rst-line treatment of oestrogen receptor-positive,
HER2-negative, advanced breast cancer
(PALOMA-1/TRIO-18): a randomised phase 2 study
Richard S Finn, John P Crown, Istvan Lang, Katalin Boer, Igor M Bondarenko, Sergey O Kulyk, Johannes Ettl, Ravindranath Patel, Tamas Pinter,
Marcus Schmidt, Yaroslav Shparyk, Anu R Thummala, Nataliya L Voytko, Camilla Fowst, Xin Huang, Sindy T Kim, Sophia Randolph, Dennis J Slamon

Summary
Background Palbociclib (PD-0332991) is an oral, small-molecule inhibitor of cyclin-dependent kinases (CDKs) 4 and 6
with preclinical evidence of growth-inhibitory activity in oestrogen receptor-positive breast cancer cells and synergy
with anti-oestrogens. We aimed to assess the safety and ecacy of palbociclib in combination with letrozole as rstline treatment of patients with advanced, oestrogen receptor-positive, HER2-negative breast cancer.

Lancet Oncol 2015; 16: 2535

Methods In this open-label, randomised phase 2 study, postmenopausal women with advanced oestrogen receptorpositive and HER2-negative breast cancer who had not received any systemic treatment for their advanced disease
were eligible to participate. Patients were enrolled in two separate cohorts that accrued sequentially: in cohort 1,
patients were enrolled on the basis of their oestrogen receptor-positive and HER2-negative biomarker status alone,
whereas in cohort 2 they were also required to have cancers with amplication of cyclin D1 (CCND1), loss of
p16 (INK4A or CDKN2A), or both. In both cohorts, patients were randomly assigned 1:1 via an interactive
web-based randomisation system, stratied by disease site and disease-free interval, to receive continuous oral
letrozole 25 mg daily or continuous oral letrozole 25 mg daily plus oral palbociclib 125 mg, given once daily for
3 weeks followed by 1 week o over 28-day cycles. The primary endpoint was investigator-assessed progressionfree survival in the intention-to-treat population. Accrual to cohort 2 was stopped after an unplanned interim
analysis of cohort 1 and the statistical analysis plan for the primary endpoint was amended to a combined analysis
of cohorts 1 and 2 (instead of cohort 2 alone). The study is ongoing but closed to accrual; these are the results of
the nal analysis of progression-free survival. The study is registered with the ClinicalTrials.gov, number
NCT00721409.

See Comment page 2

Findings Between Dec 22, 2009, and May 12, 2012, we randomly assigned 165 patients, 84 to palbociclib plus
letrozole and 81 to letrozole alone. At the time of the nal analysis for progression-free survival (median follow-up
296 months [95% CI 279360] for the palbociclib plus letrozole group and 279 months [255311] for the
letrozole group), 41 progression-free survival events had occurred in the palbociclib plus letrozole group and 59 in
the letrozole group. Median progression-free survival was 102 months (95% CI 57126) for the letrozole group
and 202 months (138275) for the palbociclib plus letrozole group (HR 0488, 95% CI 03190748; one-sided
p=00004). In cohort 1 (n=66), median progression-free survival was 57 months (26105) for the letrozole
group and 261 months (112not estimable) for the palbociclib plus letrozole group (HR 0299, 01560572;
one-sided p<00001); in cohort 2 (n=99), median progression-free survival was 111 months (71164) for the
letrozole group and 181 months (131275) for the palbociclib plus letrozole group (HR 0508, 03030853;
one-sided p=00046). Grade 34 neutropenia was reported in 45 (54%) of 83 patients in the palbociclib plus
letrozole group versus one (1%) of 77 patients in the letrozole group, leucopenia in 16 (19%) versus none, and
fatigue in four (4%) versus one (1%). Serious adverse events that occurred in more than one patient in the
palbociclib plus letrozole group were pulmonary embolism (three [4%] patients), back pain (two [2%]), and
diarrhoea (two [2%]). No cases of febrile neutropenia or neutropenia-related infections were reported during the
study. 11 (13%) patients in the palbociclib plus letrozole group and two (2%) in the letrozole group discontinued
the study because of adverse events.
Interpretation The addition of palbociclib to letrozole in this phase 2 study signicantly improved progression-free
survival in women with advanced oestrogen receptor-positive and HER2-negative breast cancer. A phase 3 trial is
currently underway.
Funding Pzer.
www.thelancet.com/oncology Vol 16 January 2015

Published Online
December 16, 2014
http://dx.doi.org/10.1016/
S1470-2045(14)71159-3

See Online for podcast interview

with Dennis Slamon
University of California Los
Angeles, Los Angeles, CA, USA
(R S Finn MD,
Prof D J Slamon MD); Irish
Cooperative Oncology Research
Group, Dublin, Ireland
(Prof J P Crown MD); Orszagos
Onkologiai Intezet, Budapest,
Hungary (I Lang MD); Szent
Margit Korhaz, Onkologia,
Budapest, Hungary
(K Boer MD); Dnipropetrovsk
Medical Academy, City
Multiple-Discipline Clinical
Hospital 4, Dnipropetrovsk,
Ukraine
(Prof I M Bondarenko MD);
Municipal Treatment and
Prophylactic Institution,
Donetsk, Ukraine
(S O Kulyk MD); Technical
University of Munich, Munich,
Germany (J Ettl MD);
Comprehensive Blood and
Cancer Center, Bakerseld, CA,
USA (R Patel MD); Petz Aladar
Megyei Oktato Korhaz, Gyor,
Hungary (T Pinter MD);
University Hospital Mainz,
Mainz, Germany
(M Schmidt MD); Lviv State
Oncologic Regional Treatment
and Diagnostic Centre, Lviv,
Ukraine (Y Shparyk MD);
Comprehensive Cancer Centers
of Nevada, Las Vegas, NV, USA
(A R Thummala MD); Kyiv City
Clinical Oncology Centre, Kyiv,
Ukraine (N L Voytko MD); Pzer
Oncology, Milan, Italy
(C Fowst MD); and Pzer
Oncology, San Diego, CA, USA
(X Huang PhD, S T Kim BS,
S Randolph MD)

25

Articles

Correspondence to:
Prof Dennis J Slamon, UCLA
Oncology, Santa Monica,
CA 90404, USA
dslamon@mednet.ucla.edu

