Palbociclib for advanced ER-positive/HER2

Horizon Scanning Centre
May 2014
Palbociclib
for advanced ER-positive/HER2negative breast cancer in postmenopausal women – first line in
combination with letrozole
SUMMARY
This briefing is
based on
information
available at the time
of research and a
limited literature
search. It is not
intended to be a
definitive statement
on the safety,
efficacy or
effectiveness of the
health technology
covered and should
not be used for
commercial
purposes or
commissioning
without additional
information.
NIHR HSC ID: 4481
Palbociclib in combination with letrozole, is intended to be used as first line
therapy for the treatment of advanced oestrogen receptor positive (ER+),
human epidermal growth factor receptor negative (HER2-) breast cancer in
post-menopausal women. If licensed, it would offer an additional treatment
option for this patient group. Palbociclib, a small molecule inhibitor of cyclindependent kinases (CDK4 and CDK6), prevents cellular DNA synthesis by
interfering with cell cycle progression from G1 to S phase. Palbociclib does
not have Marketing Authorisation in the EU for any indication.
Breast cancer is the most common type of cancer in the UK with incidence
rates increasing by 6% over the last 10 years. In 2010, over 49,500 women
and approximately 400 men were diagnosed with breast cancer in the UK.
Eight out of 10 breast cancers diagnosed are in women over the age of 50.
In England, the annual breast cancer incidence rate was 125 per 100,000
population in 2011, and there were 41,523 new cases of breast cancer
diagnosed that year. Survival rates for breast cancer are improving, with over
90% of women diagnosed with early disease, surviving a minimum of five
years, reducing to 15% in women with a diagnosis of advanced disease.
More than three-quarters of women diagnosed with breast cancer survive for
at least 10 years, and two out of three women diagnosed survive for at least
20 years.
Current treatment for advanced breast cancer in post-menopausal women
includes aromatase inhibitors (with or without everolimus), anthracyclines,
directed therapy using monoclonal antibodies, bisphosphonates, and surgery
or radiotherapy. Palbociclib is currently in phase III clinical trials comparing
its effect on progression free survival against treatment with placebo, both in
combination with letrozole. This trial is expected to complete in March 2015.
This briefing presents independent research funded by the National Institute
for Health Research (NIHR). The views expressed are those of the author
and not necessarily those of the NHS, the NIHR or the Department of Health.
NIHR Horizon Scanning Centre, University of Birmingham
Email: [email protected]
Web: http://www.hsc.nihr.ac.uk
NIHR Horizon Scanning Centre
TARGET GROUP
•
Breast cancer: advanced; ER-positive; HER2-negative; post-menopausal women – first
line in combination with letrozole.
TECHNOLOGY
DESCRIPTION
Palbociclib (PD-0332991) is a selective, small molecule inhibitor of cyclin-dependent kinases
4 and 6 which prevents cellular DNA synthesis by prohibiting progression of the cell cycle
from G1 to S phase. Palbociclib is intended for the first line treatment of post-menopausal
women with advanced ER-positive, HER2-negative breast cancer. Palbociclib is taken orally
once daily at a dose of 125mg on days 1 to 21 of a 28 day cycle with 7 days off treatment, in
combination with the aromatase inhibitor, letrozole, until disease progression.
Palbociclib does not currently have Marketing Authorisation in the EU for any indication.
Palbociclib is also undergoing a number of phase II trials for the treatment of non-small cell
lung cancer and solid tumours, squamous cell carcinoma of the head and neck, advanced
gastrointestinal stromal tumours, ovarian epithelial cancer, advanced hepatocellular
carcinoma, recurrent glioblastoma, prostate cancer, multiple myeloma and late-stage
liposarcoma.
INNOVATION and/or ADVANTAGES
If licensed, palbociclib will offer an additional treatment option for post-menopausal women
with ER-positive, HER2-negative, advanced breast cancer.
DEVELOPER
Pfizer Limited.
AVAILABILITY, LAUNCH OR MARKETING
In phase III clinical trials.
