September Horizon Scanning Research & 2016 Intelligence Centre

Pertuzumab for metastatic HER2-positive gastric cancer – first line

NIHR HSRIC ID: 7356

Lay summary

Pertuzumab is a new drug to treat stomach cancer. It is delivered straight into the blood via a drip. Pertuzumab may help the body’s immune system to fight the disease. Stomach cancer is an unusual type of cancer. Gastric and gastroesophageal junction adenocarcinoma are the most common types of stomach cancer. Pertuzumab may offer a new treatment option for people with stomach cancer that has one particular type of genetic mutation and whose disease has spread to other parts of the body.

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.

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.

Horizon Scanning Research & Intelligence Centre University of Birmingham [email protected] www.hsric.nihr.ac.uk @OfficialNHSC TARGET GROUP

• Adenocarcinoma of the stomach or gastro-oesophageal junction: metastatic; HER2- positive – first line; in combination with cisplatin and trastuzumab and either 5- fluorouracil or capecitabine.

TECHNOLOGY

DESCRIPTION

Pertuzumab (Perjeta; 2C4 antibody; Omnitarg; R-1273; RG-1273; rhuMAb 2C4; RO- 4368451) is a recombinant humanised monoclonal antibody that specifically targets the extracellular dimerisation domain (subdomain II) of the human epidermal growth factor receptor 2 (HER2) protein. It prevents the dimerisation of HER2 with other HER family receptors at the surface of cancer cells, which inhibits intracellular signalling pathways, leading to cell growth arrest and apoptosis. In addition, pertuzumab mediates antibody- dependent cell-mediated cytotoxicity. In the phase 3 trial, pertuzumab was administered via 840mg intravenous (IV) infusion every 3 weeks in combination with 5-fluorouracil (5FU) 800mg/m2/24 hours IV by continuous infusion for 120 hours (days 1-5) every 3 weeks or capecitabine 1,000mg/m2 orally twice daily, evening of day 1 to morning of day 15 (28 doses) every 3 weeks; cisplatin 80mg/m2 IV every 3 weeks; and trastuzumab 8mg/kg IV initial dose on day 1, followed by 6mg/kg IV every 3 weeks, for 6 cycles1.

Pertuzumab is licensed in the EU for the first line treatment of HER2-positive metastatic or locally recurrent unresectable breast cancer when combined with trastuzumab and docetaxel. It is also licensed for the neoadjuvant treatment of HER2-positive, locally advanced, inflammatory, or early stage breast cancer at high risk of recurrence in combination with trastuzumab and chemotherapy.

The most common adverse effects (≥50%) seen with pertuzumab in combination with trastuzumab and docetaxel are: diarrhoea, alopecia, neutropenia and nausea2. Other common (≥10%) adverse effects include: (febrile) neutropenia, leucopenia, upper respiratory tract infection, rashes, headache, fatigue, nasopharyngitis, asthenia, pruritus, arthralgia, pain in extremities, back pain and coughing.

Pertuzumab is in phase III clinical trials for the treatment of HER2-positive breast cancer as a combination therapy and ovarian cancer.

INNOVATION and/or ADVANTAGES

If licensed, pertuzumab will offer an additional treatment option for patients with HER2- positive metastatic gastric cancer.

DEVELOPER

Roche Products Ltd.

AVAILABILITY, LAUNCH OR MARKETING

Pertuzumab is currently in phase III clinical trials.

Horizon Scanning Research & Intelligence Centre

PATIENT GROUP

BACKGROUND

There are several different types of stomach cancer, the most common being gastric or gastroesophageal junction adenocarcinoma, which starts in the glandular cells of the stomach lining3. Initial symptoms are often vague and are similar to the symptoms of other stomach conditions. Early symptoms include heartburn or indigestion, burping, no appetite and feeling full after eating only a small amount4. Symptoms of advanced stomach cancer may include a lack of appetite and subsequent weight loss, fluid in the abdomen and blood in the stool5. Risk factors include increasing age, being male, a family history, infection with Helicobacter pylori, a diet low in fruit and vegetables and high in processed meats or smoked foods, smoking, being overweight, and long-term acid reflux or stomach conditions that cause changes to the stomach lining6.