See Online for appendix

26

Introduction
Breast cancer is a molecularly diverse disease with
several dened molecular subgroups. Clinically, however,
three therapeutic groups are used: those classied as
hormone receptor-positive (ie, oestrogen receptorpositive, progesterone receptor-positive, or both, with
normal HER2 expression), those classied as HER2positive, as dened by HER2 gene amplication or
overexpression (about 45% of these cancers can also have
variable expression of oestrogen receptors, progesterone
receptors, or both), and those classied as triple-negative
by virtue of low or absent hormone receptors and the
absence of the HER2 alteration.1 More than 15 million
new breast cancers are reported worldwide each year,
with roughly 6065% of cases hormone receptor-positive,
2025% HER2-positive, and 1518% triple-negative.2
Hormonally directed drugs including anti-oestrogens
have been the mainstay of treatment for women with
oestrogen receptor-positive breast cancers. However,
some of these cancers have de-novo resistance to this
approach and even more will eventually develop acquired
resistance to these treatments and recur. At that point,
patients often receive chemotherapy that has little activity
in this setting and that is often associated with clinically
signicant toxic eects.
New classes of molecularly targeted drugs can aect
the natural history of some subgroups of breast cancer
such as HER2-positive disease.3 However, until recently
the addition of such drugs to anti-oestrogens has not
resulted in similar improvements in hormone receptorpositive disease. This situation changed with the approval
of everolimus for aromatase inhibitor-resistant disease,
which, when added to oestrogen blockade with
exemestane, resulted in an improvement in investigatorassessed progression-free survival (hazard ratio [HR]
043, 95% CI 035054; p<0001) in oestrogen receptorpositive advanced disease.4
Dysregulation of the cell cycle is one of the dened
hallmarks of cancer5 and several genetic alterations in
key cell cycle regulatory proteins have been described in
various cancers, including breast cancer.5,6 The cyclindependent kinases (CDKs) are a large family of serine
threonine kinases that together with their regulatory
protein partners, the cyclins, have a crucial role in the
orderly and controlled progression through the cell cycle.
Molecular changes in several of the genes controlling the
cell cycle have been reported in various cancers, making
them an attractive potential target for new treatments.7
So far, several CDK-targeted drugs have entered clinical
development, but none have shown signicant activity in
solid tumours and several are associated with safety
concerns.8
Palbociclib (PD-0332991) is a reversible, oral, smallmolecule inhibitor of cyclin dependent kinases 4 and 6
(CDK4/6).9 CDK4/6 and cyclin D have a crucial role in the
regulation of the G1/S transition through regulation of the
phosphorylation state of pRb. When hyperphosphorylation

of pRb occurs, it causes release of transcription factors

that then allow the transition from G1 to S phase and
progression of the cell cycle.10 To investigate the therapeutic
potential for palbociclib in breast cancer, we tested its
growth inhibitory eects preclinically in a large panel of
human breast cancer cell lines and identied potent
activity in two therapeutic groups, those that were
oestrogen receptor-positive and those that were HER2amplied.11 This activity was associated with a major
blockade of pRb hyperphosphorylation, resulting in a G1
arrest in sensitive cells. We also noted that in combination
with the anti-oestrogen drug tamoxifen, palbociclib had
synergistic growth inhibitory activity as well as ecacy in
a model of acquired tamoxifen resistance.11 We noted
similar ndings in HER2-amplied breast cancer cell
lines with trastuzumab used in combination with
palbociclib.11
Based on these data, we designed a clinical study to test
the safety and ecacy of CDK4/6 inhibition by palbociclib
in combination with anti-oestrogen drugs in oestrogen
receptor-positive breast cancer. Initially, a single-arm,
phase 1b study was done to assess the safety of palbociclib
given with letrozole in patients with oestrogen receptorpositive, HER2-negative, advanced breast cancer and to
determine a recommended phase 2 dose of the
combination.12 The results suggested a dose and schedule
consisting of oral palbociclib 125 mg once daily for
3 weeks followed by 1 week o treatment in a 28-day
cycle, combined with the standard dose of oral letrozole
25 mg once daily. No drugdrug interactions were
identied and the most common treatment-related
adverse events were neutropenia, leucopenia, and
fatigue. Based on these clinical data, we planned a
randomised, open-label, phase 2 study to assess the
safety and ecacy of the palbociclib and letrozole
combination compared with letrozole alone in the rstline treatment of women with advanced oestrogen
receptor-positive, HER2-negative breast cancer.

Methods
Study design and patients
In this international, phase 2, multicentre, open-label
randomised
study
(PALOMA-1/TRIO-18),
postmenopausal women (aged 18 years or older) with
oestrogen receptor-positive, HER2-negative, advanced
breast cancer were recruited from 50 sites in 12 countries
(Canada, France, Germany, Hungary, Ireland, Italy
Russia, South Africa, South Korea, Spain, Ukraine, USA;
appendix). Patients were enrolled in two separate cohorts
that accrued sequentially: in cohort 1, patients were
enrolled on the basis of their oestrogen receptor-positive
and HER2-negative biomarker status alone, whereas in
cohort 2 they were also required to have cancers with
amplication of cyclin D1 (CCND1), loss of p16 (also
known as INK4A or CDKN2A), or both. All patients were
required to have either locally recurrent disease not
amenable to surgery or evidence of metastatic disease.
www.thelancet.com/oncology Vol 16 January 2015

Articles

400 patients assessed for eligibility (cohorts 1 and 2)

Cohort 1
81 screened
15 excluded
11 did not meet inclusion criteria
4 met exclusion criteria

Cohort 2
319 screened
220 excluded
203 did not meet inclusion criteria
13 met exclusion criteria
4 did not meet inclusion criteria and
met exclusion criteria

66 randomly assigned

99 randomly assigned

34 allocated to palbociclib plus letrozole

33 received allocated intervention
1 did not receive allocated intervention
1 withdrew consent

32 allocated to letrozole
29 received allocated intervention
3 did not receive allocated intervention
3 withdrew consent

50 allocated to palbociclib plus letrozole

50 received allocated intervention

49 allocated to letrozole
48 received allocated intervention
1 did not receive allocated intervention
1 withdrew consent

26 discontinued intervention
8 because of adverse events
16 had objective progression or relapse
2 withdrew consent

