Horizon Scanning Centre November 2013

Trastuzumab emtansine (Kadcyla) for patients with HER2 positive locally advanced or metastatic relapsed gastric cancers

SUMMARY NIHR HSC ID: 9054

Trastuzumab emtansine (Kadcyla) is intended for the treatment of patients with HER2-positive locally advanced or metastatic gastric cancers (including This briefing is adenocarcinomas of the gastro-oesophageal junction), following relapse after initial chemotherapy. If licensed, it will offer an additional treatment option for based on this patient group. Trastuzumab emtansine is a HER2 antibody-drug information conjugate that is comprised of trastuzumab linked to the anti-mitotic agent available at the time mertansine (a maytansine derivative). of research and a limited literature In England during 2010, there were 5,910 new cases of malignant neoplasm search. It is not of the stomach (including oesophageal junction). Gastric cancer has greater intended to be a incidence in older people and almost twice as many men than women are definitive statement diagnosed with gastric tumours. Less than 8% of cases are diagnosed before on the safety, the age of 55 years and the rates increase steeply from age 60, reaching a efficacy or rate of around 141 per 100,000 population in men aged 85 and over. effectiveness of the However, stomach cancer mortality rates in the UK have fallen by around health technology 75% over the last 40 years. Cancers of the oesophagus and stomach are covered and should usually diagnosed at a late stage and therefore have a poor prognosis. The not be used for proportion of patients who have metastatic disease is estimated to be 80%, commercial which is equal to approximately 4,700 people. In England during 2012-13, purposes or there were 19,661 admissions recorded for malignant neoplasm of the commissioning stomach accounting for 74,839 bed days and 24,972 finished consultant without additional episodes. There were 4,148 deaths from malignant neoplasm of the stomach information. in England and Wales during 2012.

There is currently no standard second line treatment for patients with locally advanced or metastatic gastric cancers, although most UK centres will use docetaxel and/or irinotecan chemotherapy in this patient group. Trastuzumab emtansine is in one phase III clinical trial comparing its effect on overall survival against treatment with standard taxane therapy. This trial is expected to complete in April 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

• Gastric cancer (including gastro-oesophageal junction adenocarcinoma): locally advanced or metastatic; HER2-positive; relapsed, following prior chemotherapy.

TECHNOLOGY

DESCRIPTION

Trastuzumab emtansine (Kadcyla; T-DM1; Herceptin-DM1) is a HER2 antibody-drug conjugate that is comprised of trastuzumab linked to the anti-mitotic agent mertansine (a maytansine derivative). The conjugate combines two strategies: the anti-HER2 activity of trastuzumab and the targeted intracellular delivery of mertansine, a tubulin polymerisation inhibitor that interferes with mitosis and promotes apoptosis. It is intended for the treatment of patients with HER2-positive locally advanced or metastatic gastric cancers (including adenocarcinomas of the gastro-oesophageal junction), following relapse after initial chemotherapy. Trastuzumab emtansine is administered by intravenous (IV) infusion at 2.4mg/kg once weekly.

Trastuzumab emtansine is in the following phases of clinical trials for the stated indications:

Phase III • HER2-positive metastatic breast cancer: o First line in patients with recurrence within 6 months of adjuvant therapy. o Second and third line therapy o First line in combination with pertuzumab. • Early breast cancer (adjuvant therapy). • Early breast cancer (neoadjuvant therapy).

Phase II • HER2-positive breast cancer (early stage disease, adjuvant therapy).

INNOVATION and/or ADVANTAGES

If licensed, trastuzumab emtansine will offer an additional treatment option for this patient group, following relapse after initial chemotherapy.

DEVELOPER

Roche Products Limited.

AVAILABILITY, LAUNCH OR MARKETING

In phase III clinical trials.

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PATIENT GROUP

BACKGROUND

Around 7,800 people are diagnosed with stomach cancer in the UK each year1. There are several different types of stomach cancer. The most common type is gastric or gastro- oesophageal junction adenocarcinoma, which starts in the glandular cells of the stomach lining and accounts for 95% of stomach cancers in the UK. Other rarer types of cancer that can affect the stomach include: • Soft tissue sarcomas, of which the commonest are leiomyosarcomas and gastrointestinal stromal tumours (GISTs). • Lymphomas such as mucosa associated lymphoid tissue (MALT) lymphomas. • Carcinoid tumours.

The initial symptoms of gastric cancer are often vague and may be mistaken for other conditions2, they may include: uncomplicated dyspepsia, abdominal pain and feeling full or bloated after a small meal2,3. More general symptoms may also be observed, such as decreased appetite, fatigue, weakness and weight loss. Symptoms of advanced gastric cancer may include2,3: an epigastric mass, hepatomegaly, jaundice, ascites, blood in the stool, vomiting, anorexia, Troiser’s sign (an enlarged supraclavicular node – Virchow’s node) and acanthosis nigricans.

