June 2016 Horizon Scanning Research & Intelligence Centre Pembrolizumab for relapsed or refractory classical Hodgkin lymphoma – third and fourth line LAY SUMMARY 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 Classical Hodgkin lymphoma is a cancer of the lymphatic system, which is part of the immune system In Hodgkin lymphoma, blood cells called lymphocytes become abnormal and collect in lymph nodes (glands) and other organs The most common symptom of Hodgkin lymphoma is enlarged lymph nodes in the neck Pembrolizumab is a new drug for the treatment of classical Hodgkin lymphoma, which is given via a drip directly into the blood every weeks Some studies have suggested pembrolizumab may be helpful in people whose previous treatments have not worked If pembrolizumab is licensed for use in the UK, it could be a new treatment option for patients with classical Hodgkin lymphoma that may reduce symptoms of the disease and improve survival when other treatments have not worked NIHR HSRIC ID: 10837 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 Research & Intelligence Centre, University of Birmingham Email: nihrhsric@contacts.bham.ac.uk Web: www.hsric.nihr.ac.uk Horizon Scanning Research & Intelligence Centre TARGET GROUP • Hodgkin lymphoma: classical; relapsed/refractory – third and fourth line TECHNOLOGY DESCRIPTION Pembrolizumab (Keytruda; MK-3475; SCH-900475) is a humanised monoclonal IgG4 antibody, with a stabilising sequence alteration in the Fc region that targets the programmed death-1 (PD-1) protein The PD-1 receptor is a negative regulator of T-cell activity that is involved in the control of T-cell immune responses Pembrolizumab selectively blocks the interactions of PD-1 with both the PD-L1 and PD-L2 ligands of the PD-1 protein, and potentiates T-cell responses enabling the activation of anti-tumour responses and cancer specific T-cells In clinical trials, pembrolizumab is administered by intravenous (IV) infusion at 200mg on day of each 21-day cycle for up to 24 months Pembrolizumab is currently licensed in the EU for use as a monotherapy for the treatment of advanced (unresectable or metastatic) melanoma in adults The most common adverse reactions with pembrolizumab are diarrhoea, nausea, pruritus, rash, arthralgia, and fatigue; most of which are mild to moderate in severity2 Pembrolizumab is in phase III clinical trials for: • Non-small cell lung cancer • Head and neck cancer • Renal cancer • Bladder cancer • Gastrointestinal and stomach cancer • Oesophageal cancer • Urethral cancer • Colorectal cancer Pembrolizumab is also in phase II clinical trials for: • B-cell Lymphoma • Breast cancer • Endometrial cancer • Ovarian cancer INNOVATION and/or ADVANTAGES If licensed, pembrolizumab will offer an additional treatment option for patients with relapsed or refractory classical Hodgkin lymphoma DEVELOPER Merck Sharp and Dohme Corp AVAILABILITY, LAUNCH OR MARKETING In phase II clinical trials Horizon Scanning Research & Intelligence Centre PATIENT GROUP BACKGROUND There are two main types of lymphoma: Hodgkin lymphoma and non-Hodgkin lymphoma Approximately in of all lymphomas diagnosed are Hodgkin lymphoma Hodgkin lymphoma is a heterogeneous group of malignant lymphoid neoplasms of B-cell origin characterised histologically by the presence of Hodgkin and Reed-Sternberg cells in the vast majority of cases 4,5 The World Health Organization (WHO) puts Hodgkin lymphoma into main groups: classical types (95% of Hodgkin cases) and nodular lymphocyte predominant type (5%)3 There are types of classical Hodgkin lymphoma: nodular sclerosing lymphoma, which accounts for 60% of classical Hodgkin lymphomas, mixed cellularity accounting for 15%, lymphocyte rich which accounts for 20% of cases, and lymphocyte depleted lymphomas which are very rare3 The most common sites of origin for classical Hodgkin lymphoma are the lymph nodes of the neck, axilla, chest and groin3 Hodgkin lymphoma can also occur in body organs; at diagnosis just over in 10 patients have lymphoma in the liver, bone or lung and in patients have lymphoma in their spleen3 The most common sign of Hodgkin lymphoma is enlarged lymph nodes in the neck3; general symptoms