28 discontinued intervention
1 because of adverse events
1 because of global deterioration of
health status
22 had objective progression or relapse
2 withdrew consent
2 other reasons

38 discontinued intervention
3 because of adverse events
5 because of global deterioration of
health status
26 had objective progression or relapse
1 died
3 withdrew consent

41 discontinued intervention
1 because of adverse events
2 because of global deterioration of
health status
35 had objective progression or relapse
3 withdrew consent

34 analysed by intention to treat

32 analysed by intention to treat

50 analysed by intention to treat

49 analysed by intention to treat

165 in the total intention-to-treat population

84 in the palbociclib plus letrozole group
81 in the letrozole group

Figure 1: Trial prole

Oestrogen receptor status was determined by routine

immunohistochemistry and HER2 status was assessed
by either uorescent in-situ hybridisation (FISH) or
immunohistochemistry, with both eligibility markers
reported at enrolling sites. Oestrogen receptor status
was determined on the basis of either the original tissue
staining or, if available, a biopsy from the recurrence.
For enrolment into cohort 2 of the study, central
laboratory determination of CCND1 amplication or
p16 loss was required. CCND1 amplication was dened
as a CCND1-to-chromosome enumeration probe (CEP)
11 ratio greater than 15 and p16 loss as a p16-to-CEP9
ratio less than 08. These cutos came from an internal
analysis of British Columbia Cancer Foundation data
from 778 breast cancer cases that showed the frequency
of CCND1 amplication (more than three copies) and
p16 loss (loss of heterozygosity) to be roughly 36% in
patients with luminal B breast cancer. To establish
denitions for the genomic changes used for cohort 2,
we used a four-colour FISH assay (CCND1-to-CEP11
and p16-to-CEP9) to analyse 113 breast cancer samples
from a tumour bank and, using a cuto of CCND1-towww.thelancet.com/oncology Vol 16 January 2015

CEP11 greater than 15 or p16-to-CEP9 less than 08, we

determined that 42 (37%) of 113 patients in this cohort
had CCND1 amplication, CDKN2A loss, or both.
No previous treatment for advanced disease was
permitted and all patients were required to have
measurable disease by Response Evaluation Criteria in
Solid Tumors (RECIST, version 1.0) or bone-only disease
with an Eastern Cooperative Oncology Group (ECOG)
performance status of 0 or 1 and adequate organ function
(as assessed by haematological and blood chemistry
analyses). Patients were excluded from study if they had
received letrozole as either neoadjuvant or adjuvant
treatment within the 12 months before study entry, had
received any previous treatment for advanced breast
cancer, had brain metastasis, or had previously been
treated with a CDK inhibitor.
The study was done in accordance with the
International Conference on Harmonization and Good
Clinical Practice standards. Institutional review board
approval was obtained from all participating institutions
and patients provided written informed consent before
the start of any study-specic screening procedures.
27

Articles

Median age (years)

Both cohorts

Cohort 1

Palbociclib plus Letrozole

letrozole (n=84) (n=81)

Palbociclib plus
letrozole (n=34)

Letrozole
(n=32)

Cohort 2
Palbociclib plus
letrozole (n=50)

Letrozole
(n=49)

63 (5471)

64 (5670)

66 (5672)

64 (5770)

62 (5470)

63 (5671)

ECOG performance status

0

46 (55%)

45 (56%)

23 (68%)

20 (63%)

23 (46%)

25 (51%)

38 (45%)

36 (44%)

11 (32%)

12 (38%)

27 (54%)

24 (49%)

Disease stage
III

2 (2%)

1 (1%)

2 (6%)

IV

82 (98%)

80 (99%)

32 (94%)

32 (100%)

Visceral

37 (44%)

43 (53%)

10 (29%)

Bone only

17 (20%)

12 (15%)

7 (21%)

Other (non-visceral)

30 (36%)

26 (32%)

>12 months from adjuvant treatment to recurrence

25 (30%)

12 months from adjuvant treatment to recurrence

or de-novo advanced disease

59 (70%)

1 (2%)

50 (100%)

48 (98%)

11 (34%)

27 (54%)

32 (65%)

6 (19%)

10 (20%)

6 (12%)

17 (50%)

15 (47%)

13 (26%)

11 (23%)

30 (37%)

10 (29%)

10 (31%)

15 (30%)

20 (41%)

51 (63%)

24 (71%)

22 (69%)

35 (70%)

29 (59%)

44 (52%)

37 (46%)

19 (56%)

17 (53%)

25 (50%)

20 (41%)

None

44 (52%)

37 (46%)

19 (56%)

17 (53%)

25 (50%)

20 (41%)

Chemotherapy

34 (40%)

37 (46%)

11 (32%)

14 (44%)

23 (46%)

23 (47%)

Hormonal

27 (32%)

28 (35%)

11 (32%)

11 (34%)

16 (32%)

17 (35%)

Tamoxifen

24 (29%)

24 (30%)

8 (24%)

8 (25%)

16 (32%)

16 (33%)

Anastrozole

8 (10%)

11 (14%)

4 (12%)

5 (16%)

4 (8%)

6 (12%)

Letrozole

2 (2%)

1 (1%)

2 (4%)

1 (2%)

Exemestane

4 (5%)

2 (2%)

3 (9%)

1 (3%)

1 (2%)

1 (2%)

Disease site*

Disease-free interval*

De-novo advanced disease only

Previous systemic treatment

Data are n (%) or median (IQR). ECOG=Eastern Cooperative Oncology Group. *Based on case report form data.

Table 1: Baseline characteristics (intention-to-treat population)

Randomisation and masking

Patients were randomly allocated 1:1 to receive either
palbociclib plus letrozole or letrozole alone. The
investigator or other member of the research sta used
an interactive web-based randomisation system to
register and randomly assign patients with
two stratications factors: disease site (visceral, bone
only, or other) and disease-free interval (greater than
12 months from the end of adjuvant treatment to
recurrence vs 12 months or less from the end of
adjuvant treatment to recurrence or de-novo metastatic
disease). The randomisation system generated the
random assignment of the two treatments in a block
size of six for each of the stratication levels. Although
this was an open-label study, the randomisation codes
were only released at the time of interim and nal
analyses and crossover was not allowed at any time.

