Nintedanib (Vargatef) - National Horizon Scanning Centre - NIHR

Nintedanib (Vargatef) for
epithelial ovarian, fallopian tube or
primary peritoneal carcinoma – first
or second line
April 2012
This technology summary 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.
The NIHR Horizon Scanning Centre Research Programme is part of the
National Institute for Health Research

April 2012
Nintedanib (Vargatef) for epithelial ovarian, fallopian tube or
primary peritoneal carcinoma – first or second line
Target group
• Epithelial ovarian, fallopian tube or primary peritoneal carcinoma: advanced (stage
IIB-IV) – first or second line; in combination with carboplatin and paclitaxel
following initial surgery, where indicated.
Background
Primary ovarian, fallopian and peritoneal cancers arise from the epithelial tissues of the
abdomen, fallopian tubes and ovaries. Almost 90% of adult ovarian tumours are epithelial
cancers. Regardless of its origin, ovarian cancer leads to similar symptoms and is treated
in a similar way 1
. At the time of diagnosis, ovarian cancer has typically spread within the
pelvis and abdomen (stage II-III cancer) or spread into the liver/beyond the abdominal
cavity (stage IV cancer).
Technology description
Nintedanib (Vargatef; BIBF1120) is a potent, small molecule triple angiokinase inhibitor
which suppresses tumour growth by preventing tumour angiogenesis. It inhibits three
kinases involved in the development of tumour blood vasculature: platelet derived growth
factor receptor alpha and beta (PDFR a/b), fibroblast growth factor receptor 1, 2 and 3
(FGFR 1-3) and vascular endothelial derived growth factor receptor 1, 2 and 3 (VEGFR
1-3). Inhibition of these receptors is thought to play a vital role in the prevention of
tumour growth and spread. Nintedanib is administered orally at 200mg twice daily, in
combination with carboplatin and paclitaxel.
Nintedanib is in phase III clinical trials for idiopathic pulmonary fibrosis and non-small
cell lung cancer, and in phase II trials for colorectal cancer, liver cancer, prostate cancer
and renal cancer.
Innovation and/or advantages
If licensed, nintedanib in combination with carboplatin and paclitaxel may provide an
additional treatment option for this patient group.
Developer
Boehringer-Ingelheim Pharmaceuticals.
Availability, launch or marketing dates, and licensing plans
In phase III clinical trials.
NHS or Government priority area
This topic is relevant to Improving Outcomes: A Strategy for Cancer (2011).
Relevant guidance
• NICE technology appraisal in development. Bevacizumab in combination with
paclitaxel and carboplatin for the first-line chemotherapy treatment of ovarian cancer.
Expected April 2013 2
.
• NICE technology appraisal. Trabectedin for the treatment of relapsed ovarian cancer.
3
2011 .
2

April 2012
• NICE technology appraisal. Paclitaxel, pegylated liposomal doxorubicin hydrochloride
and topotecan for second-line or subsequent treatment of advanced ovarian cancer.
2005 4
.
• NICE technology appraisal. Guidance on the use of paclitaxel in the treatment of
5
ovarian cancer. 2003 .
• NICE clinical guideline. The recognition and initial management of ovarian cancer.
6
2011 .
• European Society for Medical Oncology. Newly diagnosed and relapsed epithelial
ovarian carcinoma: ESMO clinical practice guidelines for diagnosis, treatment and
follow-up. 2010 7
.
8
• SIGN. Epithelial ovarian cancer. 2003 .
Clinical need and burden of disease
Ovarian cancer is the fourth most common cancer in women in the UK 9 , with an agestandardised
5-year survival rate of 38.2% 10 . Most women present with advanced
disease 11 and although many patients respond to initial treatment, up to 70% of patients
with advanced-stage ovarian cancer subsequently relapse 12 . The median time to
progression after primary treatment (surgery plus chemotherapy) is 16-20 months, and the
median overall survival is 31-51 months 13
.
Over 80% of cases are diagnosed in women over 50 years of age, with the highest
incidence in women aged 65 and over 14 . In 2008, there were 6,156 new cases registered
for ovarian cancer in England and Wales 14 , and 4,212 deaths occurred in 2010 15 . In
England, there were 37,898 admissions for ovarian, fallopian tube and peritoneal cancer
(ICD C56, C57 and C48 respectively) resulting in 86,674 bed days and 40,611 finished
consultant episodes in 2010-11 16
.
Existing comparators and treatments
Most women will undergo debulking surgery followed by six cycles of adjuvant
chemotherapy 11 . First line chemotherapy is invariably platinum-based therapy alone, or
in combination with paclitaxel (where the platinum agent is usually carboplatin but
occasionally cisplatin). Bevacizumab in combination with carboplatin and paclitaxel is
currently being appraised by NICE. Second line chemotherapy is non-curative and aims
to reduce symptoms and prolong survival. Ovarian tumours eventually develop multidrug
resistance. Current chemotherapy options for second and subsequent line disease
include pegylated liposomal doxorubicin (Caelyx), trabectedin, topotecan, gemcitabine,
paclitaxel 4,5,17,18
.