Risk factors associated with gastric cancer and gastro-oesophageal junction adenocarcinoma may include4: age, male sex, alcohol use, tobacco use, poor diet, Helicobacter pylori infection, gastro-oesophageal reflux disease (GORD), oesophagitis, pernicious anaemia, and Barrett’s oesophagus (abnormality of the epithelial cells of the distal oesophagus).

NHS or GOVERNMENT PRIORITY AREA

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

CLINICAL NEED and BURDEN OF DISEASE

Gastric cancer is the eighth most common cancer in males in the UK and the thirteenth in females5. In England during 2011, there were 5,681 new cases of malignant neoplasm of the stomach (including oesophageal junction) (ICD-10 C16)6. Gastric cancer has greater incidence in older people1 and almost twice as many men than women are diagnosed with gastric tumours7. Less than 8% of cases are diagnosed before the age of 55 years and the rates increase steeply from age 60, reaching a rate of around 141 per 100,000 population in men aged 85 and over1. However, stomach cancer mortality rates in the UK have fallen by around 75% over the last 40 years8.

Cancers of the oesophagus and stomach are usually diagnosed at a late stage and therefore have a poor prognosis. The proportion of patients who have metastatic disease is estimated to be 80%5, which is equal to approximately 4,700 people. Of patients with advanced disease, it is estimated that 66% have inoperable cancer, and of these 53% are estimated to be fit enough to receive first line chemotherapy9. However all of these patients will eventually relapse10. Around 17% of gastric cancers are HER-2 positive5. In England during 2012-13, there were 19,661 admissions recorded for malignant neoplasm of the stomach (ICD-10 C16) accounting for 74,839 bed days and 24,972 finished consultant

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episodes11. There were 4,148 deaths from malignant neoplasm of the stomach in England and Wales during 201212.

PATIENT PATHWAY

RELEVANT GUIDANCE

NICE Guidance

• NICE technology appraisal. Trastuzumab for the treatment of HER2-positive metastatic gastric cancer (TA208). November 201013. • NICE technology appraisal. Capecitabine for the treatment of advanced gastric cancer (TA191). July 201014.

Other Guidance

• Scottish Intercollegiate Guidelines Network. Management of oesophageal and gastric cancer (CG87). June 200615. • British Society of Gastroenterology. Guidelines for the management of oesophageal and gastric cancer. 201116. • European Society for Medical Oncology (ESMO). Gastric cancer: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up17. • The Royal College of Surgeons of England, the Association of Upper GI Surgeons and the British Society of Gastroenterology. National Oesophago-Gastric Cancer Audit. 201318.

EXISTING COMPARATORS and TREATMENTS

There is currently no standard second line treatment for patients with metastatic or locally advanced gastric cancers14, although most UK centres will use docetaxel and/or irinotecan chemotherapy in this patient group19. Wherever possible, it is recommended that patients are enrolled into a clinical trial14. The goals of therapy are symptom control (e.g. relief of dysphagia), improving survival, and improving quality of life.

Treatment options may include14,15,16: • Palliative pharmaceutical therapies. The following combination chemotherapy regimens have been used in trials: o Irinotecan in combination with cisplatin or fluoropyrimidines. o Docetaxel monotherapy. o Docetaxel in combination with oxaliplatin. o paclitaxel alone or in combination with platinum agents. o FOLFOX (folinic acid, 5-FU, oxaliplatin). • Palliative radiotherapy. • Endoscopic methods for relieving dysphagia. o Oesophageal intubation. o Oesophageal dilatation. o Brachytherapy and stents. o Iatrogenic perforation and tracheo-oesophageal fistulae. • Laser therapy and stents. • Palliative surgery – to bypass obstruction in patients with distal stomach cancers that are obstructing the passage of food out of the stomach.

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EFFICACY and SAFETY

Trial GATSBY, NCT01641939, BO27952, 2012-000660-22; trastuzumab emtansine vs standard taxane therapy; phase III. Sponsor Hoffmann-La Roche. Status Ongoing. Source of Trials registry20. information Location EU (incl UK), USA, Canada and other countries. Design Randomised, active-controlled. Participants n=412 (planned); aged 18 years and older; gastric cancer; HER2-positive tumour; unresectable and locally advanced or metastatic disease (including adenocarcinoma of the gastro-oesophageal junction); disease progression during or after first line therapy; received at least one prior chemotherapy regimen; first line therapy must have included a combination of at least a platinum- and a fluoropyrimidine-based treatment given concurrently. Schedule Randomised to trastuzumab emtansine IV 3.6mg/kg once every 3 weeks; 2.4mg/kg once every week; or standard taxane (docetaxel or paclitaxel) therapy according to investigator choice. Follow-up Active treatment period 3 years, follow-up until disease progression or death. Primary Overall survival (OS). outcome/s Secondary Objective response rate; progression-free survival; duration of response; safety; time outcome/s to gastric symptom progressiona. Expected Primary completion date reported as April 2015. reporting date