Procedures
Patients randomly allocated to letrozole received oral
letrozole 25 mg once daily. Those allocated to palbociclib
plus letrozole received the same dose of letrozole plus
oral palbociclib 125 mg, given once daily for 3 weeks
followed by 1 week o in 28-day cycles. Study treatment
continued until disease progression, unacceptable toxic
28

eects, study withdrawal, or death. Dose interruptions

and reductions were allowed for management of toxic
eects (appendix).
Tumour assessments were done locally at screening
and every 8 weeks and consisted of CT or MRI scan of
the chest, abdomen, and pelvis; radiography for bone
lesions (when applicable); and clinical assessment of
cutaneous disease. Bone scans were done at baseline and
every 12 weeks. All patients with tumour responses were
required to have response conrmation no less than
4 weeks after documentation of the initial response
report. Assessment of adverse events included incidence,
severity (graded by the National Cancer Institute
Common Terminology Criteria for Adverse Events
version 3.0), timing, seriousness, and relatedness to
study drug. Haematological and blood chemistry
analyses were done every 2 weeks for the rst two
treatment cycles and at the beginning of each cycle
thereafter.

Outcomes
The primary endpoint was investigator-assessed
progression-free survival, dened as the time from
randomisation to radiological disease progression or
death on study. Secondary ecacy endpoints were
www.thelancet.com/oncology Vol 16 January 2015

Articles

Both cohorts

90
80

Statistical analysis

Figure 2: Progression-free survival (intention-to-treat population)

HR=hazard ratio.

www.thelancet.com/oncology Vol 16 January 2015

70
60
50
40
30
20
10
HR 0488 (95% CI 03190748; one-sided p=00004)
0
0

Number at risk
Palbociclib plus letrozole 84
Letrozole 81

12

16

20

24

28

32

36

40

67
48

60
36

47
28

36
19

28
14

21
6

13
3

8
3

5
1

Cohort 1
100
90

Progression-free survival (%)

80
70
60
50
40
30
20
10
HR 0299 (95% CI 01560572; one-sided p<00001)
0
0
Number at risk
Palbociclib plus letrozole 34
Letrozole 32

12

16

20

24

28

32

36

40

26
15

23
10

18
8

15
5

13
4

11
4

8
3

8
3

5
1

28

32

36

40

Cohort 2
100
90
80
Progression-free survival (%)

We used a two-part study design (ie, two sequential

cohorts) to allow us to assess both the activity of the
palbociclib plus letrozole combination and to determine
whether further patient selection on the basis of additional
biomarkers (CCND1 or p16) was warranted. We planned
to enrol 60 patients (30 per treatment group) into cohort 1
to provide initial safety and ecacy (progression-free
survival) data in patients with oestrogen receptor-positive,
HER2-negative, advanced breast cancer. In cohort 2, we
planned to include 150 patients (75 per treatment group)
who also had CCND1 gene amplication or loss of p16.
Cohort 1 was intended to be an exploratory analysis, and
the analysis of the primary endpoint was initially intended
to be based on cohort 2 only. Assuming 114 progressionfree survival events in cohort 2 and using a one-sided of
010, a sample size of 150 would have 80% power to detect
an HR of 067 (palbociclib plus letrozole vs letrozole
alone), including one futility interim analysis. This HR
would represent a median progression-free survival of
9 months in the control group and 135 months in the
experimental group.13
However, an unplanned interim analysis of cohort 1
based on 31 progression-free survival events was done
when we noted that almost twice as many patients in the
control group were coming o the study because of
disease progression. This interim analysis showed
clinically meaningful activity of the palbociclib plus
letrozole combination compared with letrozole alone
(HR 035, 95% CI 017072, p=0006). These preliminary
results from cohort 1 also suggested that further patient
selection based on CCND1 amplication or p16 loss was
unlikely to further improve patient outcome over the use
of oestrogen receptor and HER2 status alone (HR with
CCND1 or p16 copy changes 037 [95% CI 010140;
p=013] vs HR with no CCND1 or p16 copy changes 019
[005067; p=00045]). As a result, we stopped further
enrolment into cohort 2 and amended the statistical
analysis plan such that the primary endpoint would be
analysed in cohorts 1 and 2 combined instead of cohort 2
alone. These study changes were made prospectively
without any ecacy results from cohort 2 and were

Palbociclib plus letrozole

Letrozole

100

Progression-free survival (%)

objective response (by RECIST version 1.0), clinical

benet (as dened by the sum of complete plus partial
responses and stable disease for 24 weeks or more),
duration of response, and overall survival. Additional
secondary endpoints were safety and tissue and serum
biomarker analyses. Finally, we also assessed patientreported outcomes using the modied Brief Pain
Inventory (Short Form; mBPI-sf) done on day 1 of each
treatment cycle; the mBPI-sf was used to capture whether
palbociclib adds to the commonly reported adverse event
seen with aromatase inhibitors (myalgias and joint pain).

70
60
50
40
30
20
10
HR 0508 (95% CI 03030853; one-sided p=00046)
0
0

Number at risk
Palbociclib plus letrozole 50
Letrozole 49

12

16
20
24
Time (months)

41
33

37
26

29
20

21
14

15
10

10
2

29

Articles

Hazard ratio
(95% CI)

Palbociclib plus
letrozole

Letrozole

Patients Events

Patients Events

All patients (intention-to-treat population) 84

41

81

59

0488 (03190748)

Interaction
p value*

Cohort
1

34

15

32

25

0299 (01560572)

50

26

49

34

0508 (03030853)

<65 years

47

24

42

35

0315 (01840539)

65 years

37

17

39

24

0505 (02690948)

014

Age group (years)

034

Baseline ECOG performance status

0

46

21

45

31

0434 (02460766)

38

20

36

28

0398 (02200721)

Visceral

37

21

43

34

0547 (03170944)

Bone Only

17

12

0294 (00920945)

Other

30

15

26

18

0402 (02000808)

078

Disease site
044

Previous chemotherapy
Yes

34

17

37

24

0479 (02550898)

No

50

24

44

35

0397 (02340671)

075

Previous antihormonal therapy

Yes

27

12

28

19

0460 (02220956)

No

57

29

53

40

0397 (02440646)

Yes

40

20

44

28

0539 (03020962)

No

44

21

37

31

0341 (01940599)

088

Previous systemic therapy

036

Time from end of adjuvant treatment to disease recurrence

12 months (including de-novo presentation) 59

31

51

39

0418 (02590674)

>12 months

25

10

30

20

0399 (01850858)

12 months (excluding de-novo presentation) 15

14

0765 (02322523)

0062

0125

0250

0500

Favours palociclib plus letrozole

1000

2000

095
034

4000

Favours letrozole

Figure 3: Subgroup analysis for progression-free survival

ECOG=Eastern Cooperative Oncology Group. *Two-sided p value.

overseen and approved by the study steering committee.

