Nimotuzumab for Advanced Pancreatic Cancer

Horizon Scanning Centre March 2015

Nimotuzumab for advanced pancreatic cancer – second line

SUMMARY NIHR HSC ID: 5815

Nimotuzumab is intended to be used as second line therapy for the treatment of advanced pancreatic cancer. If licensed, it will provide an additional treatment option for this patient group. Nimotuzumab is a recombinant humanised monoclonal antibody which targets the epidermal growth factor receptor (EGFR), blocking the binding of epidermal growth factor to its receptor and interfering with the cell signalling pathway. Nimotuzumab does This briefing is not currently have Marketing Authorisation in the EU for any indication. based on information Pancreatic cancer is the 10th most common cancer in the UK, accounting for available at the time around 3% of all new cases. In 2011, there were 7,276 new diagnoses in of research and a England. Pancreatic cancer is a highly aggressive cancer and has one of the limited literature worst prognoses of all solid tumours, with more than 95% of those affected search. It is not dying of their disease. The high mortality rate is due to late diagnosis, early intended to be a metastasis and poor response to treatments. The 1-year survival rate is definitive statement around 20.8%, and the 5- and 10-year survival rates are 3.3% and 1.1% on the safety, respectively. efficacy or effectiveness of the Surgery is the only curative treatment for pancreatic cancer, but this health technology approach is only suitable for patients with early stage disease. Gemcitabine- covered and should based regimens are first line standard of care for advanced disease, with a not be used for small proportion of patients being suitable for second line therapy, if fitness commercial allows. Second line options include 5-fluorouracil and oxaliplatin, or purposes or gemcitabine with or without capecitabine. Nimotuzumab has completed a commissioning phase II single arm study investigating its effect on remission rate. without additional information.

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

• Pancreatic cancer: advanced – second line.

TECHNOLOGY

DESCRIPTION

Nimotuzumab (Therolac; Anti-EGFR mAb hR3; DE-766; OSAG101) is a recombinant, humanised monoclonal antibody which targets the epidermal growth factor receptor (EGFR). Nimotuzumab blocks the binding of epidermal growth factor to its receptor, interfering with the cell signalling pathway. In clinical trials1, nimotuzumab was administered via intravenous (IV) infusion at 200mg for 6 weeks induction, then every 3 weeks thereafter.

Nimotuzumab does not currently have Marketing Authorisation in the EU for any indication.

Nimotuzumab has completed phase III clinical trials for pancreatic cancer (first line, in combination with gemcitabine). It is also in phase III trials for gastric cancer (combination therapy), glioblastoma, glioma, nasopharyngeal cancer and oesophageal cancer, and in phase II trials for brain cancer, cervical cancer, colorectal cancer, non-small cell lung cancer and prostate cancer.

INNOVATION and/or ADVANTAGES

If licensed, nimotuzumab will provide an additional treatment option for this patient group.

DEVELOPER

Oncoscience AG.

AVAILABILITY, LAUNCH OR MARKETING

In phase II clinical trials.

PATIENT GROUP

BACKGROUND

Pancreatic cancer is a highly aggressive cancer2 which may arise in the head, body or tail of the pancreas3. Pancreatic cancers are divided into 2 main groups, exocrine and endocrine tumours4. Over 95% of pancreatic cancers are classified as exocrine tumours, and around 90% of these are pancreatic ductal adenocarcinomas4, which originate in the cells lining the pancreatic ducts5. Less common subtypes include cystic tumours, acinar cell carcinomas, neuroendocrine tumours and lymphomas6. Common symptoms include pain in the back or abdomen, jaundice and weight loss, although symptoms vary and are dependent on where in the pancreas the tumour is situated7. Patients may also present with newly diagnosed diabetes or pancreatitis5. Certain genetic conditions, including hereditary pancreatitis, Peutz- Jeghers syndrome, familial malignant melanoma, hereditary breast and ovarian cancer syndrome and Lynch syndrome are associated with an increased risk, and smoking, obesity

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and dietary factors such as high consumption of processed meat also increase the risk for pancreatic cancer5.

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: Chemotherapy (Children, Teenagers and Young Adults). B12/S/b. • NHS England. 2013/14 NHS Standard Contract for Cancer: Radiotherapy (All Ages). B01/S/a.