PATIENT GROUP
BACKGROUND
Breast cancer occurs when cells within the ducts or lobules of the breast start to divide and
proliferate in an uncontrolled way. There are several types of breast cancer described
according to the receptors expressed on the surface of tumour cells, stage of diagnosis and
rate of growth 1. Breast cancers which express receptors for hormones are referred to as ERpositive (oestrogen-receptor positive) or PR-positive (progesterone-receptor positive). HERpositive indicates overexpression of human epidermal growth factor receptors (HER).
Advanced breast cancer describes cancer that has spread extensively, either locally or to
distant sites in the body, referred to as metastatic cancer 2.
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The causes of breast cancer are not completely understood, however there are a number of
known risk factors which increase its likelihood 3, such as exposure to radiation, increased
alcohol consumption, being taller, being overweight or obese, exposure to oestrogen and
hormone replacement therapy, greater breast tissue density and genetic factors. The risk of
developing breast cancer is known to increase with inheritance of certain genes (e.g.
BRCA2, BRCA1 and TP53). Breast cancer in adults can occur at any age with an increased
risk presenting in post-menopausal women. Obesity is known to increase the risk of postmenopausal breast cancer by up to 30% 4 and a previous benign breast lump or previous
diagnosis of early breast cancer further increases this risk3.
Breast cancer is normally characterised by a lump or thickened tissue in the breast area,
however not all lumps will be cancerous. Other features of breast cancer include a change in
breast size or shape, discharge from the nipple (may include blood), lumps/swelling in
armpits, dimples on the skin of the breast and rash around the nipple area. Symptoms may
include pain in the breast or axilla (under the arm). Signs and symptoms can occur in one or
both breasts 5.
NHS or GOVERNMENT PRIORITY AREA
This topic is relevant to:
• Improving Outcomes: A Strategy for Cancer (2011).
• NHS England. 2013/14 NHS Standard Contract for Cancer: Chemotherapy (Adult).
B15/S/a.
• NHS England. 2013/14 NHS Standard Contract for Cancer: Radiotherapy (All Ages).
B01/S/a.
CLINICAL NEED and BURDEN OF DISEASE
Breast cancer is the most common type of cancer in the UK and over the last 10 years,
incidence rates have increased by 6%. In 2010, over 49,500 women and approximately 400
men were diagnosed with breast cancer in the UK. Eight out of 10 breast cancers diagnosed
are in women over the age of 504.
In England, the incidence of breast cancer in women was 125 per 100,000 population in
2011 6. There were 41,523 new cases of breast cancer diagnosed in women in England
during 2011 7. Survival rates for breast cancer are improving, with over 90% of women
diagnosed with early disease, surviving a minimum of five years, reducing to 15% in women
with a diagnosis of advanced disease. More than three-quarters of women diagnosed with
breast cancer survive for at least 10 years and two out of three women diagnosed survive for
at least 20 years4.
In 2012, 10,373 deaths from malignant neoplasms of the breast were registered in England
and Wales (ICD-10 C50) 8 compared to 10,397 deaths in 2011 9. In 2012, there were 177,514
admissions for breast cancer (ICD-10 C50) in England, resulting in 109,365 bed days and
180,595 finished consultant episodes 10.
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PATIENT PATHWAY
RELEVANT GUIDANCE
NICE Guidance
•
•
•
•
•
•
•
•
•
•
•
•
•
NICE technology appraisal in development. Breast cancer (early) - intrabeam
radiosurgery system [ID618]. Expected November 2014.
NICE technology appraisal in development. Breast cancer (HER2-positive, unresectable)
- trastuzumab emtansine (after trastuzumab & taxane) [ID603]. Expected August 2014.
NICE technology appraisal. Bevacizumab in combination with capecitabine for the first
line treatment of metastatic breast cancer (TA263). August 2012.
NICE technology appraisal. Lapatinib or trastuzumab in combination with an aromatase
inhibitor for the first-line treatment of metastatic hormone receptor positive breast cancer
which over-expresses HER2 (TA257). June 2012.
NICE technology appraisal. Eribulin for the treatment of locally advanced or metastatic
breast cancer (TA250). April 2012.