At the time enrolment was stopped, 165 patients had
been randomly assigned (66 patients in cohort 1 and 99
patients in cohort 2). Based on the same original
assumption that palbociclib plus letrozole would increase
progression-free survival from 9 months to 135 months
compared with letrozole alone, this sample size would
have 80% power to detect an HR of 067 based on
114 progression-free survival events in the nal analysis.
A second interim analysis was added with these
protocol amendments, which was to be done when about
half of the expected number of progression-free survival
events across both cohorts (ie, about 57 of 114 total
events) had occurred. At the time of the second interim
analysis, 61 events had occurred and the HR for
progression-free survival for the entire intention-to-treat
population was 037 (95% CI 021063; one-sided
p<00001). After these analyses were done, we noted a
substantial fall in the event rate over time and therefore
made another adjustment to the nal analysis plan such
that the nal analysis of progression-free survival would
30

be done when 95 progression-free survival events had

accumulated, giving greater than 98% power to detect an
HR of 050 at a one-sided of 010, or 75% power to
detect an HR of 067.
We adjusted the signicance level for the nal analysis
for the interim analyses using the Lan-DeMets procedure
with an OBrien-Fleming stopping boundary. At the nal
analysis of progression-free survival, we used a gatekeeping procedure for hypotheses testing in a hierarchical
approach to further control for family-wise errors. This
process began with assessment of all randomly assigned
patients (in cohorts 1 and 2 combined). If the null
hypothesis was rejected, then the Holm procedure would
be used to test the same hypotheses for cohorts 1 and 2 as
two separate studies. Using this approach, we compared
progression-free survival data between the treatment
groups using a stratied log-rank test with stratication
for site of disease, disease-free interval, and study cohort.
We estimated the HR using the Cox proportional hazards
regression model; the proportionality of hazards assumption was veried14 and the results were satisfactory.
www.thelancet.com/oncology Vol 16 January 2015

Articles

To explore the eect of prespecied baseline prognostic

factors on progression-free survival, we did a multivariate
analysis using the Cox regression model. The primary
and secondary ecacy analyses were done in the
intention-to-treat population. The safety analyses were
done for all randomly assigned patients who received at
least one dose of the study treatment. We only controlled
the type I error for the analysis of primary endpoint, not
for any of the secondary endpoints. We did seven
prespecied sensitivity analyses for progression-free
survival (unstratied analysis; analysis stratied per case
report form data; including symptomatic deterioration as
disease progression; including disease progression or
death after 28 days of treatment discontinuation as
disease progression; forced progression-free survival
times to the planned assessment times; as-treated
population analysis; and multivariate analysis).
All statistical analyses were done with the SAS version
9.2 or later.
The study is registered with the ClinicalTrials.gov,
number NCT00721409.

Role of the funding source

The funder provided funding to the investigators for study
design, conduct, treatment administration, and data
collection. The study database was held by the funder. The
steering committee that oversaw the conduct of the study
consisted of the principal investigator (RSF), senior author
(DJS), an independent statistician, two additional investigators, and three representatives from the funder (one
clinician, one operations representative, and a statistician).
The study steering committee was involved and in all
discussions about study conduct. All authors had
unrestricted access to the raw and nal study data, and

Palbociclib
plus letrozole

were responsible for data interpretation, preparation of

the report, and the decision to submit for publication. The
authors attest to study completeness and the accuracy of
the data and data analysis.

Results
Between Dec 22, 2009, and May 12, 2012, 165 women
were randomly assigned, 84 to receive letrozole plus
palbociclib and 81 to receive letrozole alone (gure 1).
Baseline demographic characteristics and established
prognostic factors of the intention-to-treat population
were generally well balanced, although there were slight
imbalances in disease site, disease-free interval, and
previous treatment (table 1). About half of the patients in
each group had never received either adjuvant or
neoadjuvant systemic treatment. Conversely, a third of
patients in each group had received previous antihormonal treatment, with half of these individuals
having previously received aromatase inhibitors.
As of the data cuto for the nal analysis (Nov 29,
2013), median follow-up was 296 months (95% CI
279360) for the palbociclib plus letrozole group and
279 months (255311) for the letrozole group, with
19 (23%) of 84 patients in the palbociclib plus letrozole
group and eight (10%) of 81 in the letrozole group
remaining on treatment. At the time of the nal analysis
for progression-free survival, 41 progression-free survival
events had occurred in the palbociclib plus letrozole
group and 59 in the letrozole group. Median progressionfree survival was 202 months (95% CI 138275) for
the palbociclib plus letrozole group and 102 months
(57126) for the letrozole alone group (HR 0488,
95% CI 03190748; one-sided p=00004; gure 2). For
patients in cohort 1, median progression-free survival
was 261 months (95% CI 112not estimable [NE]) for
the combination and 57 months (95% CI 26105) for

Letrozole
Palbociclib plus letrozole
Letrozole

100

Intention-to-treat population*
1 (1%)

1 (1%)

Partial response

35 (42%)

26 (32%)

Stable disease

37 (44%)

30 (37%)

Stable disease 24 weeks

32 (38%)

20 (25%)

Stable disease <24 weeks

5 (6%)

10 (12%)

3 (4%)

18 (22%)

Progressive disease
Indeterminate

8 (10%)

6 (7%)

1 (2%)

Patients with measurable disease

Complete response

80
70
Overall survival (%)

Complete response

90

60
50
40
30
20

Partial response

35 (54%)

26 (39%)

Stable disease

20 (31%)

22 (33%)

10

Progressive disease

2 (3%)

15 (23%)

Indeterminate

7 (11%)

3 (5%)

Data are n (%). *n=84 in the palbociclib plus letrozole group, n=81 in the letrozole
alone group. n=65 in the palbociclib plus letrozole group, n=66 in the letrozole
alone group.

