Etirinotecan Pegol for Metastatic Breast Cancer - Second Or Subsequent Line

Horizon Scanning Centre March 2014

Etirinotecan pegol for metastatic breast cancer - second or subsequent line

SUMMARY NIHR HSC ID: 5971

Etirinotecan pegol is intended to be used as a second or subsequent line therapy for the treatment of metastatic breast cancer. If licenced, it would offer an additional treatment option for patients with this disease who have previously been treated with, or are intolerant to first line adjuvant or neoadjuvant chemotherapy, and who currently have few well tolerated, effective treatment options remaining. Etirinotecan pegol is the PEGylated form of This briefing is irinotecan, that is designed to provide continuous exposure to SN38 (the based on active moiety of irinotecan), while reducing the toxicities associated with information excessively high irinotecan and SN38 plasma concentrations that occur with available at the time direct administration. Etirinotecan pegol is not currently licenced in the EU for of research and a any indication. Etirinotecan pegol’s first generation predecessor irinotecan is limited literature licenced (as combination therapy) for the treatment of advanced and search. It is not metastatic colorectal cancer. intended to be a definitive statement Breast cancer accounts for 30% of all cancers in UK women. In 2011, there on the safety, were 41,826 new cases of breast cancer in England. Breast cancer efficacy or incidence is strongly related to age. An estimated 5% of patients present with effectiveness of the metastatic breast cancer, and approximately 30% of people who present with health technology localised breast cancer will later develop metastatic breast cancer. It is covered and should estimated that in the UK, around 36,000 women are living with metastatic not be used for breast cancer, with 12,000 being in the last year of life. In 2012, there were commercial 10,373 deaths due to breast cancer in England. purposes or commissioning For patients with metastatic breast cancer, the aims of treatment are to without additional improve quality of life and to prolong survival, without necessarily offering a information. realistic hope of cure. Current treatment options include: endocrine therapy, chemotherapy, bone-directed agents, targeted biological agents for HER2- positive disease, palliative radiotherapy, and surgery or radical radiotherapy for limited metastatic presentations. Etirinotecan pegol is currently in one phase III clinical trial comparing its effect on overall survival against treatment with physician’s choice of therapy (eribulin, ixabepilone, vinorelbine, gemcitabine, paclitaxel, docetaxel or nab-paclitaxel). This trial is expected to complete in December 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: [email protected] Web: http://www.hsc.nihr.ac.uk NIHR Horizon Scanning Centre

TARGET GROUP

• Breast cancer: locally advanced or metastatic – second and subsequent line.

TECHNOLOGY

DESCRIPTION

Etirinotecan pegol (NKTR-102) is the PEGylated form of irinotecan, a topoisomerase-I inhibitor derived from camptothecin. It consists of the topoisomerase-I inhibitor irinotecan bound to a proprietary polyethylene glycol core by a biodegradable linker. The linker slowly hydrolyses in vivo to release SN38, the active moiety of irinotecan. The drug is designed to provide continuous exposure to SN38 while reducing the toxicities associated with excessively high irinotecan and SN38 plasma concentrations reported in patients who receive irinotecan directly. In the phase III trial, 145mg/m2 of etirinotecan pegol was delivered as a 90 minute intravenous (IV) infusion on day 1 of each 21 day treatment cycle until disease progression or unacceptable toxicity1.

Etirinotecan pegol does not currently have Marketing Authorisation in the EU for any indication. However its first generation predecessor, irinotecan, is licenced for the treatment of: • Advanced colorectal cancer (combination with 5-fluorouracil and folinic acid in patients without prior chemotherapy for advanced disease, or as a single agent in patients who have failed an established 5-fluorouracil containing treatment regimen). • Epidermal growth factor receptor (EGFR)-expressing metastatic colorectal cancer after failure of irinotecan-including cytotoxic therapy (in combination with cetuximab). • Metastatic carcinoma of the colon or rectum (in combination with 5-fluorouracil, folinic acid and bevacizumab).

Very common (>10%) adverse effects of irinotecan when used for its licenced indications include: severe diarrhoea, neutropenia, anaemia, thrombocytopenia and reversible alopecia2. Etirinotecan pegol is currently in phase II clinical trials for colorectal, ovarian, non- small cell lung, small cell lung cancers and high grade glioma.

INNOVATION and/or ADVANTAGES

If licensed, etirinotecan pegol will offer an additional treatment option for patients with locally recurrent or metastatic breast cancer who have previously been treated with, or are intolerant to first line adjuvant or neo-adjuvant chemotherapy, a patient group who currently have few well-tolerated effective therapies available.

DEVELOPER

Nektar Therapeutics.

AVAILABILITY, LAUNCH OR MARKETING

Etirinotecan pegol is currently in phase III clinical trials.

