September Horizon Scanning Research & 2016 Intelligence Centre
Depatuxizumab mafodotin for recurrent EGFR-amplified glioblastoma multiforme
NIHR HSRIC ID: 11456
Lay summary
Depatuxizumab mafodotin is a new drug to treat a type of brain cancer called recurrent EGFR-amplified glioblastoma multiforme. Glioblastoma is the most common type of brain cancer and develops from cells that support the nerve tissue. Depatuxizumab mafodotin may offer a new treatment option for patients with recurrent EGFR- amplified glioblastoma multiforme whose first treatment has failed and may improve survival when other drugs have failed to work.
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
• Glioblastoma multiforme: recurrent, in patients whose tumours are EGFR-amplified — second and subsequent line; alone or in combination with temozolomide.
TECHNOLOGY
DESCRIPTION
Depatuxizumab mafodotin (ABT-414/806, ABT-414) is a monoclonal antibody-drug conjugate that targets the epidermal growth factor receptor (EGFR). EGFR is known to be over-expressed in a wide variety of human tumours, and is associated with increased metastasis, decreased survival and a poor prognosis. Depatuxizumab mafodotin is designed to be stable in the bloodstream and only release the potent monomethyl auristatin F cytotoxic agent once inside the targeted cells1.
In the phase II clinical trial, depatuxizumab mafodotin 1.0mg/kg is administered via intravenous (IV) infusion (30-40 minutes) every 2 weeks as a monotherapy or in combination with temozolomide2.
Depatuxizumab mafodotin does not currently have Marketing Authorisation in the EU for any indication. It is in phase II/III clinical trials for newly diagnosed glioblastoma with EGFR amplification and phase II trials in non-small cell lung cancer.
INNOVATION and/or ADVANTAGES
If licensed, depatuxizumab mafodotin will offer an additional treatment option for patients with recurrent EGFR-amplified glioblastoma multiforme, a group with high unmet medical need who currently have few well-tolerated and effective therapies available.
DEVELOPER
AbbVie Ltd.
AVAILABILITY, LAUNCH OR MARKETING
Depatuxizumab mafodotin is in phase II clinical trials.
PATIENT GROUP
BACKGROUND
Brain tumours are relatively rare, accounting for approximately 1.6% of all cancers in England and Wales3. Gliomas are the most common type of brain tumour. They arise from glial cells that support the nerve cells of the brain and spinal cord. There are four main types described: astrocytoma, ependymoma, oligodendroglioma and mixed tumours. Gliomas are graded according to their likely rate of growth, from grade 1 (slowest growing) to grade 4 (fastest growing). Grade 3 and 4 gliomas are considered high grade gliomas and grade 4 gliomas are usually glioblastomas4. High grade gliomas are more common in men than women and increase with age4. Horizon Scanning Research & Intelligence Centre
Patients with high grade gliomas suffer a range of symptoms which can have a severe detrimental impact on quality of life. General symptoms include raised intracranial pressure with headache, nausea, vomiting and seizures, occasionally accompanied by more global changes such as drowsiness, changes in personality and cognition5,6. Other specific focal deficit symptoms relate to the location of the tumour, and can include difficulties with speech, vision, ambulation, dexterity, and mood disturbances5,6. Following initial treatment for glioblastoma, most patients will experience tumour recurrence, following which, management is largely palliative7.
CLINICAL NEED and BURDEN OF DISEASE
The annual incidence of malignant brain tumours is 8.5 per 100,000 population, equating to approximately 3,500 cases each year in the UK8. High grade gliomas represent 50-60% of all primary brain tumours, occurring at an approximate incidence rate of 3-4 per 100,000 population per year in England and Wales4 of which glioblastoma multiforme comprises 40- 45%5. Glioblastoma multiforme is the most aggressive subtype of glioma with a median survival of 18 months, and a five year survival rate of approximately 4%9. Survival following recurrence is around 9-10 weeks and response to treatment for recurrent glioblastoma multiforme is seen in less than 10% of cases10. Expert opinion states that many patients are not fit for further treatment at progression and will die soon aftera. Expert opinion also estimates that about 90% of relapses represent local rather than distant spread, and there are around 800 patients per year who relapse after concurrent chemoradiotherapy in Englandb.
In 2014-15, there were 15,697 hospital admissions for malignant neoplasm of brain (ICD-10 C71), resulting in 94,413 bed days and 20,223 finished consultant episodes11. In 2014, 3,681 deaths were registered in England and Wales due to malignant neoplasm of the brain12.