Table 2: Best overall response

www.thelancet.com/oncology Vol 16 January 2015

HR 0813 (95% CI 04921345; two-sided p=042)

0
Number at risk
Palbociclib plus letrozole 84
Letrozole 81

12

16

80
76

78
74

73
67

68
64

20
24
Time (months)
65
59

47
37

28

32

36

40

44

35
23

22
14

17
12

7
5

2
1

Figure 4: Overall survival (intention-to-treat population)

HR=hazard ratio.

31

Articles

letrozole alone (HR 0299, 95% CI 01560572; onesided p<00001; gure 2). For patients in cohort 2,
median progression-free survival was 181 months (95%
CI 131275) for the combination and 111 months
Palbociclib plus letrozole (n=83)

Letrozole (n=77)

Grade 12

Grade 3

Grade 4

Grade 12

Grade 3

19 (23%)

49 (59%)

14 (17%)

49 (64%)

16 (21%) 0

Neutropenia

17 (20%)

40 (48%)

5 (6%)

3 (4%)

1 (1%)

Leucopenia

20 (24%)

16 (19%)

2 (3%)

Fatigue

30 (36%)

2 (2%)

1 (1%)

Anaemia

24 (29%)

4 (5%)

1 (1%)

4 (5%)

1 (1%)

Nausea

19 (23%)

2 (2%)

9 (12%)

1 (1%)

Arthralgia

18 (22%)

2 (3%)

Alopecia

18 (22%)

Diarrhoea

14 (17%)

3 (4%)

Hot ush

17 (21%)

Thrombocytopenia

12 (14%)

2 (2%)

Decreased appetite

12 (14%)

Dyspnoea

11 (13%)

Nasopharyngitis

13 (16%)

Back pain

11 (13%)

1 (1%)

Headache

12 (14%)

8 (10%)

Vomiting

12 (14%)

2 (3%)

1 (1%)

Any adverse event

1 (1%)

2 (2%)

17 (22%)

Grade 4

10 (13%)

NA

2 (3%)

NA

8 (10%)

NA

9 (12%)

NA

1 (1%)

1 (1%)

5 (6%)

2 (2%)

5 (6%)

1 (1%)

8 (10%)

1 (1%)

NA

11 (14%)

NA
0

Asthenia

9 (11%)

2 (2%)

3 (4%)

Bone pain

8 (10%)

1 (1%)

1 (1%)

3 (4%)

Constipation

10 (12%)

7 (9%)

Cough

10 (12%)

8 (10%)

Stomatitis

10 (12%)

2 (3%)

Epistaxis

9 (11%)

1 (1%)

Inuenza

8 (10%)

1 (1%)

1 (1%)

Musculoskeletal pain

8 (10%)

1 (1%)

5 (6%)

Upper respiratory tract infection

8 (10%)

1 (1%)

2 (3%)

Dizziness

8 (10%)

3 (4%)

Peripheral neuropathy

8 (10%)

4 (5%)

Oropharyngeal pain

8 (10%)

1 (1%)

Pain in extremity

8 (10%)

6 (8%)

Data are n (%) unless otherwise specied. One (1%) grade 5 adverse event occurred in the palbociclib plus letrozole group
(from disease progression) and none in the letrozole group. Additional grade 4 adverse events reported in the palbociclib
plus letrozole group that are not shown in the table are neutropenia (ve [6%]), pulmonary embolism (four [5%]), bone
pain (one [1%]), chest pain (one [1%]), increased blood uric acid increased (1 [1%]), gangrene (one [1%]), and humerus
fracture (one [1%]). No additional grade 4 adverse events were reported in the letrozole group. Additional grade 3
adverse events reported in the palbociclib plus letrozole group that are not shown in the table are abdominal pain (two
[2%]), increased -glutamyl transferase (two [2%]), decreased white blood cell count (two [2%]), increased aspartate
aminotransferase (one [1%]), pain (one [1%]), spinal pain (one [1%]), increase blood lactate dehydrogenase (one [1%]),
joint stiness (one [1%]), pneumonia (one [1%], wound (one [1%]), decreased blood potassium (one [1%]), cancer pain
(one [1%]), ischaemic colitis (one [1%]), coronary artery disease (one [1%]), exertional dyspnoea (one [1%]), fallopian
tube cancer (one [1%]), fractured sacrum (one [1%]), gastrointestinal disorder (one [1%]), granulocytopenia (one [1%]),
hypermagnesaemia (one [1%]), intervertebral disc protrusion (one [1%]), nephrolithiasis (one [1%]), decreased
neutrophil count (one [1%]), pathological fracture (one [1%]), periostitis (one [1%]), petechiae (one [1%]), renal disorder
(one [1%]), staphylococcal bacteraemia (one [1%]), and urethral obstruction (one [1%]). Additional grade 3 adverse
events reported in the letrozole group that are not shown in the table are pleural eusion (two [3%]), hypertension (one
[1%]), chest pain (one [1%]), decreased haemoglobin (one [1%]), pain (one [1%]), spinal pain (one [1%]), dysphagia (one
[1%]), hypocalcaemia (one [1%]), mucosal inammation (one [1%]), neck pain (one [1%]), pelvic pain (one [1%]), cardiac
failure (one [1%]), hip fracture (one [1%]), ileus (one [1%]), laceration (one [1%]), oesophageal achalasia (one [1%]),
pneumothorax (one [1%]), and subcutaneous emphysema (one [1%]).

Table 3: Most common all-cause adverse events that occurred in at least 10% of patients (safety
population)

