Tisagenlecleucel for Treating Relapsed Or Refractory Aggressive B-Cell Non-Hodgkin Lymphoma – Second Line

$Tisagenlecleucel for Treating Relapsed Or Refractory Aggressive B-Cell Non-Hodgkin Lymphoma – Second Line$

HEALTH TECHNOLOGY BRIEFING JUNE 2021

Tisagenlecleucel for treating relapsed or refractory aggressive B-cell non-Hodgkin lymphoma – second line

NIHRIO ID 24353 NICE ID 10580

Developer/Company Novartis UKPS ID 648673 Pharmaceuticals UK Ltd

Licensing and Currently in phase III clinical trials. market availability plans

SUMMARY Tisagenlecleucel is in clinical development for second-line treatment of relapsed or refractory aggressive B-cell non-Hodgkin lymphoma (NHL). NHL is a type of blood cancer that develops when white blood cells, called lymphocytes, grow out of control. The lymphocytes lose their infection fighting ability, making the body more susceptible to infection. Relapsed cancer refers to cancer that returned following initial response to treatment and refractory cancer refers to cancer that did not respond to treatment. The prognosis for relapsed or refractory NHL is poor, so there is a need to develop additional treatment options. Tisagenlecleucel is given by intravenous infusion and contains the patient’s own T-cells that have been genetically modified to make a protein called chimeric antigen receptor (CAR). This CAR protein can attach to CD-19 which is a protein found on the surface of cancer cells, enabling the modified T-cells to kill the cancer cells. If approved, this would be a label extension for tisagenlecleucel’s existing Marketing Authorisation for the third- line treatment of relapsed or refractory diffuse large B-cell lymphoma (DLBCL).

This briefing reflects the evidence available at the time of writing 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. A version of the briefing was sent to the company for a factual accuracy check. The company was available to comment. Page 1 of 9

PROPOSED INDICATION

Adult patients with relapsed or refractory aggressive B-Cell NHL.1

TECHNOLOGY

DESCRIPTION Tisagenlecleucel (Kymriah, CTL019) is a CD19-directed, genetically modified autologous T-cell immunotherapy that involves reprogramming autologous T cells isolated from each individual with a transgene encoding a chimeric antigen receptor (CAR).2,3 The CAR is comprised of a murine single-chain antibody fragment which recognises CD19 and is fused to intracellular signalling domains from 4-1BB (CD137) and CD3 zeta.4 Upon binding to CD19 expressing cancerous and other B cells, the CAR transmits a signal to promote T cell expansion, activation, target-cell elimination, and persistence of the tisagenlecleucel cells.5 The CD3 zeta component is critical for initiating T-cell activation and anti-tumour activity, while 4-1BB enhances the expansion and persistence of tisagenlecleucel.4 Tisagenlecleucel is a one-time treatment designed to empower a patient’s immune system to fight the cancer.6

In the phase III trial BELINDA (NCT03570892, EudraCT 2016-002966-29), participants are given lymphodepleting chemotherapy followed by a single intravenous (IV) infusion of 0.6-6.0x108 CAR-T cells.1,7

INNOVATION AND/OR ADVANTAGES The outcomes for patients with relapsed or refractory diffuse large B- cell lymphoma (DLBCL) and other forms of aggressive NHL are poor.8,9 There is an unmet need for more effective treatment options given the low levels of response to treatment and associated limited level of survival in relapsed or refractory patients.9 CAR-T cell therapy is specifically developed for each individual patient and involves reprogramming the patient’s own immune system cells which are then used to target their cancer. It has been shown as a potentially curative option in some patients, even those with quite advanced cancer and where other treatments have failed.10 The CAR-T therapy tisagenlecleucel has already been approved for use in DLBCL patients who have relapsed after receiving two lines of therapy.4 It is hypothesised that earlier administration of tisagenlecleucel sooner across treatment regimens would improve progression free-survival as compared to standard of care.11

Tisagenlecleucel is an advanced therapy medicinal product (ATMP) within the definition of a gene therapy medicine. The scientific recommendation for an ATMP classification is issued by the EMA’s Committee for Advanced Therapies (CAT).12,13