CLINICAL NEED and BURDEN OF DISEASE

Gastric cancer is the 16th most common cancer in the UK, accounting for around 2% of all new cases7. In England, there were 5,342 cases of malignant neoplasm of stomach (ICD-10 C16) recorded in 20148. Gastric cancer is more common in men, with approximately twice as many cases diagnosed in men as in women2. Gastric or gastroesophageal junction adenocarcinoma are the most common types of stomach cancer and accounts for 95% of stomach cancers in the UK3,7. Due to the nature of symptoms, stomach cancer is often diagnosed at an advanced stage, with around 14% diagnosed at stage 3 (locally advanced), and 80% diagnosed at stage 4 (metastatic)9. It is estimated that 22% of patients with advanced gastric cancer have HER2-positive disease10.

Survival is poor, with around 75% of cases presenting with disease too established for curative treatment11. In 2014-15, there were 19,534 hospital admissions for malignant neoplasm of stomach, resulting in 68,097 bed days and 24,849 finished consultant episodes12. In 2014, there were 3,949 deaths from malignant neoplasm of stomach in England and Wales13.

PATIENT PATHWAY

RELEVANT GUIDANCE

NICE Guidance

• NICE technology appraisal. Ramucirumab for treating advanced gastric cancer or gastro- oesophageal junction adenocarcinoma after chemotherapy (TA378). January 2016. • NICE technology appraisal guidance. Trastuzumab for the treatment of HER2-positive metastatic gastric cancer (TA208). November 2010. • NICE technology appraisal guidance. Capecitabine for the treatment of advanced gastric cancer (TA191). July 2010. • NICE clinical guidelines in development. Oesophago-gastric cancer. Expected January 2018. • NICE interventional procedure guidance. Endoscopic submucosal dissection of gastric lesions (IPG360). October 2010.

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• NICE interventional procedure guidance. Laparoscopic gastrectomy for cancer (IPG269). July 2008.

NHS England Policies and Guidance

• 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. • NHS England. 2013/14 NHS Standard Contract for Cancer: Oesophageal and Gastric (Adult). B11/S/a.

Other Guidance

• London Cancer Alliance. LCA Oesophageal and gastric cancer clinical guidelines. 201411. • European Society for Medical Oncology. Gastric cancer: ESMO-ESSO-ESTRO clinical practice guidelines. 201314. • British Society of Gastroenterology. Guidelines for the management of oesophageal and gastric cancer. 201115. • Scottish Intercollegiate Guidelines Network. Management of oesophageal and gastric cancer (87). 200616.

CURRENT TREATMENT OPTIONS

The aim of treatment in advanced gastric or gastroesophageal junction adenocarcinoma is to prevent progression, extend survival and relieve symptoms with minimal adverse effects. Current treatment options for advanced gastric cancer include9,14,17: • Chemotherapy – ECF (epirubicin, cisplatin and fluorouracil), EOF (epirubicin, oxaliplatin and fluorouracil), ECX (epirubicin, cisplatin and capecitabine), EOX (epirubicin, oxaliplatin and capecitabine), docetaxel and irinotecan, FOLFIRI (leucovorin, fluorouracil and irinotecan), mitomycin C and capecitabine. • Biological therapy – trastuzumab (for HER2-positive disease).

EFFICACY and SAFETY

Trial JOSHUA, NCT01461057, BP27836; JACOB, NCT01774786, BP25114; pertuzumab, in combination with cisplatin, pertuzumab vs placebo, both in capecitabine and trastuzumab; phase II. combination with 5-fluorouracil, capecitabine, cisplatin and trastuzumab; phase III. Sponsor Hoffmann-La Roche. Hoffmann-La Roche. Status Published. Ongoing. Source of Publication18, trial registry19, Trial registry1, manufacturer. information manufacturer. Location EU (not UK) and Republic of Korea. EU (not UK), USA, Canada and other countries. Design Randomised, uncontrolled. Randomised, placebo-controlled. Participants n=30; aged ≥18 yrs; adenocarcinoma of n=780 (planned); aged ≥18 yrs; the stomach or gastroesophageal adenocarcinoma of the stomach or junction; HER2-positive; inoperable; gastroesophageal junction; HER2- locally advanced or metastatic; no prior positive; metastatic; no prior cytotoxic