32

(71164) for letrozole alone (HR 0508, 95% CI

03030853; one-sided p=00046; gure 2). The eect
of the combination treatment relative to letrozole alone
was consistent across all demographic subgroups and
patient baseline prognostic factors, apart from patients
with disease recurrence 12 months or less from the end
of adjuvant treatment, although this subgroup is limited
by small numbers in both groups (gure 3). The results
from prespecied sensitivity analyses were consistent
with those of the main analysis (data not shown).
Table 2 shows best responses to treatment. A greater
proportion of patients in the palbociclib plus letrozole
group than in the letrozole group had an objective
response to treatment, both in the intention-to-treat
population (36 [43%, 95% CI 3254] vs 27 [33%, 2345];
p=013) and in the population with measurable disease
(36 [55%, 4368] vs 26 [39%, 2852]; one-sided p=0047).
Similarly, a greater proportion of patients in the
intention-to-treat population achieved clinical benet
(68 [81%, 95% CI 7189] vs 47 [58%, 4769]; one-sided
p=00009). The median duration of response for patients
who had a complete or partial response was 203 months
(95% CI 134258) for the palbociclib plus letrozole
group and 111 months (93316) for the letrozole
group. At the same time as the nal progression-free
survival analysis, we also assessed overall survival.
Median overall survival was 375 months (95% CI
284NE; 30 events) in the palbociclib plus letrozole
group and 333 months (264NE; 31 events) in the
letrozole alone group (HR 0813, 95% CI 04921345;
two-sided p=042; gure 4).
The most common adverse events reported for the
palbociclib plus letrozole group were neutropenia,
leucopenia, and fatigue (table 3). All 83 patients who
received palbociclib plus letrozole had at least one
adverse event, compared with 65 (84%) of 77 who received
letrozole alone. Despite the increase in all grades of
neutropenia and leucopenia with palbociclib plus
letrozole, no cases of neutropenic fever were reported.
Other adverse events (of any cause) that were increased
in the palbociclib plus letrozole group included anaemia,
nausea, arthralgia, and alopecia, but most of these were
low grade (table 3). Of these adverse events, the dierence
between treatment groups was signicant only for
anaemia (two-sided p<00001) and alopecia (two-sided
p=00002). Serious adverse events that occurred in more
than one patient in the palbociclib plus letrozole group
were pulmonary embolism (three [4%] patients), back
pain (two [2%]), and diarrhoea (two [2%]). No serious
adverse events occurred in more than one patient in the
letrozole group.
27 (33%) patients in the palbociclib plus letrozole had
dose interruptions because of adverse events, compared
with only three (4%) patients in the letrozole group. In
the combination group, 37 (45%) patients required a
delay in the start of a subsequent treatment cycle because
of an adverse event and 33 (40%) patients had a dose
www.thelancet.com/oncology Vol 16 January 2015

Articles

reduction. However, the mean relative dose intensity for

palbociclib in the combination group was 94% (SD 26).
Cycle delays and dose reductions are not applicable to the
letrozole group.
The main reason for study discontinuation in both
treatment groups was disease progression (42 [50%]
patients in the palbociclib plus letrozole group vs 57 [70%]
patients in the letrozole group). 11 (13%) patients in the
palbociclib plus letrozole group and two (2%) patients in
the letrozole group discontinued the study because of an
adverse event. Of these discontinuations, six (7%)
patients in palbociclib plus letrozole group and two (2%)
patients in the letrozole group discontinued because of
treatment-related adverse events. One death occurred
during the study in the palbociclib plus letrozole group
because of disease progression; no treatment-related
deaths occurred. We noted no signicant dierences in
pain severity or the eect of pain on daily activities
between the two treatment groups.

Discussion
The results of this open-label, phase 2 study show that
patients with oestrogen receptor-positive, HER2-negative
advanced breast cancer had signicantly longer
progression-free survival when treated with palbociclib
and letrozole than when treated with letrozole alone.
Additionally, the proportions of patients with an objective
response and clinical benet were greater in the
combination group than in the letrozole alone group.
The study was not powered to detect an overall survival
advantage and few overall survival events had occurred at
the time of this analysis; however, the initial data suggest
no detrimental eect on overall survival with the addition
of palbociclib in the rst-line setting (panel).
Hormone directed drugs have been the mainstay of
treatment for advanced oestrogen receptor-positive
breast cancer for more than four decades. Improvements
in clinical outcomes have occurred with several drugs
that target either specic hormone production (ie,
ligands or the hormone receptor pathway), including
tamoxifen, steroidal and non-steroidal aromatase
inhibitors, and fulvestrant.15 Despite eorts to further
improve clinical outcomes for patients with oestrogen
receptor-positive breast cancer with drugs that target
other pathways thought to have a role in the development
of resistance to hormone drugs, most results have been
largely disappointing, including eorts to target the
HER1 and HER2 pathways, angiogenesis, and IGFR.1618
Recently, however, targeting of mTOR, a crucial
component of the PI3K pathway, with everolimus, used
in combination with a steroidal aromatase inhibitor,
resulted in improved progression-free survival, although
not overall survival, in patients with oestrogen receptorpositive, advanced disease who had progressed on antihormonal treatment.4,19
Our ndings need to be interpreted in the context of
the limitations of the study design. Specically, the study
www.thelancet.com/oncology Vol 16 January 2015

is open-label and did not use central radiology review to

prospectively assess the primary endpoint, but rather a
retrospective, masked, independent review after accrual
was completed. This analysis was limited by the fact that
scans were obtained retrospectively and were not used to
make on-treatment decisions. On-treatment decisions
were made on the basis of scan reviews at the individual
study sites. We noted some baseline imbalances based
on the case report form data; however, sensitivity analyses
including multivariate analysis to control for baseline
factors consistently showed treatment benet in the
combination group across all demographic and clinical
subgroups.
These clinical results are supported by preclinical data11
that provide a clear biological rationale for the
development of palbociclib in this patient population. As
with most other molecularly targeted drugs in oncology,
the greatest gains are often seen when rational and
appropriate patient selection can be used prospectively.
Preclinical data11 with palbociclib identied oestrogen
receptor-positive breast cancer cells as one of the subtypes
most sensitive to CDK4/6 inhibition, the other being
HER2 amplication. Our results provide clinical
validation of these preclinical data and support the further
development of palbociclib for the oestrogen receptorpositive, HER2-negative subgroup of breast cancers.
Genetic changes in cyclin D1 and p16 are known to
occur in breast cancer and might have a role in the
further selection of patients for treatment with a CDK4/6
inhibitor. In cohort 2, we investigated the potential for
these genetic changes to be used to improve patient
selection beyond use of oestrogen receptor-positive status
alone. However, our results did not substantiate this
hypothesis. This analysis conrmed that oestrogen
receptor positivity is currently the best and most eective
predictive marker for the identication of patients likely
to respond to CDK4/6 inhibition. Further biomarker
Panel: Research in context
Systematic review
We searched PubMed for reports of clinical trials published in English between Nov 1,
2004, and Nov 1, 2014, using the terms breast cancer and cyclin-dependent kinase
inhibitors. We did not identify any studies that investigated cyclin-dependent kinase
(CDK) inhibitors specically in women with breast cancer, despite laboratory data
suggesting a role for CDK inhibition in breast cancer.7,8
Interpretation
Our results show that palbociclib, a novel, oral, inhibitor of CDK4/6, used in combination
with letrozole resulted in longer progression-free survival than letrozole alone in
postmenopausal women with advanced oestrogen receptor-positive, HER2-negative
breast cancer. These results provide the rst clinical data to show a role for CDK4/6
inhibition in breast cancer. The safety prole of the combination was predictable and
manageable. Overall, our results suggest that palbociclib in combination with letrozole
could become an important treatment option, substantially improving upon letrozole
alone for the treatment of postmenopausal women with oestrogen receptor-positive,
HER2-negative, advanced breast cancer.