NICE technology appraisal. Fulvestrant for the treatment of locally advanced or
metastatic breast cancer (TA239). London. December 2011.
NICE technology appraisal. Bevacizumab in combination with a taxane for the first-line
treatment of metastatic breast cancer (TA214). February 2011.
NICE technology appraisal. Gemcitabine for the treatment of metastatic breast cancer
(TA116). January 2007.
NICE technology appraisal. Hormonal therapies for the adjuvant treatment of early
oestrogen-receptor-positive breast cancer (TA112). November 2006.
NICE technology appraisal. Guidance on the use of trastuzumab for the treatment of
advanced breast cancer (TA34). March 2002.
NICE clinical guideline. Familial breast cancer: Classification and care of people at risk of
familial breast cancer and management of breast cancer and related risks in people with
a family history of breast cancer (CG164). June 2013.
NICE clinical guideline. Advanced breast cancer – diagnosis and treatment (CG81).
February 2009.
NICE clinical guideline. Breast cancer (early & locally advanced): diagnosis and
treatment (CG80). February 2009.
•
NICE quality standard. Breast cancer quality standard (QS12). September 2011.
•
Cancer Service Guideline CSGBC. Improving outcomes in breast cancer. August 2002.
Other Guidance
•
•
•
SIGN. Treatment of primary breast cancer (SIGN 134). 2013 11.
European Society for Medical Oncology. Locally recurrent or metastatic breast cancer:
ESMO clinical practice guidelines for diagnosis, treatment and follow-up. 2012 12.
Cancer Services Collaborative Improvement Partnership. Breast cancer service
improvement guide. 2003 13.
CURRENT TREATMENT OPTIONS
Patients with advanced breast cancer now typically undergo multiple episodes of relapse
and remission, and thus require multiple serial episodes of treatment over a median of two
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years, with a range of six to 46 months a. Treatment for patients with advanced breast cancer
aims to slow disease progression, manage symptoms associated with the disease and
improve patient quality of life. Treatment options for advanced disease in post-menopausal
women include:
• Aromatase inhibitors (steroidal or non-steroidal, with or without everolimusa) – for postmenopausal women with ER-positive breast cancer and no prior history of endocrine
therapy; and for post-menopausal women with ER-positive breast cancer previously
treated with tamoxifen 14,15.
• First line chemotherapy – treatment with anthracyclines unless unsuitable, in which case
docetaxel as first line therapy14,15.
• Alternatively, directed therapy – trastuzumab in combination with paclitaxel for HER2positive patients14. Docetaxel plus trastuzumab and pertuzumab in combination,
trastuzumab emtansine, lapatinib and capecitabinea.
• Bisphosphonates – for women undergoing ovarian suppression or in a post-menopausal
state and for treatment-related bone loss15 with denosumab offered as an alternativea.
• Surgery or radiotherapy with adjuvant systemic therapy may be considered15.
EFFICACY and SAFETY
Trial
NCT01709370, OOTRN007/LET-CDK; palbociclib
in combination with
letrozole; phase II.
Sponsor
Status
Source of
information
Location
Organisation for Oncology
and Translational
Research.
Ongoing.
16
Trial registry ,
manufacturer.
China.
Design
Uncontrolled, single arm.
Participants
n=45 (planned); 18 years
and older; female; postmenopausal; invasive
breast cancer; tumour
greater than 2cm diameter;
b
ER+; HER2-; ECOG ≤1 or
Karnofsky performance
status ≥70%.
a
b
NCT01740427, A5481008,
PALOMA-2; palbociclib or
placebo, both in
combination with letrozole;
phase III.
Pfizer.
NCT00721409, A5481003,
PALOMA-1; palbociclib in
combination with letrozole
or letrozole alone; phase
I/II.
Pfizer.
Ongoing.
17
Trial registry ,
manufacturer.
EU (incl UK), USA, Canada
and other countries.
Randomised, placebocontrolled.
n=450 (planned); 18 years
and older; female;
locoregionally recurrent or
metastatic disease not
amenable to curative
therapy; ER+, HER2-; no
prior anti-cancer therapy
for ER+ disease; postmenopausal; measurable
disease (RECIST or boneonly disease); ECOG 0-2.