ESTIMATED COST and IMPACT

COST

The cost of tratuzumab emtansine 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 Services

 Increased use of existing services: the  Decreased use of existing services company anticipate an increase in treatment duration, as a result more infusions per patient will be required. However, due to the small number of patients with HER2-positive metastatic gastric cancer the company estimate that this may have a relatively low service impact.

a Measured by the European Organisation for Research and Treatment of Cancer questionnaire (EORTC QLQ-STO22)

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 Re-organisation of existing services  Need for new services

 Other:  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  None identified identified

REFERENCES

1 Macmillan Cancer Support. Cancer information: stomach cancer. http://www.macmillan.org.uk/Cancerinformation/Cancertypes/Stomach/Stomachcancer.aspx Accessed 21 November 2013. 2 NHS Choices. Conditions. Stomach cancer - introduction http://www.nhs.uk/Conditions/Cancer-of- the-stomach/Pages/Introduction.aspx Accessed 21 November 2013. 3 Medscape. Gastric cancer: practice essentials. September 2013. http://emedicine.medscape.com/article/278744-overview Accessed 21 November 2013. 4 NHS Choices. Conditions. Stomach cancer – causes. http://www.nhs.uk/Conditions/Cancer-of- the-stomach/Pages/Causes.aspx Accessed 21 November 2013. 5 National Institute for Health and Clinical Excellence. Gastric cancer (HER2-positive metastatic) – trastuzumab TA208: costing template. London: NICE; November 2010. 6 Office of National Statistics. Cancer Statistics Registrations, England (Series MB1), No. 41, 2011. http://www.ons.gov.uk 7 Cancer Research UK. Stomach cancer: stomach cancer risks and causes. http://www.cancerresearchuk.org/cancer-help/type/stomach-cancer/about/stomach-cancer-risks- and-causes Accessed 21 November 2013. 8 Cancer Research UK. Cancer stats: stomach cancer key facts. http://www.cancerresearchuk.org/cancer-info/cancerstats/keyfacts/stomach-cancer/ Accessed 21 November 2013. 9 National Institute for Health and Clinical Excellence. Costing statement: Capecitabine for the treatment of inoperable gastric cancer. London: NICE; July 2010. 10 Wesolowski R, Lee C and Kim R. Is there a role for second-line chemotherapy in advanced gastric cancer? The Lancet 2009;10:903-912. 11 Health & Social Care Information Centre. Hospital episode statistics for England. Inpatient statistics, 2012-13. www.hesonline.nhs.uk 12 Office of National Statistics. Mortality statistics: deaths registered in 2011 (Series DR) Table 5. http://www.ons.gov.uk 13 National Institute for Health and Clinical Excellence. Trastuzumab for the treatment of HER2- positive metastatic gastric cancer. Technology appraisal TA208. London: NICE; November 2010. 14 National Institute for Health and Clinical Excellence. Capecitabine for the treatment of advanced gastric cancer. Technology appraisal TA191. London: NICE; July 2010. 15 Scottish Intercollegiate Guidelines Network. Management of oesophageal and gastric cancer CG87. Edinburgh: SIGN; June 2006. 16 Allum WH, Blazeby JM, Griffin SM. Guidelines for the management of oesophageal and gastric cancer. Gut 2011;60:1449-1472. 17 Okines A, Verheij M, Allum W et al. Gastric cancer: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Annals of Oncology 2010;21 (Supplement 5):v50–v54. 18 The Royal College of Surgeons of England, The Association of Upper GI Surgeons and the British Society of Gastroenterology. National Oesophago-Gastro Cancer Audit. Leeds: The Health and Social Care Information Centre; 2013.

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19 NIHR Horizon Scanning Centre. Ramucirumab monotherapy for advanced gastric cancer and gastro-oesophageal junction adenocarcinoma – after prior chemotherapy. University of Birmingham, September 2013. http://www.hsc.nihr.ac.uk/ 20 ClinicalTrials.gov. A randomized, multicenter, adaptive phase II/III study to evaluate the efficacy and safety of trastuzumab emtansine (T-DM1) versus taxane (docetaxel or paclitaxel) in patients with previously treated locally advanced or metastatic HER2-positive gastric cancer, including adenocarcinoma of the gastro-oesophageal junction. http://clinicaltrials.gov/ct2/show/NCT01641939?term=trastuzumab+emtansine&rank=6 Accessed 21 November 2013.

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