CLINICAL NEED and BURDEN OF DISEASE

Pancreatic cancer is the 10th most common cancer in the UK, accounting for around 3% of all new cases8. In 2011, there were 7,276 new diagnoses in England, representing an age standardised incidence rate of 9.6 per 100,000 population8. 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 to late diagnosis (up to 95% are diagnosed at an advanced stage9), early metastasis and poor response to chemo- and radiotherapy5. Survival rates are poor patients with unresectable, locally advanced disease have a median survival of 6-11 months, and for metastatic disease, median survival is only 2-6 months10. The 1-year survival rate is low, at around 20.8%, and the 5- and 10-year survival rates are 3.3% and 1.1% respectively10. Pancreatic cancer usually affects people aged over 50 years, with around 75% of people diagnosed being over the age of 6511.

In 2013-14, there were 22,254 hospital admissions in England due to pancreatic cancer (ICD10: C25), accounting for 31,610 finished consultant episodes and 88,564 bed days12, and in 2013, 7,546 deaths were registered in England and Wales13. The population likely to be eligible to receive nimotuzumab could not easily be estimated from available published sources.

PATIENT PATHWAY

RELEVANT GUIDANCE

NICE Guidance

• NICE technology appraisal in development. Liposomal cisplatin in combination with gemcitabine for untreated locally advanced or metastatic pancreatic cancer (ID658). Expected date of issue to be confirmed. • NICE technology appraisal in development. Nimotuzumab for the first line treatment of metastatic pancreatic cancer (ID513). Expected date of issue to be confirmed. • NICE technology appraisal in development. Paclitaxel as albumin-bound nanoparticles in combination with gemcitabine for previously untreated metastatic pancreatic cancer (ID680). Expected date of issue to be confirmed. • NICE technology appraisal. Guidance on the use of gemcitabine for the treatment of pancreatic cancer (TA25). May 2001.

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• NICE interventional procedure guidance. Endoscopic bipolar radiofrequency ablation for treating biliary obstruction caused by cholangiocarcinoma or pancreatic adenocarcinoma (IPG464). September 2013. • NICE interventional procedure guidance. Irreversible electroporation for treating pancreatic cancer (IPG442). February 2013.

Other Guidance

• National Comprehensive Cancer Network. Clinical practice guidelines in oncology. Pancreatic adenocarcinoma. 201514. • European Society for Medical Oncology. Pancreatic adenocarcinoma: ESMO-ESDO clinical practice guidelines for diagnosis, treatment and follow-up. 20125.

CURRENT TREATMENT OPTIONS

The only curative treatment option for pancreatic cancer is radical surgery, however this approach is only suitable for patients with early stage disease5. As the majority of cases are diagnosed at an advanced stage, the aim of treatment is palliative – to improve quality of life, relieve symptoms and provide a modest improvement on survival. Gemcitabine-based regimens (with capecitabine or nab-paclitaxel) are standard of care for advanced disease, and FOLFIRINOX (5-fluorouracil [5-FU], oxaliplatin and irinotecan) may be considered for patients with a good performance status5. Second line therapy is only considered for a small proportion of patients, if fit enough for subsequent treatment. Second line options include5,14: • 5-FU and oxaliplatin (after first line gemcitabine), or gemcitabine with/without capecitabine (after first line FOLFIRINOX). • Palliative surgery and endoscopic placement of biliary drainage stents to control symptoms such as those due to jaundice and gastric obstruction. • Chemoradiation (if radiotherapy not previously given and if primary site is the sole site of progression). • Radiotherapy for severe refractory pain.

EFFICACY and SAFETY

Trial Nimotuzumab; phase II. Sponsor Oncoscience AG. Status Complete. Source of Publication1. information Location Germany. Design Single arm. Participants n=54; aged ≥18 years; pancreatic cancer; locally advanced or metastatic; ≥1 prior cytotoxic treatment. Schedule All participants received nimotuzumab, 200mg IV for 6 weeks induction, then every 3 weeks thereafter. Follow-up Active treatment until death or disease progression; follow-up until death. Primary Remission rate. outcome Secondary Progression free survival (PFS); overall survival (OS); tumour response; safety; outcomes symptom control. Key results Patients evaluable for response, 35; complete response/partial response, 0; stabilised disease, 6, with median duration of disease control, 19.2 weeks (95% CI 14.1-26.1); patients evaluable for PFS/OS, 54; median PFS, 6.7 weeks (95% CI 6.3-7.0); PFS after 1 year, 10.3%; median OS, 18.1 weeks (95% CI 16.3-19.8).

