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Horizon Scanning Centre

January 2013

Abraxane in combination with


gemcitabine for metastatic pancreatic
cancer first line
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: 5059

Abraxane is intended to be used as first line therapy for the treatment of


metastatic pancreatic cancer and is given in combination with gemcitabine. If
licensed, it may offer an additional treatment option for this patient group who
currently have limited effective treatment options. Abraxane is an albuminbound formulation of paclitaxel designed to overcome the insolubility
problems associated with conventional paclitaxel and is currently licensed for
the second line treatment of metastatic breast cancer.
In 2010, there were 8,463 new cases of pancreatic cancer diagnosed in the
UK and 7,434 deaths registered in England and Wales in 2011. Pancreatic
cancer has one of the worst prognoses of all solid tumours, with >95% of
those affected dying of their disease. The high mortality rate is due, in part,
to the majority of patients (approximately 80%) presenting at an advanced
stage and patients with metastatic disease have a median survival of 2-6
months. The 1-year survival rate is low, at around 15-20%, and less than 3%
survive to 5 years. Pancreatic cancer affects both sexes equally, with a
lifetime risk of 1 in 77 for men and 1 in 79 for women. It is rare before the age
of 45 years; 80% of cases occur between 60-80 years of age.
As the majority of pancreatic cancer cases are diagnosed at advanced
stages, the aim of treatment is usually palliative; to improve quality of life and
relieve symptoms. Current standard treatment includes chemotherapy
regimens such as FOLFIRINOX (5-FU, oxaliplatin and irinotecan) and
gemcitabine monotherapy. Abraxane with gemcitabine is in one phase III
clinical trial comparing its effect on overall survival against treatment with
gemcitabine alone. This trial is expected to complete in 2014.

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: nihrhsc@contacts.bham.ac.uk
Web: http://www.hsc.nihr.ac.uk

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TARGET GROUP

Pancreatic cancer: metastatic; adenocarcinoma first line; in combination with


gemcitabine.

TECHNOLOGY
DESCRIPTION
Abraxane (ABI-007) is an albumin-bound formulation of paclitaxel designed to overcome the
insolubility problems associated with conventional paclitaxel formulations. Abraxane utilises
albumin binding proteins, such as (gp60)/caveolin-1 (CAV1) and SPARC (secreted protein
acidic and rich in cysteine) to achieve high intratumoral paclitaxel accumulation. It eliminates
the need for toxic solvents like cremophor, which are associated with allergic reactions,
allowing for the delivery of higher doses and shorter infusion times compared with solventbased paclitaxel. Abraxane is intended to be used as first line treatment for metastatic
adenocarcinoma of the pancreas and is administered by intravenous (IV) infusion at
125mg/m2 on days 1, 8 and 15 of a 28 day cycle in combination with gemcitabine.
Abraxane is licensed for the second line treatment of metastatic breast cancer. Common
recognised adverse effects (10%) include: neutropenia, anaemia, leukopenia,
thrombocytopenia, lymphopenia, anorexia, neuropathy, hypoaesthesia, paraesthesia,
nausea, diarrhoea, vomiting, constipation, stomatitis, alopecia, rash, arthralgia, myalgia,
fatigue, asthenia and pyrexia 1.
Abraxane is in phase III trials for non-small cell lung cancer and melanoma. It is also in
phase II trials for bladder cancer, gastric cancer and ovarian cancer.

INNOVATION and/or ADVANTAGES


If licensed, abraxane may offer an additional treatment option for this patient group who
currently have limited effective treatment options.

DEVELOPER
Celgene.

AVAILABILITY, LAUNCH OR MARKETING


Phase III clinical trials.

PATIENT GROUP
BACKGROUND
Pancreatic cancer is the ninth most common cancer in the UK and the fifth most common
cause of death from cancer 2. It may arise in the head, body or tail of the pancreas and
symptoms, which include jaundice, nausea, diarrhoea, weight loss, loss of appetite and
severe pain, vary depending on the tumour site 3,4. There are three main types described:

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infiltrating ductal adenocarcinomas, which account for around 90% of pancreatic cancers,
acinar cell carcinoma, and pancreatoblastoma 5.

NHS or GOVERNMENT PRIORITY AREA


This topic is relevant to: Improving Outcomes: A Strategy for Cancer (2011).