33

Articles

research designed to improve on oestrogen receptorpositive status as the selection biomarker is ongoing;
however, in view of the large proportion of patients in
our study who achieved a clinical benet response (more
than 80%), the benet of additional biomarkers could be
dicult to ascertain.
Negative-selection biomarkers of resistance might be
more easily identied and will also be assessed in ongoing
and future molecular studies. One of the most important
markers of sensitivity to palbociclib is the presence of an
intact Rb pathway; however, since pRb loss is uncommon
in oestrogen receptor-positive, HER2-negative breast
cancers, it was not used as a prospective independent
biomarker for patient selection in the present study.
Potentially, relative amounts of pRb (rather than its
presence or absence) in the various breast cancer subtypes
might be of predictive importance and early preclinical
data11 suggest that this possibility should be investigated.
When comparing median progression-free survival in
the letrozole alone groups, we noted a dierence between
cohorts 1 and 2, suggesting a potential predictive value
for cyclin D1 gains, p16 loss, or both in determining
response to letrozole alone. However, this nding could
simply be an artifact of the sample size in cohort 1, so
further study is necessary.
Since the initiation of this study, additional laboratory
ndings have linked CDK 4/6 inhibition to endocrine
sensitivity in oestrogen receptor-positive breast cancer.20,21
The Cancer Genome Atlas has been used to identify
common changes in the Rb pathway in all breast cancer
subtypes, including the luminal oestrogen receptorpositive, HER2-negative subgroup. However, our ndings
suggest that limiting patient selection to those with
dened genetic changes in the Rb pathway might exclude
a much larger group of patients that could benet from
CDK4/6 inhibition. Additionally, the results of a recent
phase 2, single-arm study22 of palbociclib in patients with
heavily pretreated advanced breast cancer showed singleagent activity in some patients with oestrogen receptorpositive, HER2-negative breast cancers.
Our results also provide useful data for the safety
prole of the combination of palbociclib and letrozole,
suggesting that adverse events are predictable and
manageable. Neutropenia, although common, was not
accompanied by serious clinical outcomes and is likely to
be the result of an on-target eect of CDK4/6 inhibition
on marrow progenitor cells. The absence of serious
complications resulting from palbociclib-associated
neutropenia probably reects a cytostatic rather than
cytotoxic eect of the drug on bone marrow progenitor
cells,23 dierent from what is seen with typical cytotoxic
drugs. Additional analyses of the eect of palbociclib on
quality-of-life measures are ongoing in the context of
phase 3 studies.
Taken together, the data from this study provides a
proof of concept for the activity and safety of CDK4/6
inhibition in advanced, oestrogen receptor-positive,
34

HER2-negative breast cancer. The improvement in

progression-free survival is substantial in this population
and is accompanied by manageable toxic eects. These
data clearly warrant further investigation of the ecacy
and safety of palbociclib in combination with hormonal
blockade, both in patients with this subtype of breast
cancer and in other cancer settings. A phase 3, doubleblind, placebo-controlled study (NCT01740427) in a
similar patient population (n=650) with the aim of
conrming the present phase 2 ndings is now fully
enrolled and ongoing. Additionally, other phase 3 studies
of palbociclib in combination with various anti-hormonal
drugs in additional breast cancer settings are now
ongoing (NCT01942135 and NCT01864746).
Contributors
RSF, SOK, CF, XH, STK, SR, and DJS contributed to the design of the
study. RSF, DJS, and JPC were members of the steering committee that
oversaw the conduct of the study. RSF, JPC, IMB, SOK, RP, ART, and
NLV contributed substantially to patient recruitment. RSF, JPC, IL, KB,
IMB, SOK, JE, RP, TP, MS, YS, NLV, DJS, ART, and STK contributed to
data collection. JPC, RP, and SR contributed to data review. RSF, JPC,
IMB, SOK, RP, CF, XH, STK, SR, and DJS contributed to data analysis.
RSF, IL, KB, IMB, SOK, JE, RP, TP, MS, YS, CF, XH, STK, SR, and DJS
contributed to data interpretation. RSF, JE, MS, CF, XH, STK, SR, and
DJS contributed to the writing and revision of the report. DJS searched
the scientic literature. DJS and XH contributed to production of the
gures. All authors contributed to review of the report and approved the
nal submitted version.
Declaration of interests
RSF and DJS received research support from Pzer and have served as
consultants to the same company. DJS has common stock in Pzer.
JPC has received conference support from Pzer. JE has received
honoraria from Pzer for attending advisory board meetings. MS has
received research support, served as a consultant, and received honoraria
from Pzer. He has also received personal fees from Novartis,
AstraZeneca, Roche, GlaxoSmithKline, Sano-Aventis, Sividon, PierreFabre, Celgene, and Eisai. CF, XH, STK, and SR are employees of Pzer.
KB, SOK, TP, IL, IMB, YS, RP, ART, and NLV declare no competing
interests.
Acknowledgments
The study was funded by Pzer. DJS has received funding for the
preclinical work on cyclin-dependent kinase 4/6 inhibition that
generated translational concepts for this clinical study from the US
Department of Defense Breast Cancer Innovator Award, the Revlon/
UCLA Womens Cancer Research Program, and the Peter and Denise
Wittich Breast Cancer Program. We thank all the study participants and
their families, as well as the sta of Translational Research in Oncology
for their support. We also thank Nicholas J Robert (Virginia Cancer
Specialists, US Oncology, Fairfax, VA, USA) and Marc Buyse (IDDI,
Louvain-la-Neuve, Belgium) for their contributions. Karen Miller and
Cynthia Gobbel from Complete Healthcare Communications (Chadds
Ford, PA, USA) provided administrative support for the report
submission (funded by Pzer).
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