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treatment for advanced or metastatic chemotherapy for advanced or metastatic disease; prior (neo)adjuvant therapy disease. allowed if completed ≥6 mths before study enrolment; no prior platinum-based (neo)adjuvant therapy. Schedule Randomised to pertuzumab 840mg IV for Randomised to pertuzumab 840mg IV cycle 1 (a cycle is 3 wks), followed by once every 3 wks; or placebo IV once 420mg IV for cycles 2–6 (arm A); or every 3 wks; both in combination with 5- pertuzumab 840mg IV for cycles 1–6 FU 800mg/m2/24 hrs IV by continuous (arm B); both in combination with cisplatin infusion for 120 hrs (days 1-5) every 3 80 mg/m2 IV once every 3 wks and wks, (6 cycles) or capecitabine capecitabine 1,000 mg/m2 orally twice 1,000mg/m2 orally twice daily, evening of daily for 14 days in every cycle. All day 1 to morning of day 15 (28 doses) patients receive trastuzumab at 8 mg/kg every 3 weeks (6 cycles), and cisplatin for cycle 1, followed by 6 mg/kg for 80 mg/m2 IV every 3 weeks (6 cycles), subsequent cycles. and trastuzumab, 8mg/kg IV initial dose on day 1, followed by 6mg/kg IV every 3 weeks. Follow-up Active treatment with pertuzumab, Active treatment up to 6 cycles (18 wks). trastuzumab, cisplatin and capecitabine Some patients will continue to receive for up to 6 cycles (18 wks) or continuation pertuzumab and trastuzumab; or with trastuzumab until investigator- pertuzumab placebo and trastuzumab assessed disease progression or until disease progression, unacceptable unmanageable toxicity, follow-up 41 toxicity or withdrawal from the study for mths. another reason. Follow-up up to 5 yrs after last dose. Primary Pharmacokinetics; adverse events (AEs). Overall survival. outcomes Secondary Exploratory efficacy endpoint to assess Progression-free survival; objective outcomes anti-tumour activity. No quality of life response rates; duration of objective measurement included in trial outcomes. response; clinical benefit; AEs; incidence of left ventricular systolic dysfunction; European Organization for Research and Treatment of Cancer (EORTC) QLQ- C30a; EORTC QLQ-STO22b; EQ-5Dc. Key results Safety profiles were similar between arms - and treatment was well tolerated; partial responses were achieved by 86% and 55% of patients in arms A and B, respectively. Adverse The total number of grade ≥3 AEs was 78 - effects in arm A and 60 in arm B. The most (AEs) frequent grade ≥3 AEs were neutropenia, anaemia, diarrhoea, decreased appetite, febrile neutropenia, fatigue, hypokalaemia, hyponatraemia, nausea, stomatitis, hypophosphataemia and mucosal inflammation. 73% and 67% of patients in arms A and B, respectively, experienced at least one serious AE and the total number of all serious AEs was 35 in arm A and 19 in arm B. Serious AEs that occurred in ≥2 patients overall were diarrhoea, febrile neutropenia, acute renal failure, asthenia, fatigue, gastric

a A quality of life measure for cancer patients b A modular supplement to QLQ-C30 for stomach cancer c A standardised measure of health outcome providing a single index value for health status.

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obstruction, hyponatraemia, mucosal inflammation, neutropenia, pneumonia, pulmonary embolism and vomiting. One serious AE in arm B (fungal pneumonia) resulted in death. This was considered by the investigator to be related to the chemotherapy agents. Two patients in arm A experienced asymptomatic left ventricular ejection fraction (LVEF) decline. After delaying study treatment, their LVEF values recovered and these patients continued receiving study treatment Expected - Study completion date reported as reporting December 2021. date

ESTIMATED COST and IMPACT

COST

Pertuzumab is already marketed in the UK for the treatment of breast cancer. A 420mg vial (30mg/mL) costs £2,39520.