DEVELOPMENT STATUS AND/OR REGULATORY DESIGNATIONS Tisagenlecleucel is currently licensed in the EU/UK for the treatment of:4 • Paediatric and young adult patients up to and including 25 year of age with B-cell acute lymphoblastic leukaemia that is refractory, in relapse post-transplant, or in second or later relapse • Adult patients with relapsed or refractory DLBCL after two or more lines of systemic therapy

Very common adverse events of tisagenlecleucel (affecting more than one in ten people) include infections, anaemia, haemorrhage, neutropenia, thrombocytopenia, cytokine release syndrome, hypogammaglobulinemia, anxiety delirium, sleep disorder, headache, encephalopathy, arrhythmia, hypotension, cough, dyspnoea, hypoxia, diarrhoea, nausea, vomiting, constipation, abdominal pain, rash, arthralgia, acute kidney pain, pyrexia, fatigue, oedema, pain, chills, decreased lymphocytes, white blood cells, haemoglobin, neutrophils, platelets and increased aspartate aminotransferase.4

Tisagenlecleucel is currently in phase II and/or phase III clinical development for several other indications, including: relapsed or refractory follicular lymphoma; NHL; multiple myeloma; and adult acute lymphoblastic leukaemia.14

Tisagenlecleucel was designated an orphan drug in the EU in 2016 for the treatment of DLBCL.15,16

PATIENT GROUP

DISEASE BACKGROUND Lymphoma is a cancer of the lymph nodes that occurs when lymphocytes grow and multiply uncontrollably.17 Lymphomas are categorised into two broad groups: Hodgkin lymphoma which is marked by the presence of Reed-Sternberg cells and NHL where these Reed- Sternberg cells are not present.18,19 The majority (around 85%) of NHL arise from B- lymphocytes, with DLBCL being the most common subtype.20 Other types of aggressive B-cell NHL include: mantle cell lymphoma, primary effusion lymphoma, chronic lymphocytic leukaemia, and Burkitt lymphoma.21,22 In NHL, the affected lymphocytes start to divide before they are fully mature and lose their infection-fighting properties which make the body more vulnerable to infection.23,24 Refractory NHL is when the disease has not responded to initial treatment and relapsed NHL is when the disease initially responded to treatment but then subsequently returned.25

The lymphatic system runs throughout the entire body and therefore NHL can appear anywhere.23 The first symptom is often a painless swelling in the neck, armpit or groin due to enlarged lymph nodes. Sometimes other parts of the body outside the lymph nodes can also be affected such as the stomach, bowel, lever, testis, skin, brain or eye. Symptoms are directly related to the amount of pressure the lymphoma is putting on the particular body part affected.26 Some people with NHL may have other more general symptoms which include: night sweats, unintentional weight loss or high temperature.27

NHL is caused by a mutation in the DNA of lymphocytes resulting in them multiplying and growing uncontrollably, but the exact reason why this happens is not known. A person’s risk of developing the disease is increased by factors including having a medical condition that weakens the immune system; having an autoimmune condition such a lupus or Sjogren’s syndrome; taking immunosuppressant medication and previous exposure to the Epstein-Barr virus. There is also a slightly increased risk of developing NHL if a first degree relative has had the condition.28,29

CLINICAL NEED AND BURDEN OF DISEASE NHL is the 6th most common cancer in the UK, accounting for 4% of all new cancer cases.30 In 2017, the age standardised registrations of newly diagnosed cases of NHL (ICD-10 code C82- C85) in England were 27.6 per 100,000 in males and 19.5 per 100,000 in females. There were 12,065 newly diagnosed cases of NHL (ICD-10 code C82-C85).31 According to the 2019-20 Hospital Episode Statistics data, there were 39,515 finished consultant episodes (FCE) for DLBCL, (ICD-10 code C83.3) which resulted in 35,369 admissions, 27,422 day cases and 86,744 FCE bed days.32

For deaths registered in 2017, there were 4,096 deaths where NHL (ICD-10 code C82-C85) was recorded as the underlying cause. The age standardised rates per 100,000 population of registered deaths from NHL was 9.7 for males and 6.4 for females.31 In England, between 2013 and 2017 for a total of 56,350 NHL patients followed up to 2018, the age-standardised one- year and five-year survival rate was 79.4% and 65.6% respectively.33

PATIENT TREATMENT PATHWAY

TREATMENT PATHWAY Since NHL can advance quickly, it usually requires immediate treatment, with the aim of achieving complete remission.34 DLBCL often responds well to treatment and approximately 50-60% of patients achieve and maintain complete remission following first-line therapy. many patients go into complete remission.26