PATIENT PATHWAY
RELEVANT GUIDANCE
NICE Guidance
• NICE technology appraisal in development. Glioblastoma – bevacizumab (ID80) Expected date of issue to be confirmed. (GID-TAG413) • NICE technology appraisal in development. Brain tumours (primary) and brain metastases in adults (GID-NG10003). Expected July 2018. • NICE technology appraisal. Carmustine implants and temozolomide for the treatment of newly diagnosed high grade glioma (TA121). June 2007. • NICE technology appraisal. Temozolomide for the treatment of recurrent malignant glioma (brain cancer) (TA23). April 2001. • NICE cancer service guidance. Improving outcomes for people with brain and other central nervous system tumours (CSG10). June 2006. • NICE guidelines. Suspected cancer: recognition and referral (NG12). June 2015. • NICE quality standards. Suspected cancer (QS124). June 2016. • NICE quality standards. Quality standard for end of life care for adults (QS13). August 2011.
a Expert personal communication.
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• NICE interventional procedure guidance. Photodynamic therapy for brain tumours (IPG290). March 2009.
NHS England Policies and Guidance
• NHS England. 2013/14 NHS Standard Contract for Radiotherapy (All Ages). B01/S/a. • NHS England. 2013/14 NHS Standard Contract for Cancer: Chemotherapy (Adult). B15/S/a. • NHS England. 2013/14 NHS Standard Contract for Cancer: brain/central nervous system (Adult). B13/S/a.
Other Guidance
• European Society for Medical Oncology. High-grade glioma: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. 201413.
CURRENT TREATMENT OPTIONS
Once a glioblastoma recurs, treatment options are usually limited and no uniformly accepted standard of care existsb. Treatment of recurrent glioblastoma multiforme should be individualised, depending on patient’s clinical condition and performance status, age and quality of life14. The standard treatment options for glioblastoma multiforme include9,15: • Surgical resection. • Radiotherapy. • Concomitant adjunctive chemotherapy. • Nitrosourea monotherapy and combination regimens (e.g. carmustine, lomustine, nimustine, fotemustine). These are DNA alkylating agents that cross the blood–brain barrier and have been extensively used in glioma treatment. • Temozolomide, as monotherapy or in combination regimens.
Temozolomide is recommended as an option for treating glioblastoma multiforme or anaplastic astrocytoma, in those who show recurrence or progression after standard therapy (given a Karnofsky performance status score of 70 or more and have a life expectancy of 12 weeks or more)5. Expert opinion states that the usual practice is to rechallenge with temozolomide if there has been an interval between finishing adjuvant temozolomide and progression. If progression has occurred on temozolomide, it is assumed they are resistant to this agent and patients are usually treated with combination chemotherapyc. The overall survival of patients with glioblastoma multiforme is still poor, largely due to recurrence of tumour after initial treatment with surgical resection, radiotherapy and chemotherapy14. Current treatment options for glioblastoma multiforme remains challenging and no long-term treatments are currently available9.
EFFICACY and SAFETY
Trial INTELLANCE 2, NCT02343406, M14-483, EORTC 1410-BTG, EudraCT2014- 004438-24; depatuxizumab mafodotin alone or in combination with temozolomide (TMZ) vs lomustine or TMZ; phase II. Sponsor AbbVie Ltd. Status Ongoing.
b Company information. c Expert personal communication.