Efficacy and safety
Trial NCT00710762, 1199.99; adults;
nintedanib vs placebo; phase II.
AGO-OVAR12/LUME-OVAR 1,
NCT01015118, 1199.15, 2008-006831-
10; adults; nintedanib with chemotherapy
vs placebo with chemotherapy; phase III.
Sponsor Boehringer-Ingelheim Pharmaceuticals. Boehringer-Ingelheim Pharmaceuticals.
Status Published. Ongoing.
Source of
information
Publication 19 , trial registry 20
.
21
Trial registry .
Location UK. EU (inc UK), USA, Canada, Australia,
Ukraine and Russia.
Design Randomised, controlled. Randomised, controlled.
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April 2012
Participants
and schedule
n=84 (planned); ovarian, fallopian tube
or primary peritoneal cancer; advanced;
responded to second, third or fourth line
chemotherapy.
Randomised to: nintedanib, oral, 250mg
twice daily continuously for nine 28 day
cycles (36 weeks) or placebo, twice daily
for nine 28 day cycles (36 weeks).
Nintedanib dose reduced to 150mg, twice
daily and subsequently to 100mg, twice
daily in the event of unacceptable drug
related toxicity. Patients alive and
progression free after nine cycles allowed
to continue unblinded treatment.
n=1,300 (planned); epithelial ovarian,
fallopian tube or primary peritoneal
cancer; stages IIB-IV; prior surgery or
biopsy.
Randomised to: nintedanib, oral, 200mg
twice daily with carboplatin, AUC 5-6
and paclitaxel, IV, 175mg/m 2 , every 21
days for six cycles, followed by
nintedanib monotherapy for up to 120
weeks, or placebo with carboplatin AUC
5-6 and paclitaxel, IV, 175mg/m 2 , every
21 days for six cycles followed by
placebo monotherapy for up to 120
weeks.
Active treatment period up to 120 weeks;
5 years follow-up.
Follow-up Active treatment period 36 weeks, plus
continuing treatment where appropriate.
Primary
outcome
Progression free survival (PFS). PFS.
Secondary Tumour progression; overall survival; Overall survival; time to tumour marker
outcome treatment compliance; safety.
progression; objective response; safety;
health-related quality of life.
Key results For nintedanib and placebo respectively
(%): PFS at 36 weeks, 16.3 (95% CI 5.2
– 27.3), 5.0 (95% CI 0.0 – 11.8); PFS
hazard ratio (HR) 0.65 (95% CI 0.42-
1.02); overall survival HR, 0.84 (95% CI
0.51 – 1.39); median time on treatment
(mths), 2.8, 2.8.
-
Adverse Grade 3 or 4 AEs for nintedanib and -
effects (AEs) placebo respectively (%): abdominal pain
9.3, 7.5; diarrhoea, 9.3, 2.5; nausea, 2.3,
0; vomiting 4.6, 2.5; fatigue 4.6, 0;
anorexia 2.3, 0; constipation 7.0, 10.0;
hypertension, 4.6, 0; ascites, 7.0, 10.0;
any grade 3 or 4 AE, 34.9, 27.5 (p=0.49).
Expected
reporting
date
- July 2016.
Estimated cost and cost impact
The cost of nintedanib is not yet known. The costs of other selected treatments for
epithelial ovarian cancer are 22
:
Drug Dose 23
a
Cost per cycle
Paclitaxel 80mg/m 2 IV, on days 1, 8 and 15 of a 28 day
cycle.
£902
Liposomal
doxorubicin (Caelyx)
40mg/m 2 IV, every 28 days. £1,073
Topotecan
4mg/m
(Hycamtin)
2 IV, on days 1, 8 and 15 of a 28 day £1,744
cycle.
a Based on average surface area of 1.7m 2 . Assumes wastage.
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April 2012
Claimed or potential impact – speculative
Patients
� Reduced mortality or increased
length of survival
� Reduction in associated morbidity
or improved quality of life for
patients and/or carers
Other: None identified
Services
Increased use
Costs
Quicker, earlier or more accurate
diagnosis or identification of
disease
Service organisation Staff requirements
Decreased use Other: � None identified
Increased unit cost compared to
alternative
� New costs: uncertain unit cost
compared to alternatives
Increased costs: more patients Increased costs: capital
coming for treatment
investment needed
Savings: Other:
Other issues
Clinical uncertainty or other research question identified: � None identified
References
1 Cancer Research UK. http://www.cancerhelp.org.uk/type/ovarian-cancer/ Accessed 6 December 2011.
2 National Institute for Health and Clinical Excellence. Bevacizumab in combination with paclitaxel and
carboplatin for the first-line chemotherapy treatment of ovarian cancer. Technology appraisal in development.
Expected date of issue April 2013.
3 National Institute for Health and Clinical Excellence. Trabectedin for the treatment of relapsed ovarian cancer.
Technology appraisal TA222. London: NICE; April 2011.
