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Evofosfamide for Locally Advanced, Unresectable Or Metastatic Pancreatic Cancer – First Line in Combination with Gemcitabine

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Evofosfamide for Locally Advanced, Unresectable Or Metastatic Pancreatic Cancer – First Line in Combination with Gemcitabine Horizon Scanning Centre March 2015 Evofosfamide for locally advanced, unresectable or metastatic pancreatic cancer – first line in combination with gemcitabine SUMMARY NIHR HSC ID: 7060 Evofosfamide is intended to be used as a first line treatment option for patients with locally advanced, unresectable or metastatic (late stage) This briefing is pancreatic cancer. Evofosfamide is an intravenously administered, cytotoxic, hypoxia-activated prodrug (HAP), it is a nitromidazole-linked prodrug of based on dibromo isophoramide mustard, a potent DNA alkylator. Evofosfamide is information essentially inactive under normal oxygen levels. The trigger molecule keeps available at the time the toxin inactive until it is in the hypoxic region of the tumour so as to of research and a prevent general toxicity and it is activated by the low oxygen concentrations limited literature thus killing cells in its vicinity. Evofosfamide is administered at 340mg/m2 in search. It is not combination with 1,000mg/m2 gemcitabine, both via intravenous (IV) infusion intended to be a over 30 minutes on days 1, 8 and 15 of every 28 day cycle. definitive statement on the safety, Pancreatic cancer affects both sexes equally, with a lifetime risk of I in 77 for efficacy or men and 1 in 79 for women. In the UK, around 8,800 people were effectiveness of the diagnosed with pancreatic cancer in 2011. Pancreatic cancer has one of the health technology worst prognoses of all solid tumours with >95% of those affected dying of covered and should their disease. not be used for commercial As the majority of pancreatic cancer is diagnosed at an advanced stage, the purposes or aim of treatment is usually palliative; to improve quality of life and relieve commissioning symptoms. Surgery with the intention of a cure is only possible in around without additional one-fifth of new cases. Evofosfamide is currently in two phase III clinical trials information. in combination with gemcitabine comparing its effects on survival vs gemcitabine alone. These trials are expected to complete in 2014 and 2017. 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: locally advanced, unresectable or metastatic (late stage) – first line; in combination with gemcitabine. TECHNOLOGY DESCRIPTION Evofosfamide (TH-302, HAP-302) is a cytotoxic, hypoxia-activated prodrug (HAP) for the treatment of cancer. It is a nitroimidazole-linked prodrug of dibromo isophoramide mustard, a potent DNA alkylator. To prevent general toxicity, the trigger molecule keeps the toxin inactive until the prodrug is in the hypoxic region of the tumour, where it is then activated by the low oxygen concentration, thus killing cells in its vicinity. Evofosfamide is essentially inactive under normal oxygen levels, however in areas of hypoxia, evofosfamide becomes activated and converts to an alkylating cytotoxic agent resulting in DNA cross-linking. This renders cells unable to replicate their DNA and divide, leading to apoptosis1. Evofosfamide is used in combination with gemcitabine, a cytotoxic drug which has poor tissue penetration but targets the regions of tumours that are located in proximity to the tumour blood vessels. Combining gemcitabine with evofosfamide may enable the targeting of both the normoxic and hypoxic regions of tumoursa. In phase III clinical trials, patients received 340mg/m2 evofosfamide, in combination with 1,000mg/m2 gemcitabine, both via intravenous (IV) infusion over 30 minutes on days 1, 8 and 15 of every 28 day cycle2. Evofosfamide in combination with doxorubicin is also in phase III clinical trials for the first line treatment of locally advanced, unresectable, or metastatic soft tissue sarcoma. Evofosfamide in combination with pemetrexed is in phase II trials for advanced non- squamous non-small cell lung cancer and evofosfamide monotherapy phase II trials for advanced melanoma. INNOVATION and/or ADVANTAGES If licenced, evofosfamide will provide an additional treatment option for patients with locally advanced, unresectable or metastatic pancreatic cancer. DEVELOPER Merck KGaA. AVAILABILITY, LAUNCH OR MARKETING In phase III clinical trials. a Company provided information. 