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PATIENT GROUP

BACKGROUND

Breast cancer arises from the tissues of the breast duct or the lobules of the breast; metastatic disease represents spread to distant sites of the body. The most common sites for metastases include the lymph nodes, bone, liver, lungs and brain3,4. Once breast cancer becomes metastatic it is rarely, if ever, curable5.

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 cancer in UK, accounting for 30% of all cancers in women6. In England, in 2011, there were 41,826 new cases of breast cancer in both men and women and 41,523 cases in women alone (representing 124.8 cases per 100,000 population)7. In 2012, there were 10,373 deaths from breast cancer registered in England and Wales (ICD C50), as well as 177,514 admissions for malignant neoplasm of the breast (ICD C50) in England, which resulted in 109,365 bed days and 180,595 finished consultant episodes 8,9.

Breast cancer risk is strongly related to age, with 81% of cases occurring in women aged over 50 years, and while the incidence of breast cancer is highest in those from higher socioeconomic groups10,11, survival is lowest in those from lower socioeconomic groups. This pattern persists even after allowing for the higher overall premature all-cause mortality observed in lower socioeconomic groups compared to the higher socioeconomic groups12. An estimated 5% of patients present with metastatic breast cancer, and approximately 30% of people who present with localised breast cancer will later develop metastatic breast cancer13. Women with metastatic disease have an average survival of about 2 years5. Cases of secondary breast cancer, which occur after an initial diagnosis of primary breast cancer, are not recorded nationally, but it is estimated that in the UK, around 36,000 women are living with progressive disease, with 12,000 being in the last year of life14,15.

PATIENT PATHWAY

RELEVANT GUIDANCE

NICE Guidance

• NICE technology appraisal in development. Breast cancer (early) - intrabeam radiosurgery system [ID618]. Expected November 201416. • NICE technology appraisal in development. Breast cancer (HER2 positive, unresectable) - trastuzumab emtansine (after trastuzumab & taxane) [ID603]. Expected August 201417.

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• NICE technology appraisal. Bevacizumab in combination with capecitabine for the first line treatment of metastatic breast cancer (TA263). August 201218. • 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 201219. • NICE technology appraisal. Eribulin for the treatment of locally advanced or metastatic breast cancer (TA250). April 201220. • NICE technology appraisal. Fulvestrant for the treatment of locally advanced or metastatic breast cancer (TA239). London. December 201121. • NICE technology appraisal. Bevacizumab in combination with a taxane for the first line treatment of metastatic breast cancer (TA214). London. February 201122. • NICE clinical guideline. Advanced breast cancer – diagnosis and treatment (CG81). February 200923. • 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 201324. • NICE quality standard. Breast cancer quality standard (QS12). September 201125.

Other Guidance

• European Society for Medical Oncology. Locally recurrent or metastatic breast cancer. Clinical practice guidelines for diagnosis, treatment and follow-up. 201026. • SIGN. Management of breast cancer in women. 200527. • Cancer Services Collaborative Improvement Partnership. Breast cancer service improvement guide. 200328.

CURRENT TREATMENT OPTIONS

For patients with metastatic breast cancer, the aims of treatment are to improve quality of life and to prolong survival, without necessarily offering a realistic hope of cure29. The central aspects of treatment are therefore to use anti-cancer treatments to control disease-related symptoms and slow disease progression, minimise treatment-related toxicity, and reduce the intrusion of the disease and treatment on a patient’s life29. Whenever possible, isolated loco- regional recurrence should be treated with a curative intent; if feasible, complete excision of recurrent tumour is recommended26. At the time of recurrence, most women will have received a taxane and an anthracycline as adjuvant treatment, therefore very few pharmaceutical anti-cancer treatment options remain available for metastatic breast cancer30.

Systemic treatment options for metastatic breast cancer include: • Endocrine therapy: this is the treatment of ﬁrst choice in ER-positive and HER2-negative disease regardless of metastatic site, unless rapid response is needed26,30. • First line chemotherapy: this generally includes repeated anthracycline and/or taxanes, possibly combined with cyclophosphamide. In patients without directly life-threatening or severely symptomatic disease, single-agent chemotherapy is the preferred option26,30. • Second line chemotherapy: this may include 5-fluorouracil, gemcitabine, or vinorelbine. • Bone-directed agents: such as bisphosphonates, denosumab26,30. • Targeted biological agents for HER2-positive disease: such as trastuzumab and lapatinib26,30. • Palliative radiotherapy: the most common indications for palliative radiotherapy include; bone metastases which are painful or carry a risk of fracture and/or neurological complications, and brain metastases26.

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• For limited metastatic presentations: surgery or radical radiotherapy may be considered26.