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Adverse AEs with possible relation to study drug (no. of participants), constitutional (fever, effects (AEs) chills), 7; dermatology/skin, 5; fatigue, 5; nausea, 4; pain, 2; allergic reaction, 2; anorexia, 1; musculoskeletal, 1; cardiac arrhythmia, 1; vascular (deep vein), 1; haemorrhage/bleeding, 1; gastrointestinal, 1; neurologic 1.

ESTIMATED COST and IMPACT

COST

The cost of nimotuzumab is now yet known. The costs of selected treatments for advanced pancreatic cancer are summarised below:

Drug Dose Cost for 3 months15,a Gemcitabine 1,000mg/m2, once weekly infusion for 7 weeks of an 8 week £3,240.00 cycle, followed by 3 weekly infusions in a 4 week cycle. 5-FU 12mg/kg for 4 days, then 6mg/kg on alternate days for 4 further £230.40 doses, repeated every 4 weeks.

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  None identified existing treatment.

Other Issues

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

REFERENCES

1 Strumberg D, Schultheis B, Scheulen ME et al. Phase II study of nimotuzumab, a humanised monoclonal anti-epidermal growth factor receptor (EGFR) antibody, in patients with locally advanced or metastatic pancreatic cancer. Investigational New Drugs 2012;30:1138-1143.

a Based on an average surface area of 1.88m2 and an average weight of 77.3kg. Assumes wastage.

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2 Bosetti C, Bertuccio P, Negri E et al. Pancreatic cancer: overview of descriptive epidemiology. Molecular Carcinogenesis 2012;51:3-13. 3 Cancer Research UK. Types of pancreatic cancer. http://www.cancerresearchuk.org/about- cancer/type/pancreatic-cancer/about/types-of-pancreatic-cancer Accessed 26 February 2015. 4 National Institute for Health and Care Excellence. Irreversible electroporation for treating pancreatic cancer: overview. London: NICE; February 2013. 5 Seufferlein T, Bachet JB, Van Cutsem E et al. Pancreatic adenocarcinoma: ESMO-ESDO clinical practice guidelines for diagnosis, treatment and follow-up. Annals of Oncology 2012;23(supplement 7)vii33-vii40. 6 Macmillan Cancer Support. Types of pancreatic cancer. http://www.macmillan.org.uk/Cancerinformation/Cancertypes/Pancreas/Symptomsdiagnosis/Type s.aspx Accessed 26 February 2015. 7 Cancer Research UK. Pancreatic cancer symptoms. http://www.cancerresearchuk.org/about- cancer/type/pancreatic-cancer/about/pancreatic-cancer-symptoms Accessed 26 February 2015. 8 Cancer Research UK. Pancreatic cancer incidence statistics. http://www.cancerresearchuk.org/cancer-info/cancerstats/types/pancreas/incidence/ Accessed 26 February 2015. 9 Macmillan Cancer Support. Staging of pancreatic cancer. http://www.macmillan.org.uk/Cancerinformation/Cancertypes/Pancreas/Symptomsdiagnosis/Stagi ng.aspx Accessed 26 February 2015. 10 Cancer Research UK. Pancreatic cancer survival statistics. http://www.cancerresearchuk.org/cancer-info/cancerstats/types/pancreas/survival/pancreatic- cancer-survival-statistics Accessed 26 February 2015. 11 National Institute for Health and Care Excellence. Liposomal cisplatin in combination with gemcitabine for previously untreated locally advanced or metastatic pancreatic cancer. Draft scope (pre-referral). London: NICE; June 2014. 12 Health & Social Care Information Centre. Hospital episode statistics for England. Inpatient statistics, 2013-14. www.hscic.gov.uk 13 Office for National Statistics. Mortality statistics: deaths registered in England and Wales 2013 (series DR). www.ons.gov.uk 14 National Comprehensive Cancer Network. NCCN clinical practice guidelines in oncology. Pancreatic adenocarcinoma. Version 1.2015. www.nccn.org 15 The Royal Pharmaceutical Society. British National Formulary. BNF March 2015. www.medicinescomplete.com/mc/bnf/current/