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Source of Trial registry2. information Location EU (incl.UK) USA, Canada and other countries. Design Randomised, active-controlled. Participants n=240 (planned); age 18-99 yrs; confirmed primary glioblastoma multiforme with unequivocal tumour progression or recurrence; presence of EGFR amplification; World Health Organization (WHO) Performance status 0–2; ≤1 prior line of chemotherapy (concurrent and adjuvant TMZ based chemotherapy including in combination with another investigational agent is considered one line of chemotherapy) and chemotherapy must have been completed ≤4 wks prior to randomisation; surgery completed <2 wks before randomisation and pts should have fully recovered; no prior treatment with nitrosoureas or bevacizumab; no prior radiation therapy with a dose over 65 Gy, stereotactic radiosurgery or brachytherapy unless the recurrence is histologically proven. Schedule Randomised to depatuxizumab mafodotin 1.0mg/kg IV infusion every 2 wks as monotherapy or in combination with TMZ 150mg/m2 oral daily on days 1 to 5 of the first 28-day cycle with dose escalation to 200mg/m2 on days 1-5 in subsequent cycles; or lomustine 110mg/m2 oral on day 1 of every 42 day treatment period for patients relapsing during TMZ treatment or within 16 wks after first day of last TMZ cycle; or TMZ 150mg/m2 oral daily on days 1 to 5 for the first 28-day cycle, with dose escalation to 200mg/m2 on days 1-5 in subsequent cycles for patients that relapse >16 wks after the first day of last dose of TMZ cycle. Follow-up Active treatment until treatment withdrawal criteria met (disease progression, intolerable toxicity, patients’ best interest or refusal, start of any other anti-cancer agent/modality, or pregnancy; maximum 1 year treatment for lomustine), follow up 13 months after end of accrual is required. Primary Overall survival (OS) and progression-free survival (PFS). outcome/s Secondary PFS, overall response rate (ORR), OS in sub-group with EGFRvIII mutation. outcome/s Expected Completion date reported as June 2017 (final data collection date for primary reporting outcome measure). date
ESTIMATED COST and IMPACT
COST
The cost of depatuxizumab mafodotin 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
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Impact on Health and Social Care Services
Increased use of existing services: expert Decreased use of existing services opinion notes that 2 weekly IV infusions replace oral therapyd.
Re-organisation of existing services Need for new services
Other None identified
Impact on Costs and Other Resource Use
Increased drug treatment costs: expert Reduced drug treatment costs opinion notes that patients are now surviving long enough to receive more cycles of chemotherapye.
Other increase in costs Other reduction in costs
Other None identified
Other Issues
Clinical uncertainty or other research question None identified identified
REFERENCES
1 Phillips AC, Boghaert ER, Vaidya KS et al. ABT-414: An anti-EGFR antibody-drug conjugate as a potential therapeutic for the treatment of patients with squamous cell tumours [Abstract]. Molecular Cancer Therapeutics 2013;12:A250. 2 ClinicalTrials.gov. ABT-414 alone or ABT-414 plus temozolomide vs. lomustine or temozolomide for recurrent glioblastoma: a randomized phase II study of the Eortc Brain Tumor Group (EORTC protocol 1410-BTG). https://clinicaltrials.gov/ct2/show/NCT02343406 Accessed 12 July 2016. 3 National Institute for Health and Clinical Excellence. Improving outcomes for people with brain and other CNS tumours – the manual. Cancer service guideline C5G10. London: NICE; June 2006. 4 National Institute for Health and Clinical Excellence. Carmustine implants and temozolomide for the treatment of newly diagnosed high grade glioma. Technology appraisal TA121. London: NICE; June 2007. 5 National Institute for Health and Clinical Excellence. Guidance on the use of temozolomide for the treatment of recurrent malignant glioma (brain cancer). Technology appraisal TA23. London: NICE; April 2001. 6 NIHR Horizon Scanning Centre. Cilengitide (Impetreve) for glioblastoma multiforme. University of Birmingham, February 2012. www.hscri.nihr.ac.uk 7 Dinnes J, Cave C, Huang S et al. The effectiveness and cost-effectiveness of temozolomide for the treatment of recurrent malignant glioma: a rapid and systematic review. Health Technology Assessment 2001;5(13):1-73. 8 National Institute for Health and Clinical Excellence. Bevacizumab for the treatment of recurrent glioblastoma multiforme (ID80) – final scope, Appendix A. London: NICE; December 2009. 9 National Brain Tumour Society. Tumour Types: understanding brain tumours http://braintumor.org/brain-tumor-information/understanding-brain-tumors/tumor-types/ Accessed 13 July 2016. 10 Chamberlain MC. Bevacizumab for the treatment of recurrent glioblastoma. Clinical Medicine Insights: Oncology 2011;5:117-129. 11 Health & Social Care Information Centre. Hospital episode statistics for England. Admitted Patient Care, 2014-15. www.hscic.gov.uk
d Expert personal communication.
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12 Office for National Statistics. Mortality statistics: deaths registered in 2014 (Series DR) Table 5. www.ons.gov.uk 13 Stupp R, Brada M, Van Den Bent VJ et al. High-grade glioma: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Annals of Oncology 2014;25(suppl3):iii93-iii101. 14 Montemurro N, Perrini P, Blanco MO et al. Second surgery for recurrent glioblastoma: A concise overview of the current literature. Clinical Neurology and Neurosurgery 2016;(142):60–64. 15 Seystahl K, Wick W and Weller M. Therapeutic options in recurrent glioblastoma – An update. Critical Reviews in Oncology/Hematology 2016;(99):389–408.
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