EFFICACY and SAFETY

Trial BEACON study, NCT01492101; NCT00802945; etirinotecan pegol; phase II. etirinotecan pegol vs treatment of physician's choice (TPC); phase III. Sponsor Nektar Therapeutics. Nektar Therapeutics. Status Ongoing. Published. Source of Poster31, trial registry1, manufacturer. Publication32, trial registry33, manufacturer. information Location EU (incl UK), USA, Canada, Russia, EU (incl UK), USA. and Republic of Korea. Design Randomised, active-controlled. Randomised. Participants n=852; aged 18 years and over; n=70; aged 18 years and over: inoperable females; metastatic breast cancer; metastatic or locally advanced breast cancer; participants must have received prior participants must have received no more than therapy (administered in the 2 prior chemotherapy regimens given in a neoadjuvant, adjuvant and/or metastatic metastatic or locally advanced setting and setting) with an anthracycline, a taxane prior treatment in the metastatic setting must and capecitabine. have included a taxane. Schedule Randomised to etirinotecan pegol Randomised to etirinotecan pegol 145mg/m2 145mg/m2 as a 90 minute IV infusion on as a 90 min IV infusion on day 1 of a 14 day day 1 of a 21 day cycle; or one of the cycle; or 145mg/m2 etirinotecan pegol, 90 min following: eribulin 1.23mg/m2 (in EU IV infusion on day 1 of a 21 day cycle. locations 1.4mg/m2 all other locations) on days 1 and 8 of a 21 day cycle, ixabepilone 40mg/m2 every 21 days, vinorelbine, gemcitabine, paclitaxel, docetaxel, or nab-paclitaxel (administered as per standard of care). Follow-up Active treatment until disease Active treatment until disease progression, or progression, or unacceptable toxicity. unacceptable toxicity. Primary Overall survival (OS). ORR. outcome/s Secondary Health-related quality of lifea, PFS, OS, 6 month survival, 1 year survival, outcome/s progression free survival (PFS), and safety. No quality of life measurement objective response rate (ORR). included in trial outcomes. Key results - For the 14 day vs 21 day schedule respectively: ORR, 29% (95% CI 14.6-46.3) vs 29% (95% CI 14.6-46.3); PFS, 3.3 months (95% CI 2.7- 5.7) vs 5.6 months (95% CI 1.8-6.2); 6 month survival, 57.1% (95% CI 39.3–71.5) vs 82.9% (95% CI 65.8–91.9); 1 year survival, 42.9% (95% CI 26.4–58.3) vs 51·4% (95% CI 34.0– 66.4). Adverse - 1 death due to acute renal failure and 1 death effects (AEs) due to septic shock, both in the 14 day arm, and both deemed as possibly related to etirinotecan pegol. AEs reported in ≥10 % of patients included diarrhoea (20%), fatigue (11%), severe neutropenia (11%) and a HRQoL measured by the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire - Core 30 (EORTC QLQ-C30) and the BR23 subscale.

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alopecia (16%). Expected Primary completion date reported as - reporting December 2014. date

ESTIMATED COST and IMPACT

COST

The cost of etirinotecan pegol is not yet known.

IMPACT - SPECULATIVE

Impact on Patients and Carers

 Reduced mortality/increased length of survival  Reduced symptoms or disability: if clinical trial results show an improved AE profile compared to existing alternatives.

 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  None identified current alternative therapies.

Other Issues

 Clinical uncertainty or other research question  None identified identified:

REFERENCES

1 ClinicalTrials.gov. The BEACON study; breast cancer outcomes with NKTR-102. http://www.clinicaltrials.gov/ct2/show/NCT01492101?term=BEACON&rank=2 Accessed 21 January 2014. 2 Electronic medicines compendium. SPC irinotecan medac 20mg/ml, concentrate for solution for infusion. http://www.medicines.org.uk/emc/medicine/22806/SPC/Irinotecan+medac+20+mg+ml%2c+conce ntrate+for+solution+for+infusion/#CLINICAL_PARTS Accessed 21 January 2014. 3 NHS Choices. Breast cancer (female). http://www.nhs.uk/conditions/cancer-of-the-breast- female/pages/introduction.aspx Accessed 28 January 2014. 4 Weigelt B, Johannes LP, and Van't Veer LJ. Breast cancer metastasis: markers and models. Nature reviews cancer 2005;5(8):591-602. 5 Stockler MR, Wilcken N, Coates A, et al. Duration of chemotherapy for metastatic breast cancer. Cochrane Database of Systematic Reviews 2004;3.Art. No.:CD004922.