However, the prognosis for the 30-40% of patients who relapse and 10% who have refractory DLBCL is poor.35 Most people with relapsed or refractory disease are offered further immunochemotherapy, known as salvage treatment. The aim of salvage treatment is to reduce the lymphoma as much as possible rather than provide curative or overall survival benefit. In those patients who are fit enough after salvage treatment, a stem cell transplant may increase the chance of having long-lasting remission.26,36,37

CURRENT TREATMENT OPTIONS Salvage therapy using multi-agent immunochemotherapy should be offered to patients with relapsed or refractory DLBCL who are fit enough to tolerate intensive therapy. The most commonly used salvage treatments include:38,39 • R-GDP – rituximab with gemcitabine, dexamethasone and cisplatin • R-DHAP – rituximab with dexamethasone, high-dose cytarabine and cisplatin • R-ICE – rituximab with isofamide, carboplatin and etoposide

NICE currently recommends using R-GDP immunochemotherapy as salvage therapy which is as effective as other commonly used salvage regimens and less toxic.39 In patients with relapsed or refractory DLBCL who cannot have haematopoietic stem cell transplant NICE recommends polatuzumab vedotin with rituximab and bendamustine.39 NICE currently does not make any recommendations for the second line treatment of other aggressive forms of B-cell NHL.36

PLACE OF TECHNOLOGY If approved, tisagenlecleucel would offer an additional treatment option for patients with relapsed or refractory aggressive B-Cell NHL.1 This would be a label extension from the Marketing Authorisation tisagenlecleucel currently has for the third-line treatment of relapsed or refractory DLBCL (and acute lymphoblastic leukaemia).4,36

CLINICAL TRIAL INFORMATION Trial BELINDA, NCT03570892, 2016-002966-29; Tisagenlecleucel versus standard of care in adult patients with relapsed or refractory aggressive B-cell non-Hodgkin Lymphoma Phase III – Recruiting Locations: 8 EU countries, UK, USA and other countries Estimated primary completion date: September 2026 Trial design Randomised, open-label, parallel assignment Population N=355; histologically confirmed aggressive B-cell NHL (including DLBCL); relapse or progression within 365 days from last dose of anti-CD20 antibody and anthracycline first- line immunochemotherapy or refractory to first-line treatment; eligible for autologous haematopoietic stem cell (HSCT) Intervention(s) Lymphodepleting chemotherapy and a single dose of tisagenlecleucel (IV infusion) Comparator(s) Standard of care chemotherapy Outcome(s) Event-free survival [Time Frame: 5 years]

See trial record for full list of outcome measures Results (efficacy) - Results (safety) -

ESTIMATED COST

Tisagenlecleucel is already marketed in the UK. The list price for tisagenlecleucel is £282,000 per infusion. A confidential agreement is in place between the manufacturer and NHS for the supply of tisagenlecleucel in its current indications.9,40

RELEVANT GUIDANCE

NICE GUIDANCE

• NICE technology appraisal guidance in development. Axicabtagene ciloleucel for treating relapsed or refractory diffuse large B-cell lymphoma after 1 systemic therapy (GID- TA10580). Expected date of issue to be confirmed. • NICE technology appraisal guidance in development. Nivolumab for treating relapsed or refractory diffuse large B-cell lymphoma. Expected date of issue to be confirmed.

• NICE technology appraisal guidance. Polatuzumab vedotin with rituximab and bendamustine for treating relapsed or refractory diffuse large B-cell lymphoma (TA649). September 2020. • NICE clinical guideline. Non-Hodgkin’s lymphoma: diagnosis and management (NG52). July 2016.

NHS ENGLAND (POLICY/COMMISSIONING) GUIDANCE • NHS England. 2013/14 NHS standard Contract for Cancer: Chemotherapy (Adult). B15/S/a. • NHS England. 2013/14 NHS Standard Contract for Haematopoietic Stem Cell Transplantation (Adult). B04/S/a. • NHS Commissioning Board. Clinical Commissioning Policy: Haematopoietic Stem Cell Transplantation (HSCT) (All Ages): Revised. NHSCB/B04/P/a. April 2013.