CLINICAL NEED and BURDEN OF DISEASE


Pancreatic cancer has one of the worst prognoses of all solid tumours, with >95% of those
affected dying of their disease5. The high mortality rate is due, in part, to the majority of
patients (approximately 80% 6) presenting at an advanced stage 7 and the prevalence of
innate resistance to currently available treatments a. Patients with unresectable, locally
advanced disease have a median survival of 6-11 months, and patients with metastatic
disease have a median survival of 2-6 months 8. Without treatment, the median overall
survival for metastatic pancreatic cancer is approximately 12 weeks; this improves to
approximately 6 months with treatmentb. Expert opinion suggests that the use of
chemotherapy in metastatic pancreatic cancer has significantly increased over the past
decade, and estimates that over 50% of patients are now likely to receive chemotherapyb.
The 1-year survival rate is low, at around 15-20%, and less than 3% survive to 5 years7, 9.
Overall, UK pancreatic cancer survival rates are poorer than in the USA and many other
European countries7.
Pancreatic cancer affects both sexes equally, with a lifetime risk of 1 in 77 for men and 1 in
79 for women 10. It is rare before the age of 45 years; 80% of cases occur between 60-80
years of age 11. In 2010, there were 8,463 new diagnoses of pancreatic cancer in the UK10,
and 7,434 deaths regsitered in England and Wales in 2011 12. In 2011-12, there were 24,871
hospital admissions due to pancreatic cancer (ICD C25) in England, resulting in 95,819 bed
days and 31,351 finished consultant episodes 13.

PATIENT PATHWAY
RELEVANT GUIDANCE
NICE Guidance

NICE technology appraisal in development. Masitinib for the treatment of locally


advanced or metastatic pancreatic cancer (ID566). Expected January 2014 14.
NICE technology appraisal. The use of gemcitabine for the treatment of pancreatic
cancer (TA25). May 20014.
NICE interventional procedure guidance in development. IRE for the treatment of
pancreatic cancer. Expected winter 2013 15.

Other Guidance

European Society for Medical Oncology and European Society of Digestive Oncology.
Pancreatic adenocarcinoma: ESMO-ESDO clinical practice. Guidelines for diagnosis,
treatment and follow-up. 2012 16.
ESMO. Pancreatic cancer: ESMO Clinical Practice Guidelines for diagnosis, treatment
and follow-up. 20105.
Expert personal communication.

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Pancreatic Section of the British Society of Gastroenterology, Pancreatic Society of


Great Britain and Ireland, Association of Upper Gastrointestinal Surgeons of Great
Britain and Ireland, and Royal College of Pathologists, Special Interest Group for GastroIntestinal Radiology. Guidelines for the management of patients with pancreatic cancer,
periampullary and ampullary carcinomas. 200511.

EXISTING COMPARATORS and TREATMENTS


Curative surgery is currently a treatment option for only around 8% of the overall patient
population with pancreatic cancer 17, and following surgery, the majority of patients relapse
with advanced disease within 2-3 years b. As the majority of cases are diagnosed at
advanced stages, the aim of treatment is usually palliative; to improve quality of life and
relieve symptoms4. Current options include4,5,18:
Chemotherapy:
o FOLFIRINOX (5-FU, oxaliplatin and irinotecan).
o Gemcitabine monotherapy.
o Gemcitabine in combination with capecitabine (may have possible
benefit)c.
Second line therapy may be considered for a small proportion of patients, if fit
enough for subsequent treatment fluoropyrimidines (5-FU or capecitabine) or
oxaliplatin in combination with gemcitabine.
Concurrent chemo-radiotherapy for locally advanced disease only.
Palliative surgery and endoscopic placement of biliary drainage stents to control
symptoms such as jaundice and gastric outlet obstruction.
Palliative radiotherapy for control of symptoms associated with localised disease,
such as pain.

EFFICACY and SAFETY


Trial

Sponsor
Status
Source of
information
Location
Design
Participants

Schedule

Follow-up

MPACT, NCT00844649, CA046;


abraxane with gemcitabine vs
gemcitabine alone; phase III.
Celgene Corporation.
Ongoing.
19
20
Trial registry , abstract .

NCT00398086, CA040; abraxane with


gemcitabine; phase I/II.
Celgene Corporation.
Published.
21
22
Trial registry , publication .

EU, USA, Canada, Russia and Australia.


Randomised, active-controlled.
n=861; 18-79 years; pancreatic cancer;
adenocarcinoma; metastatic; no previous
radiotherapy, chemotherapy, surgery or
investigational therapy for metastatic
disease.
2

Randomised to abraxane 125mg/m IV in


combination with gemcitabine
2
1,000mg/m IV on days 1, 8, and 15 of a
4 week cycle; or gemcitabine
2
monotherapy 1,000mg/m IV once weekly
for 7 out of 8 weeks, followed by infusions
on days 1, 8 and 15 of 28 day cycles.
Active treatment until disease progression
or unacceptable toxicity.

USA.
Non-randomised, open-label.
n=67; 18 years; pancreatic cancer;
adenocarcinoma; metastatic; no prior
therapy for metastatic disease.