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6 Cancer Research UK. Cancer incidence Statistics in the UK in 2011. http://publications.cancerresearchuk.org/downloads/Product/CS_REPORT_INCIDENCE.pdf 7 Cancer Research UK. Data Table: Cancer cases and rates by country in the UK 2011 http://publications.cancerresearchuk.org/cancerstats/statsincidence/dtinccountries.html 8 UK National Statistics. Mortality Statistics: Deaths registered in England and Wales (Series DR) - 2012. October 2013. 9 Health & Social Care Information Centre. Hospital episode statistics for England. Inpatient statistics, 2012-13. www.hscic.gov.uk/hes 10 Cancer Research UK. Cancer stats – Breast cancer UK May 2009. http://publications.cancerresearchuk.org/downloads/product/CSBREA09breast.pdf 11 Shack L, Jordan C, Thomson CS et al. Variation in incidence of breast, lung and cervical cancer and malignant melanoma of skin by socioeconomic group in England. BMC cancer 2008;8(1):271. 12 National Institute for Health and Clinical Excellence. Breast cancer: diagnosis and treatment: an assessment of need. A report to the National Collaborating Centre for Cancer. Clinical Guidelines, No. 80-81S. Cardiff. February 2009. 13 National Institute for Health and Clinical Excellence. Lapatinib or trastuzumab in combination with an aromatase inhibitor for the first-line treatment of metastatic hormone-receptor-positive breast cancer that overexpresses HER2. Technology appraisal TA257. London June 2012. 14 Breast Cancer Care: Secondary breast cancer taskforce. Stand up and be counted: The need for the collection of data on incidence of secondary breast cancer and survival. October 2007. http://www.breastcancercare.org.uk/upload/pdf/statistics_briefing_final_0.pdf Accessed 20 January 2014. 15 Reed E, Corner J, and Simmonds P. Defining the illness trajectory of metastatic breast cancer. British Medical Journal; Supportive & Palliative Care 2013;0:1-8. 16 National Institute for Health and Care Excellence. Breast cancer (early) - intrabeam radiosurgery system [ID618]. Technology appraisal in development. Expected November 2014. 17 National Institute for Health and Care Excellence. Breast cancer (HER2 positive, unresectable) - trastuzumab emtansine (after trastuzumab & taxane) [ID603]. Technology appraisal in development. Expected August 2014. 18 National Institute for Health and Clinical Excellence. Bevacizumab in combination with capecitabine for the first-line treatment of metastatic breast cancer. Technology appraisal TA263. London. August 2012. 19 National Institute for Health and Clinical Excellence. 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. Technology appraisal TA257. London. June 2012. 20 National Institute for Health and Clinical Excellence. Eribulin for the treatment of locally advanced or metastatic breast cancer. Technology appraisal TA250. NICE . London April 2012. 21 National Institute for Health and Clinical Excellence. Fulvestrant for the treatment of locally advanced or metastatic breast cancer. Technology appraisal TA239. London: NICE; December 2011. 22 National Institute for Health and Clinical Excellence. Bevacizumab in combination with a taxane for the first-line treatment of metastatic breast cancer. Technology appraisal TA214. London: NICE; February 2011. 23 National Institute for Health and Clinical Excellence. Advanced breast cancer – diagnosis and treatment. Clinical guideline CG81. London: London; February 2009. 24 National Institute for Health and Clinical Excellence. 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. Clinical Guideline CG164. London. June 2013. 25 National Institute for Health and Clinical Excellence. Breast cancer. Quality standard QS12. London. September 2011. 26 European Society for Medical Oncology. Locally recurrent or metastatic breast cancer: ESMO clinical practice guidelines for diagnosis, treatment and follow-up. Annals of Oncology 2010;21(5):v15-v19. 27 Scottish Intercollegiate Guidelines Network. Management of breast cancer in women. Clinical guideline 84. Edinburgh: SIGN; December 2005. 28 Cancer Services Collaborative Improvement Partnership. Breast cancer service improvement guide. October 2003.

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29 Wilcken N, and Dear R. Chemotherapy in metastatic breast cancer: a summary of all randomised trials reported 2000–2007. European Journal of Cancer 2008;44(15):2218-2225. 30 Kümler I, Brünner N, Stenvang J et al. A systematic review on topoisomerase 1 inhibition in the treatment of metastatic breast cancer. Breast cancer research and treatment 2013;1-12. 31 Awada A, Zhao C, Hannah AL, et al. The BEACON Study (breast cancer outcomes with NKTR- 102): A phase 3 open-label, randomized, multicenter study of NKTR-102 versus Treatment of Physician’s Choice (TPC) in patients with locally recurrent or metastatic breast cancer previously treated with an anthracycline, a taxane, and capecitabine. San Antonio breast cancer conference. December 2011. 32 Awada A, Garcia AA, Chan S et al. Two schedules of etirinotecan pegol (NKTR-102) in patients with previously treated metastatic breast cancer: a randomised phase 2 study. The Lancet Oncology 2013;14(12):1216-1225. 33 ClinicalTrials.gov. Study to evaluate the safety and efficacy of NKTR-102 in patients with metastatic or locally advanced breast cancer. http://www.clinicaltrials.gov/ct2/show/NCT00802945?term=nktr-102&rank=3 Accessed 22 January 2014.