OTHER GUIDANCE

• British Society for Haematology. Management of Diffuse Large b-cell Lymphoma. 2016.41 • European Society for Medical Oncology (ESMO). Diffuse large B-cell lymphoma (DLBCL): ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. 2015.42 • National Comprehensive Cancer Network (NCCN). NCCN Clinical Practice Guidelines in Oncology: Non-Hodgkin’s Lymphomas. 2015.43

ADDITIONAL INFORMATION

♦

REFERENCES 1 Clinicaltrials.gov. Tisagenlecleucel Versus Standard of Care in Adult Patients With Relapsed or Refractory Aggressive B-cell Non-Hodgkin Lymphoma: A Randomized, Open Label, Phase III Trial (BELINDA). Trial ID: NCT03570892. 2018. Status: Recruiting. Available from: https://clinicaltrials.gov/ct2/show/NCT03570892 [Accessed 20 May 2021]. 2 DrugBank. Tisagenlecleucel: Mechanism of action. 2017. Available from: https://go.drugbank.com/drugs/DB13881 [Accessed 20 May 2021]. 3 Clinical Trials Arena. Kymriah (tisagenlecleucel) for the Treatment of Acute Lymphoblastic Leukaemia. 2021. Available from: https://www.clinicaltrialsarena.com/projects/kymriah- tisagenlecleucel-for-the-treatment-of-acute-lymphoblastic- leukaemia/#:~:text=Kymriah's%20mechanism%20of%20action,removing%20CD19%2Dexpress ing%20malicious%20cells. [Accessed 20 May 2021]. 4 Electronic Medicines Compendium (EMC). Kymriah cells dispersion for infusion. 2018. Available from: https://www.medicines.org.uk/emc/product/9456 [Accessed 20 May 2021]. 5 Novartis. Kymriah (tisagenlecleucel) suspension for IV infusion. 2020. Available from: https://www.hcp.novartis.com/products/kymriah/diffuse-large-b-cell-lymphoma- adults/mechanism-of-action/#important-safety-info [Accessed 20 May 2021]. 6 Novartis. Novartis analyses confirm benefit of Kymriah® with clinically meaningful rates of complete response seen in patients with certain advanced lymphomas. 2020. Available from: https://www.novartis.com/news/media-releases/novartis-analyses-confirm-benefit-kymriah- clinically-meaningful-rates-complete-response-seen-patients-certain-advanced-lymphomas [Accessed 27 May 2021].