4 National Institute for Health and Clinical Excellence. Paclitaxel, pegylated liposomal doxorubicin
hydrochloride and topotecan for second-line or subsequent treatment of advanced ovarian cancer. Technology
appraisal TA91. London: NICE; May 2005.
5 National Institute for Health and Clinical Excellence. Guidance on the use of paclitaxel in the treatment of
ovarian cancer. Technology appraisal TA55. London: NICE; January 2003.
6 National Institute for Health and Clinical Excellence. The recognition and initial management of ovarian
cancer. Clinical guideline CG122. London: NICE; April 2011.
7 Colombo N, Peiretti M, Parma G et al. Newly diagnosed and relapsed epithelial ovarian carcinoma: ESMO
clinical practice guidelines for diagnosis, treatment and follow-up. Annals of Oncology 2010;21(suppl 5):v23v30.
8 Scottish Intercollegiate National Guidelines. Epithelial ovarian cancer. Clinical guideline 75. October 2003.
9 Cancer Research UK. Ovarian cancer statistics – key facts.
http://info.cancerresearchuk.org/cancerstats/types/ovary/uk-ovarian-cancer-statistics Accessed 3 November
2011.
10 Rachet B, Maringe C, Nur U et al. Population-based cancer survival trends in England and Wales up to 2007:
an assessment of the NHS cancer plan for England. Lancet Oncology 2009;10(4):351-369.
11 Morgan Jr RJ, Alvarez RD, Armstrong DK et al. Ovarian cancer. Clinical practice guidelines in oncology. The
Journal of the National Comprehensive Cancer Network 2008;6:766-94.
12 Herzog TJ and Pothuri B. Ovarian cancer: a focus on management of recurrent disease. Nature Clinical Practice
Oncology 2006;3:604-11.
13 Friedlander M, Hannock KC, Rischin D et al. A phase II, open-label study evaluating pazopanib in patients
with recurrent ovarian cancer. Gynaecologic Oncology 2010;119:32-37.
14 Cancer Research UK. Ovarian cancer – UK incidence statistics.
http://info.cancerresearchuk.org/cancerstats/types/ovary/incidence/ Accessed 21 March 2012.
15 Office for National Statistics. Mortality statistics: deaths registered in 2010 (Series DR) Table 5.
www.ons.gov.uk
16 NHS. Hospital episode statistics. NHS England 2010-11. HES data 2011. www.hesonline.nhs.uk
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April 2012
17 CancerResearchUK. Chemotherapy for ovarian cancer. http://cancerhelp.cancerresearchuk.org/type/ovariancancer/treatment/chemotherapy-for-ovarian-cancer
Accessed 17 April 2012.
18 National Horizon Scanning Centre. Lapatinib (Tyverb) in combination with trastuzumab for HER2-positive
metastatic breast cancer. http://www.nhsc-healthhorizons.org.uk/topics/lapatinib-tyverb-in-combination-withtrastuzumab-f/
Accessed 21 March 2012.
19 Ledermann JA, Hackshaw A, Kaye S et al. Randomized phase II placebo-controlled trial of maintenance
therapy using the oral triple angiokinase inhibitor BIBF 1120 after chemotherapy for relapsed ovarian cancer.
Journal of Clinical Oncology 2011;29(28):3798-3804.
20 ClinicalTrials.gov. A randomised placebo-controlled phase II study of continuous maintenance treatment with
BIBF 1120 following chemotherapy in patients with relapsed ovarian cancer.
http://clinicaltrials.gov/ct2/show/NCT00710762?term=nct00710762&rank=1 Accessed 22 March 2012.
21 ClinicalTrials.gov. LUME-Ovar 1: nintedanib (BIBF 1120) or placebo in combination with paclitaxel and
carboplatin in first line treatment of ovarian cancer.
http://clinicaltrials.gov/ct2/show/NCT01015118?term=nct01015118&rank=1 Accessed 22 March 2012.
22 British Medical Association and Royal Pharmaceutical Soceity of Great Britain. British National formulary.
BNF 62. London: BMJ Group and RPS Publishing, September 2011.
23 National Horizon Scanning Centre. Paclitaxel (Paclical) for epithelial ovarian cancer, fallopian tube cancer or
peritoneal cancer – second or third line. http://www.nhsc-healthhorizons.org.uk/topics/paclitaxel-paclical-forepithelial-ovarian-cancer/
Accessed 21 March 2012.
The National Institute for Health Research Horizon Scanning Centre Research Programme is
funded by the Department of Health.
The views expressed in this publication are not necessarily those of the NHS, the NIHR or the
Department of Health
The NIHR Horizon Scanning Centre,
Department of Public Health and Epidemiology
University of Birmingham, 90 Vincent Drive, Edgbaston, Birmingham, B15 2SP, England
Tel: +44 (0)121 414 7831 Fax +44 (0)121 414 2269
www.haps.bham.ac.uk/publichealth/horizon
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