Abraxane 100, 125 or 150mg/m IV, all in


combination with gemcitabine
2
1,000mg/m IV on days 1, 8, and 15 of a
28 day cycle.

Active treatment until disease progression


or unacceptable toxicity.

Expert personal communication.

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Primary
outcome/s
Secondary
outcome/s

Key results

Adverse
effects (AEs)

Expected
reporting
date

Overall survival (OS).


Safety and tolerability; progression free
survival (PFS); objective tumour
response. No quality of life measurement
included in trial outcomes.
For abraxane in combination with
gemcitabine vs gemcitabine alone:
median OS, 8.5 vs 6.7 months (p<0.01);
1 year survival, 35 vs 22% (p<0.01); PFS,
5.5 vs 3.7 months (p<0.01); median time
to treatment failure, 5.1 vs 3.6 months
(p<0.01); overall response rate, 23 vs 7%
(p<0.01).
Most common grade 3 AEs reported
were (for abraxane with gemcitabine vs
gemcitabine alone): neutropenia (38 vs
27%), fatigue (17 vs 7%), and
neurotherapy (17 vs 1%). Febrile
neutropenia was reported in 3 vs 1% of
patients.

Study completion date reported as Oct


2014.

Maximum tolerated dose (MTD) and


dose-limiting toxicities (DLT).
Safety and tolerability; objective antitumour response.
2

MTD was 125mg/m . For patients treated


2
at 125mg/m : median PFS, 7.9 months
(95% CI 5.8-11.0); median OS, 12.2
months (95% CI 8.9-17.9); 1-year
survival, 48%. For all patients: median
PFS, 7.1 months (95% CI 5.7-8.0);
median OS, 10.3 months (95% CI 8.413.6); overall response rate, 46%.
The main DLTs were sepsis and
neutropenia. The most common
treatment-related AEs were anaemia
(98%), leukopenia (91%), neutropenia
(89%), thrombocytopenia (83%), fatigue
(76%), alopecia (76%), sensory
neuropathy (63%) and nausea (48%).
The most common grade 3 AEs were
neutropenia, leukopenia,
thrombocytopenia, fatigue and sensory
neuropathy.
-

ESTIMATED COST and IMPACT


COST
Abraxane is already marketed in the UK for the treatment of metastatic breast cancer; a
100mg vial costs 246 23 and treatment with 125mg/m2 on days 1, 8 and 15 of a 28 day cycle
would cost 2,214 c. The costs of selected comparator treatments for pancreatic cancer are
summarised below23:
Drug
Gemcitabine
5-fluorouracil

Dose
2
1,000mg/m once weekly infusion for 7 weeks of an 8 week
cycle, followed by 3 weekly infusions in 4 week cycles.
12mg/kg for three days, then 6mg/kg on alternate days for a
further 3 doses. Repeated every 4 weeks.

Cost for 3 months


3,240

172

IMPACT - SPECULATIVE
Impact on Patients and Carers
Reduced mortality/increased length of survival

Reduced symptoms or disability

Other:

No impact identified

c
d

Based on average surface area of 1.88m2.


Costings based on average adult bodyweight of 77.9kg and average surface area of 1.88m2. Assumes wastage.

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Impact on Services
Increased use of existing services: short
increase in drug delivery time (30 minutes) as
abraxane is administered before gemcitabine.

Decreased use of existing services

Re-organisation of existing services

Need for new services

Other: may be a small increase in hospital


admissions due to additional toxicities e.g.
febrile neutropenia as a result of
myelosuppression.

None identified

Impact on Costs
Increased drug treatment costs

Reduced drug treatment costs

Other increase in costs:

Other reduction in costs:

Other:

None identified

Other Issues
Clinical uncertainty or other research question
identified: Expert opinion suggests the
benefits of abraxane with gemcitabine should
be investigated in other patient groups e.g.
locally advanced disease, previously treated
patients (second line setting) and in the
perioperative setting. Expert opinion also
suggests additional research is required to
compare the benefits of abraxane with
gemcitabine to other standard of care options,
such as FOLFIRINOX and gemcitabine in
combination with capecitabine. In addition, the
value of abraxane monotherapy is not known.
Also, as previous data has suggested that
abraxane in combination with gemcitabine
may be more beneficial in patients with
tumours that express high levels of SPARC,
expert opinion suggests further research into
SPARC expression in pancreatic tumours
would be valuable in identifying patients most
likely to benefit from this treatment regimen
and in determining the utility of SPARC as a
predictive biomarker for pancreatic cancer.