Ongoing.
18
19
Abstract , poster , trial
20
registry , manufacturer,
EU (incl UK), USA, Canada
and other countries.
Randomised.
n=177; 18 years and older;
female; inoperable ER+
and HER2- locally
recurrent or metastatic
breast cancer; postmenopausal; previously
untreated for
metastatic/advanced
disease; measurable
disease (according to
RECIST 1.0) or bone-only
disease; ECOG 0 or 1; no
prior/current brain
metastases. Phase II
requires CCND1
amplification and/or loss of
p16 as determined by the
central laboratory.
Expert personal opinion.
Eastern Cooperative Oncology Group.
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NIHR Horizon Scanning Centre
Schedule
Patients receive palbociclib
125mg orally once daily for
3 out of 4 weeks in
repeated cycles for 16
weeks before surgery; in
combination with 2.5mg
letrozole once daily for 16
weeks before surgery.
Follow-up
Active treatment for 16
weeks, follow-up not
reported.
Objective response rates.
Primary
outcome/s
Secondary
outcome/s
Key results
Adverse events (AEs);
pathological response
rates.
-
Patients randomised to
palbociclib 125mg orally
once daily, days 1 to 21 of
every 28 day cycle with 7
days off treatment, in
combination with letrozole,
2.5mg orally once daily,
continuously; or placebo
125mg orally once daily on
days 1 to 21 of every 28
day cycle with 7 days off
treatment, in combination
with letrozole, 2.5mg orally
once daily, continuously.
Active treatment period
until disease progression.
Follow-up up to 6 years.
Progression-free survival
(PFS).
Probability of participant
survival; overall survival;
objective response;
duration of response;
disease control; QTc
interval; pharmacokinetics;
quality of life (EQ-5D and
c
FACT-B ); functional
assessment of cancer
therapy; tumour tissue
biomarkers.
-
Patients randomised to
palbociclib 125mg orally,
once daily for 3 out of 4
weeks in repeated cycles,
in combination with
letrozole 2.5mg orally once
daily on a continuous
regimen; or letrozole 2.5mg
orally once daily on a
continuous regimen.
Active treatment period
until disease progression.
Follow-up 3.5 years.
Phase I: safety.
Phase II: PFS.
Phase I: pharmacokinetics.
Phase II: anti-tumour
activity, overall survival,
patient reported outcome of
pain, tumour tissue
biomarkers, selected gene
polymorphism, overall
safety profile.
Interim results.
Phase II, part 1
For palbociclib (n=34) vs
placebo (n=32),
respectively:
objective response rate,
52% (95% CI 32, 71) vs
32% (95% CI 15, 55);
stable disease ≥24 weeks,
35% vs 25%;
PFS, 18.2 months vs 5.7
d
months [HR 0.35 (95% CI
0.17, 0.72), p=0.006], no
complete responses
reported.
Phase II, part 2
For palbociclib (n=84) vs
placebo (n=81),
respectively:
PFS, 26.2 vs 7.5 months
[HR 0.32 (95% CI 0.19,
0.56), p<0.001]; response
rate, 31% vs 26%; clinical
benefit rate, 68% vs 44%.
c
d
Functional assessment of cancer therapy – breast cancer.
Hazard ratio.
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Adverse
effects
(AEs)
-
-
Expected
reporting
date
Not reported.
Primary completion date
March 2015.
Trial
NCT02040857, 13-559; palbociclib in
combination with adjuvant endocrine
therapy; phase II.
Dana-Farber Cancer Institute and Pfizer.
Ongoing.
21
Trial registry .
NCT01684215, A5481010; palbociclib in
combination with letrozole; phase I/II.
USA.
Uncontrolled, single arm.
n=120 (planned); 18 years and older;
female; stage II (except T2NO) or stage III
invasive breast cancer HR+, HER2-; postmenopausal; ECOG status 0-1; patients
may have received neoadjuvant
chemotherapy or adjuvant radiotherapy,
but must be at least 30 days after last
dose, with no more than grade 1 residual
toxicity at time of screening; if most recent
therapy was surgery, must be at least 30
days from definitive surgery with no active
wound healing complications.