2 NIHR Horizon Scanning Centre PATIENT GROUP BACKGROUND Pancreatic cancer is the tenth most common cancer in the UK and the fifth most common cause of death from cancer3. Pancreatic cancer may arise in the head, body or tail of the pancreas and symptoms, which include jaundice, nausea, diarrhoea, weight loss, loss of appetite and severe pain, vary depending on the tumour site4,5. There are three main types of pancreatic cancer: infiltrating ductal adenocarcinoma, which account for around 90% of cancers, acincar cell carcinoma, and pancreablastoma6. NHS or GOVERNMENT PRIORITY AREA • NHS England. 2013/14 NHS Standard Contract for Cancer: Pancreatic (Adult). A02/S/b. • 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 has one of the worst prognoses of all solid tumours, with >95% of those affected dying of their disease6. The high mortality rate is due in part to the majority of patients (approximately 80%7) presenting at an advanced stage8. Even with early diagnosis the prognosis for pancreatic cancer is still poor; of all adults with pancreatic cancer, about 19% live for at least 1 year after they are diagnosed, about 4% live for 5 years after diagnosis and only about 3% live for at least 10 years after diagnosis. For pancreatic cancer that has spread to other parts of the body, the average life expectancy is only a few months9. Pancreatic cancer affects both sexes equally, with a lifetime risk of 1 in 77 for men and 1 in 79 for women10. Around 8,800 people were diagnosed with pancreatic cancer in 2011 in the UK11. In 2013, 7,549 deaths were registered in England and Wales12. In 2013-2014, there were 11,759 admissions due to pancreatic cancer (ICD-10 C25) in England, resulting in 15,050 bed days and 11,548 finished consultant episodes13. PATIENT PATHWAY RELEVANT GUIDANCE NICE Guidance • NICE technology appraisal in development. Pancreatic cancer (locally advanced, metastatic) – masitinib [ID566]. Expected date of issue to be confirmed. • NICE technology appraisal in development. Pancreatic cancer (metastatic) – nimotuzumab (1st line) [ID513]. Expected date of issue to be confirmed. • NICE technology appraisal in development. Pancreatic cancer – capectitabine [ID389]. Expected date of issue to be confirmed. 3 NIHR Horizon Scanning Centre • NICE technology appraisal in development. Pancreatic adenocarcinoma (untreated, metastatic) – paclitaxel albumin-bound nanoparticles (with gemcitabine) [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. • NICE interventional procedures guidance in development. Arterial reconstruction for locally advanced pancreatic cancer. Expected date of issue to be confirmed. • NICE interventional procedures guidance. Endoscopic bipolar radiofrequency ablation for treating biliary obstruction caused by cholangiocarcinoma or pancreatic adenocarcinoma (IPG464). September 2013. • NICE interventional procedures guidance. Irreversible electroporation for treating pancreatic cancer (IPG442). February 2013. • NICE interventional procedures guidance. Autologous pancreatic islet cell transplantation for improved glycaemic control after pancreatectomy (IPG274). September 2008. • NICE interventional procedures guidance. Laparoscopic distal pancreatectomy (IPG204). January 2007. Other Guidance • European Society for Medical Oncology and European Society of Digestive Oncology. Pancreatic adenocarcinoma: ESMO-ESDO clinical practice. Guidelines for diagnosis, treatment and follow-up. 201214. • ESMO. Pancreatic cancer: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. 20106. CURRENT TREATMENT OPTIONS Surgery with the intention of a cure is only possible in around one-fifth (20%) of new cases15. As the majority of cases are diagnosed at an advanced stage, the aim of treatment is usually palliative; to improve quality of life and relieve symptoms5. Current treatment options include5,6,16: • Chemotherapy: - FOLFIRINOX (5-FU, oxaliplatin and irinotecan). - Gemcitabine monotherapy. - Gemcitabine in combination with capecitabine. - Gemcitabine in combination with nab-paclitaxel. - Second line therapy may be considered for a small proportion of patients, if they are fit enough for further treatment. - Fluoropyramidines (5-FU or capecitabine) or oxaliplatin in combination with gemcitabine. • Concurrent chemo-radiotherapy – for locally advanced disease only. • Palliative surgery and endoscopic placement of biliary drainage stents to control symptoms such as jaundice and gastric outlet obstruction. • Palliative radiotherapy for control of symptoms associated with localised disease, such as pain. EFFICACY and SAFETY Trial NCT01144455; evofosfamide
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