7 EU Clinical Trials Register. Tisagenlecleucel versus standard of care in adult patients with relapsed or refractory aggressive B-cell non-Hodgkin lymphoma: A randomized, open label, phase III trial (BELINDA). Trial ID: 2016-002966-29. 2018. Status: Ongoing. Available from: https://www.clinicaltrialsregister.eu/ctr-search/trial/2016-002966-29/GB [Accessed 20 May 2021]. 8 Chao M. Treatment challenges in the management of relapsed or refractory non- Hodgkin’s lymphoma – novel and emerging therapies. Cancer Management and Research. 2013:251. Available from: https://doi.org/10.2147/cmar.s34273. 9 National Institute for Health and Care Excellence (NICE). Tisagenlecleucel for treating relapsed or refractory diffuse large B-cell lymphoma after 2 or more systemic therapies (TA567). Last Update Date: 13 March 2019. Available from: https://www.nice.org.uk/guidance/ta567/resources/tisagenlecleucel-for-treating-relapsed-or- refractory-diffuse-large-bcell-lymphoma-after-2-or-more-systemic-therapies-pdf- 82607087377861 [Accessed 20 May 2021]. 10 NHS England. CAR-T Therapy. 2021. Available from: https://www.england.nhs.uk/cancer/cdf/car-t-therapy/ [Accessed 20 May 2021]. 11 Cancer Therapy Advisor. BELINDA Trial Tests Earlier Use of Tisa-Cel in Aggressive B-Cell Non- Hodgkin Lymphoma. 2019. Available from: https://www.cancertherapyadvisor.com/home/cancer-topics/lymphoma/belinda-trial-tests- earlier-use-of-tisa-cel-in-aggressive-b-cell-non-hodgkin-lymphoma/ [Accessed 21 May 2021]. 12 European Medicines Agency (EMA). Advanced therapy medicinal products: Overview. 2017. Available from: https://www.ema.europa.eu/en/human-regulatory/overview/advanced- therapy-medicinal-products-overview [Accessed 04 June 2021]. 13 European Medicines Agency (EMA). Assessment report: Kymriah. 2018. Available from: https://www.ema.europa.eu/en/documents/assessment-report/kymriah-epar-public- assessment-report_en.pdf [Accessed 04 June 2021]. 14 Clinicaltrials.gov. Search for tisagenlecleucel studies: phase II and III. 2021. Available from: https://clinicaltrials.gov/ct2/results?cond=tisagenlecleucel&age_v=&gndr=&type=&rslt=&pha se=1&phase=2&Search=Apply [Accessed 20 May 2021]. 15 European Medicines Agency (EMA). Kymriah; tisagenlecleucel. 2018. Available from: https://www.ema.europa.eu/en/medicines/human/EPAR/kymriah [Accessed 20 May 2021]. 16 European Medicines Agency (EMA). Public summary of opinion on orphan designation: Autologous T cells transduced with lentiviral vector containing a chimeric antigen receptor directed against CD19 for the treatment of diffuse large Bcell lymphoma 2016. Available from: https://www.ema.europa.eu/en/documents/orphan-designation/eu/3/16/1745-public- summary-positive-opinion-orphan-designation-autologous-t-cells-transduced-lentiviral_en.pdf [Accessed 20 May 2021]. 17 Live Science. Lymphatic System: Facts, Functions & Diseases. 2018. Available from: https://www.livescience.com/26983-lymphatic-system.html [Accessed 19 May 2021]. 18 Memorial Sloan Kettering Cancer Center. Types of Lymphoma. 2021. Available from: https://www.mskcc.org/cancer-care/types/lymphoma/types [Accessed 19 May 2021]. 19 Cancer Treatment Centers of America. Non-Hodgkin lymphoma types. 2021. Available from: https://www.cancercenter.com/cancer-types/non-hodgkin-lymphoma/types [Accessed 19 May 2021]. 20 European Medical Journal. Management of multiply relapsed aggressive non-Hodgkin Lymphoma: New perspectives. 2017. Available from: https://www.emjreviews.com/hematology/symposium/management-of-multiply-relapsed- aggressive-non-hodgkin-lymphoma-new-perspectives/ [Accessed 22 June 2021]. 21 Said JW. Aggressive B-cell lymphomas: how many categories do we need? Modern Pathology. 2013;26(S1):S42-S56. Available from: https://doi.org/10.1038/modpathol.2012.178. 22 WebMD Cancer Center. What is B-Cell Lymphoma? 2020. Available from: https://www.webmd.com/cancer/lymphoma/what-is-b-cell-lymphoma [Accessed 22 June 2021].