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  None identified

Other Issues

 Clinical uncertainty or other research question  None identified identified

REFERENCES

1 ClinicalTrials.gov. A double-blind, placebo-controlled, randomized, multicenter phase III study evaluating the efficacy and safety of pertuzumab in combination with trastuzumab and

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chemotherapy in patients with HER2-positive metastatic gastroesophageal junction or gastric cancer. www.clinicaltrials.gov/show/NCT01774786 Accessed 3 August 2016. 2 electronic Medicines Compendium (eMC). Perjeta 420 mg Concentrate for Solution for Infusion. www.medicines.org.uk/emc/medicine/27473 Accessed 3 August 2016. 3 Cancer Research UK. Types of stomach cancer. www.cancerresearchuk.org/about- cancer/type/stomach-cancer/about/types-of-stomach-cancer Accessed 3 August 2016. 4 Macmillan Cancer Support. Signs and symptoms of stomach cancer. www.macmillan.org.uk/information-and-support/stomach-cancer/understanding-cancer/signs- symptoms-stomach.html Accessed 3 August 2016. 5 Cancer Research UK. Stomach cancer symptoms. www.cancerresearchuk.org/about- cancer/type/stomach-cancer/about/stomach-cancer-symptoms#adv Accessed 3 August 2016. 6 Macmillan Cancer Support. Risk factors and causes of stomach cancer. www.macmillan.org.uk/information-and-support/stomach-cancer/diagnosing/causes-and-risk- factors/causes-and-risk-factors-stomach.html Accessed 3 August 2016. 7 Cancer Research UK. Stomach (gastric) Cancer. www.cancerresearchuk.org/about- cancer/type/stomach-cancer Accessed 3 August 2016. 8 Health & Social Care Information Centre. Cancer Registration Statistics for England, 2013. www.hscic.gov.uk 9 Cancer Research UK. Survival statistics for stomach cancer. www.cancerresearchuk.org/about- cancer/type/stomach-cancer/treatment/statistics-and-outlook-for-stomach-cancer Accessed 3 August 2016. 10 Bang Y, Chung J, Xu F et al. Pathological features of advanced gastric cancer (GC): Relationship to human epidermal growth factor receptor 2 (HER2) positivity in the global screening programme of the ToGA trial. Journal of Clinical Oncology 2009;27:S15. 11 London Cancer Alliance. LCA oesophageal and gastric cancer clinical guidelines. London: LCA; April 2014. 12 Health & Social Care Information Centre. Hospital Episode Statistics for England. Inpatient statistics, 2014-15. www.hscic.gov.uk 13 Office for National Statistics. Mortality statistics: Deaths registered in England and Wales, (Series DR), 2014. www.ons.gov.uk 14 Waddell T, Verheij M, Allum W et al. Gastric cancer: ESMO-ESSO-ESTRO clinical practice guidelines. Annals of Oncology 2013;24(suppl6):vi57-vi63. 15 Allum WH, Blazeby JM, Griffin SM. Guidelines for the management of oesophageal and gastric cancer. Gut 2011;60:1449-1472. 16 Scottish Intercollegiate Guidelines Network. Management of oesophageal and gastric cancer. National clinical guideline 87. Edinburgh: SIGN; June 2006. 17 Cancer Research UK. Types of treatment for stomach cancer. www.cancerresearchuk.org/about- cancer/type/stomach-cancer/treatment/which-treatment-for-stomach-cancer#Chemoradiation Accessed 12 August 2016. 18 Kang YK, Rha SY, Tassone P et al. A phase IIa dose-finding and safety study of first-line pertuzumab in combination with trastuzumab, capecitabine and cisplatin in patients with HER2- positive advanced gastric cancer. British Journal of Cancer 2014;111:660-666. 19 ClinicalTrials.gov. An open-label, randomized, multicenter phase IIa study evaluating pertuzumab in combination with trastuzumab and chemotherapy in patients with HER2-positive advanced gastric cancer. www.clinicaltrials.gov/ct2/show/study/NCT01461057 Accessed 12 August 2016. 20 Joint Formulary Committee. British National Formulary. BNF January 2016. BMJ Group and Pharmaceutical Press. www.medicinescomplete.com

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