Patients receive palbociclib 125mg orally
once daily for 21 days with 7 days off
treatment in ongoing 28-day cycles, in
combination with letrozole, 2.5mg,
anastrozole 1mg or exemestane 25mg, all
once daily.
Japan.
Uncontrolled, single arm.
n=58 (planned); 20 years and older;
female; post-menopausal; proven
diagnosis of ER+, HER2- adenocarcinoma
of the breast; evidence of locoregionally
recurrent or metastatic disease (including
bone only disease) not amenable to
resection or radiation therapy with curative
intent; chemotherapy not clinically
indicated; ECOG 0-1 (phase II ECOG 02).
Follow-up
Active treatment and follow-up 2 years.
Primary
outcome/s
Secondary
outcome/s
Treatment discontinuation rate.
Expected
reporting
date
Primary completion date October 2017.
Active treatment until disease progression.
Follow-up 2.5 years.
Number of participants with dose-limiting
toxicities; PFS.
Pharmacokinetics; objective response;
disease control; duration of response;
overall survival; quality of life (FACT-B);
tumour tissue biomarkers.
Primary completion date December 2016.
Sponsor
Status
Source of
information
Location
Design
Participants
Schedule
No quality of life measurement included in
trial outcomes.
Treatment discontinued
due to AEs in 9% vs 3% for
palbociclib vs placebo,
respectively. Neutropenia,
leukopenia, anaemia and
fatigue were the most
commonly reported AEs in
the combination treatment
arm.
-
Pfizer.
Ongoing.
22
Trial registry .
Patients receive palbociclib, 125mg orally
once daily for 3 weeks with 1 week off
treatment (dose reduction dependent on
treatment related toxicity) in ongoing 28day cycles; in combination with letrozole
2.5mg orally once daily, continuously
(dose interruptions at investigator’s
judgement).
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ESTIMATED COST and IMPACT
COST
The cost of palbociclib is not yet known.
IMPACT - SPECULATIVE
Impact on Patients and Carers
 Reduced mortality/increased length of survival
 Reduced symptoms or disability
 Other:
 No impact identified
Impact on Health and Social Care Services
 Increased use of existing services
 Decreased use of existing services
 Re-organisation of existing services
 Need for new services
 Other:
 None identified
Impact on Costs and Other Resource Use
 Increased drug treatment costs
 Reduced drug treatment costs
 Other increase in costs:
 Other reduction in costs:
 Other: uncertain unit cost compared to
existing treatments
 None identified
Other Issues
 Clinical uncertainty or other research question
identified:
 None identified
REFERENCES
1
2
3
4
5
6
7
8
9
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Advanced Breast Cancer Community. Defining Advanced Breast Cancer. 2013.
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NHS choices. Breast Cancer (female) – Causes. July 2012. http://www.nhs.uk/Conditions/Cancerof-the-breast-female/Pages/Causes.aspx Accessed 9 April 2014.
Cancer Statistics Key Facts. Breast Cancer. January 2014.
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10 Health and Social Care Information Centre. Hospital episode statistics for England. Admitted
patient care, 2012-2013. www.hscic.gov.uk
11 Scottish Intercollegiate Guidelines Network. Treatment of primary breast cancer (SIGN 134).
Edinburgh: SIGN, September 2013.
12 Cardoso F, Harbeck N, Fallowfield L et al. Locally recurrent or metastatic breast cancer: ESMO
clinical practice guidelines for diagnosis, treatment and follow-up. Annals of Oncology 2012;23:
vii11–vii19.
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13 Accessed 9 April 2014.
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treatment of postmenopausal women with ER+/HER2- advanced breast cancer (PALOMA-2).
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7 Accessed 10 April 2014.
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http://www.clinicaltrials.gov/ct2/show/NCT01684215?cond=breast+cancer&intr=palbociclib&rank=
4 Accessed 11 April 2014.
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