23 Cancer Research UK. What is non-Hodgkin lymphoma? 2020. Available from: What is non- Hodgkin lymphoma? [Accessed 19 May 2021]. 24 National Health Service (NHS). Non-Hodgkin lymphoma: Overview. 2018. Available from: https://www.nhs.uk/conditions/non-hodgkin-lymphoma/ [Accessed 19 May 2021]. 25 Leukemia & Lymphoma Society. Relapsed and Refractory NHL. 2021. Available from: https://www.lls.org/lymphoma/non-hodgkin-lymphoma/treatment/refractory-and-relapsed [Accessed 19 May 2021]. 26 Lymphoma Action. Diffuse large B-cell lymphoma. 2019. Available from: https://lymphoma- action.org.uk/types-lymphoma-non-hodgkin-lymphoma/diffuse-large-b-cell-lymphoma [Accessed 19 May 2021]. 27 Cancer Research UK. Diffuse large B cell lymphoma. 2020. Available from: https://www.cancerresearchuk.org/about-cancer/non-hodgkin-lymphoma/types/diffuse- large-B-cell-lymphoma [Accessed 19 May 2021]. 28 NHS Inform. About non-Hodgkin lymphoma. 2021. Available from: https://www.nhsinform.scot/illnesses-and-conditions/cancer/cancer-types-in-adults/non- hodgkin-lymphoma [Accessed 19 May 2021]. 29 NHS Inform. Causes of non-Hodgkin lymphoma. 2021. Available from: https://www.nhsinform.scot/illnesses-and-conditions/cancer/cancer-types-in-adults/non- hodgkin-lymphoma#causes-of-non-hodgkin-lymphoma [Accessed 19 May 2021]. 30 Cancer Research UK. Non-Hodgkin Lymphoma (NHL) incidence. 2020. Available from: https://www.cancerresearchuk.org/health-professional/cancer-statistics/statistics-by-cancer- type/non-hodgkin-lymphoma/incidence#heading-Zero [Accessed 19 May 2021]. 31 Office for National Statistics (ONS). Cancer Registration Statistics - England (2017). 2019. Available from: https://www.ons.gov.uk/peoplepopulationandcommunity/healthandsocialcare/conditionsand diseases/datasets/cancerregistrationstatisticscancerregistrationstatisticsengland [Accessed 28 May 2021]. 32 NHS Digital. Hospital Admitted Patient Care Activity 2019-20. Available from: https://digital.nhs.uk/data-and-information/publications/statistical/hospital-admitted- patient-care-activity/2019-20 [Downloaded 17 September 2020]. 33 Office for National Statistics (ONS). Cancer Survival in England: adults diagnosed between 2013 and 2017 and followed up to 2018. Available from: https://www.ons.gov.uk/peoplepopulationandcommunity/healthandsocialcare/conditionsand diseases/datasets/cancersurvivalratescancersurvivalinenglandadultsdiagnosed [Downloaded 12 August 2019]. 34 Macmillan Cancer Support. Treating Non-Hodgkin Lymphoma (NHL). 2018. Available from: https://www.macmillan.org.uk/cancer-information-and-support/lymphoma/treating-non- hodgkin-lymphoma-nhl [Accessed 22 June 2021]. 35 Raut LS, Chakrabarti PP. Management of relapsed-refractory diffuse large B cell lymphoma. South Asian journal of cancer. 2014;3(1):66-70. Available from: https://doi.org/10.4103/2278- 330X.126531. 36 National Institute for Health and Care Excellence (NICE). Non-Hodgkin’s lymphoma: diagnosis and management NICE guideline (NG52). Last Update Date: 20 July 2016. Available from: https://www.nice.org.uk/guidance/ng52/chapter/Recommendations [Accessed 19 May 2021]. 37 British Society for Haematology. Management of Diffuse Large B-cell Lymphoma. 2016. Available from: https://b-s-h.org.uk/guidelines/guidelines/management-of-diffuse-large-b- cell-lymphoma/ [Accessed 19 May 2021]. 38 European Medicines Agency (EMA). Kymriah: Assessment Report. 2018. Available from: https://www.ema.europa.eu/en/documents/assessment-report/kymriah-epar-public- assessment-report_en.pdf [Accessed 21 May 2021]. 39 National Institute for Health and Care Excellence (NICE). Treating diffuse large B-cell lymphoma; everything NICE says in an interactive flowchart. 2021. Available from: https://pathways.nice.org.uk/pathways/non-hodgkins-lymphoma/treating-diffuse-large-b-

cell-lymphoma#content=view-node%3Anodes-relapsed-or-refractory-disease [Accessed 21 May 2021]. 40 National Institute for Health and Care Excellence (NICE). NICE recommends another revolutionary CAR T-cell therapy for adults with lymphoma. 2019. Available from: https://www.nice.org.uk/news/article/nice-recommends-another-revolutionary-car-t-cell- therapy-for-adults-with- lymphoma#:~:text=This%20involves%20taking%20some%20of,as%20a%20single%20intraveno us%20infusion. [Accessed 20 May 2021]. 41 Chaganti S, Illidge T, Barrington S, McKay P, Linton K, Cwynarski K, et al. Guidelines for the management of diffuse large B-cell lymphoma. British Journal of Haematology. 2016;174(1):43-56. Available from: https://doi.org/https://doi.org/10.1111/bjh.14136. 42 Tilly H, Gomes da Silva M, Vitolo U, Jack A, Meignan M, Lopez-Guillermo A, et al. Diffuse large B-cell lymphoma (DLBCL): ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Annals of Oncology. 2015;26:v116-v25. Available from: https://doi.org/10.1093/annonc/mdv304. 43 West Midlands Clinical Networks and Clinical Senate (NHS England). Clinical Guidelines for the Management of Breast Cancer. 2016. Available from: https://www.england.nhs.uk/mids- east/wp-content/uploads/sites/7/2018/02/guidelines-for-the-management-of-breast-cancer- v1.pdf [Accessed 28 May 2021].

NB: 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.