None identified

REFERENCES
1

2
3

Electronic Medicines Compendium (eMC). Summary of product characteristics (SPC) Abraxane


5mg/ml powder for suspension for infusion.
http://www.medicines.org.uk/EMC/medicine/21384/SPC/Abraxane+5+mg+ml+powder+for+suspe
nsion+for+infusion/ Accessed 3 January 2013.
CancerResearchUK. Key facts pancreatic cancer.
http://publications.cancerresearchuk.org/downloads/Product/CS_KF_PANCR.pdf
CancerResearchUK. Types of pancreatic cancer.
http://cancerhelp.cancerresearchuk.org/type/pancreatic-cancer/about/types-of-pancreatic-cancer
Accessed 30 November 2012.
National Institute for Health and Clinical Excellence. The use of gemcitabine for the treatment of
pancreatic cancer. Technology appraisal TA25. London: NICE; May 2001.

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5
6
7
8

10

11

12
13
14

15
16
17
18

19

20

21

22

23

European Society for Medical Oncology. Pancreatic cancer: ESMO clinical practice guidelines for
diagnosis, treatment and follow-up. Annals of Oncology 2010; 21(suppl5):v55-v58.
El Kamar F, Grossbard L, Kozuch P. Metastatic pancreatic cancer: emerging strategies in
chemotherapy and palliative care. The Oncologist. 2003; 8:18-34.
Pancreatic Cancer UK. Pancreatic cancer UK study for survival 2011.
http://www.pancreaticcancer.org.uk/media/100292/report_final_for_web.pdf
Cancer Research UK. Pancreatic cancer survival statistics.
http://info.cancerresearchuk.org/cancerstats/types/pancreas/survival/ Accessed 12 December
2012.
National Cancer Intelligence Network. One-year relative survival rates for patients diagnosed with
cancer of the oesophagus, stomach, primary liver, gallbladder, biliary tract and pancreas in
England, 1985-2009.
http://www.ncin.org.uk/cancer_type_and_topic_specific_work/cancer_type_specific_work/upper_g
i_cancers/default.aspx Accessed 24 January 2013.
Cancer Research UK. Pancreatic cancer UK incidence statistics.
http://info.cancerresearchuk.org/cancerstats/types/pancreas/incidence/ Accessed 12 December
2012.
Pancreatic Section of the British Society of Gastroenterology, Pancreatic Society of Great Britain
and Ireland, Association of Upper Gastrointestinal Surgeons of Great Britain and Ireland, Royal
College of Pathologists, Special Interest Group for Gastro-Intestinal Radiology. Guidelines for the
management of patients with pancreatic cancer periampullary and ampullary carcinomas. Gut.
2005;54:1-16.
Office for National Statistics. Mortality statistics: deaths registered in England and Wales (Series
DR). 2011. www.ons.gov.uk
NHS Hospital episode statistics. NHS England 2011-12. HES data 2012. www.hesonline.nhs.uk
National Institute for Health and Clinical Excellence. Masitinib for the treatment of locally
advanced or metastatic pancreatic cancer. Technology appraisal in development (ID566).
London: NICE; expected January 2014.
National Institute for Health and Clinical Excellence. IRE for the treatment of pancreatic cancer.
Interventional procedure guidance in development. Expected winter 2013.
Cascinu S, Falconi M, Valentini V et al. Pancreatic cancer: ESMO-ESDO clinical practice
guidelines for diagnosis, treatment and follow-up. Annuals of Oncology. 2012;23(7):33-40.
National Cancer Intelligence Network (NCIN). Major surgical resections England, 2004-2006.
http://www.ncin.org.uk/view.aspx?rid=540 Accessed 24 January 2013.
Cancer Research UK. Types of treatment for pancreatic cancer.
http://www.cancerresearchuk.org/cancer-help/type/pancreatic-cancer/treatment/which-treatmentfor-pancreatic-cancer Accessed 13 December 2012.
ClinicalTrials.gov. Phase III study of ABI-007 (albumin-bound paclitaxel) plus gemcitabine versus
gemcitabine in metastatic adenocarcinoma of the pancreas.
http://www.clinicaltrials.gov/ct2/show/NCT00844649?term=nct00844649&rank=1 Accessed 13
December 2012.
Von Hoff D, Ervin T, Arena F et al. randomised phase III study of weekly nab-paclitaxel plus
gemcitabine versus gemcitabine alone in patients with metastatic adenocarcinoma of the
pancreas (MPACT). American Society of Clinical Oncology. 2013; Abstract LBA148.
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metastatic pancreatic cancer.
http://www.clinicaltrials.gov/ct2/show/NCT00398086?term=NCT00398086&rank=1 Accessed 13
December 2012.
Von Hoff D, Ramanathan R, Borad M et al. Gemcitabine plus nab-paclitaxel is an active regimen
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