experienced by 25% of patients, include high temperatures, weight loss, itching, coughing, abdominal pain and night sweats3 The bone marrow is affected in 5% of patients with Hodgkin lymphoma3 NHS or GOVERNMENT PRIORITY AREA This topic is relevant to: • Improving Outcomes: A Strategy for Cancer (2011) • NHS Commissioning Board January 2015 Clinical Commissioning Policy: Haematopoietic Stem Cell Transplantation (HSCT) (All Ages): NHSCB/B04/P/a • 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 Haematopoietic Stem Cell Transplantation (Adult) B04/S/a CLINICAL NEED and BURDEN OF DISEASE In England, there were 1,631 cases of Hodgkin lymphoma (ICD-10 C81) recorded in 2013 Hodgkin lymphoma is most common in young adults followed by a second cohort of more elderly patients About 15-20% of patients relapse or not respond to first line therapy In 2013, 121 patients with Hodgkin lymphoma underwent autologous stem cell transplant in the UK With treatment, more than 80% of people with Hodgkin lymphoma will live for 10 or more years6 In 2014, in England and Wales, there were approximately 311 deaths from Hodgkin lymphoma (ICD-10 C81) and more than a third occurred in patients aged 75 and over 10 In 2014-15, there were 18,853 admissions for Hodgkin lymphoma (ICD-10 C81) in England, resulting in a total of 17,272 bed days and 19,556 finished consultant episodes 11 Horizon Scanning Research & Intelligence Centre PATIENT PATHWAY RELEVANT GUIDANCE NICE Guidance • NICE technology appraisal in development Lymphoma (Hodgkin's, CD30-positive) brentuximab vedotin (ID722) Expected January 2017 • NICE technology appraisal Pembrolizumab for advanced melanoma not previously treated with ipilimumab (TA366) November 2015 • NICE technology appraisal Pembrolizumab for treating advanced melanoma after disease progression with ipilimumab (TA357) October 2015 • NICE Guidance on Cancer Services: Improving Outcomes in Haematological Cancers; The Manual 2003 Other Guidance • British Committee for Standards in Haematology Guidelines for the first line management of classical Hodgkin lymphoma 2014 12 • European Society for Medical Oncology Hodgkin’s lymphoma: ESMO clinical practice guidelines for diagnosis, treatment and follow-up 2014 13 • British Committee for Standards in Haematology Guidelines for the management of primary resistant and relapsed classical Hodgkin lymphoma 2013 14 CURRENT TREATMENT OPTIONS The treatment of Hodgkin lymphoma depends upon the disease stage, other symptoms, the size of affected lymph nodes and disease spread, and the patient’s age and general health3,12 Guidelines recommend the use of a combination of chemotherapy and radiotherapy for the first line treatment of early and advanced stage Hodgkin lymphoma14 This may include: • ABVD chemotherapy (doxorubicin, bleomycin, vinblastine, dacarbazine) with 20Gy radiotherapy • BEACOPP chemotherapy (bleomycin, etoposide, doxorubicin, clyclophosphamide, vincristine, procarbazine, prednisone) with ABVD and 20Gy radiotherapy For patients who not respond to treatment and/or relapse, high-dose chemotherapy followed by autologous stem cell transplant (ASCT) is a frequently used therapy option8 A clinical expert stated the choice of therapy is dependent on age, stage and co-morbidities ABVD is the most commonly used first line regimen followed by BEACOPP a Some elderly patients may be treated with ChlVPP (chlorambucil, vinblastine, procarbazine, prednisolone) or VEPEM-B (vinblastine, cyclophosphamide, procarbazine, etoposide, mitoxantrone, bleomycin, prednisolone)a Second line treatment in transplant eligible patients consists of a platinum based regimen (e.g ESHAP [etoposide, methylprednisolone, cytarabine, cisplatin] or Gem-P [gemcitabine, cisplatin, methylprednisolone]) followed by autologous stem cell transplantation Brentuximab is currently available through the cancer drugs fund for 3rd line treatment of transplant ineligible patients and those who fail autologous stem cell transplanta Radiotherapy is an option in some cases of limited stage disease Patients failing to achieve a Expert personal communication Horizon Scanning Research & Intelligence Centre an adequate response with these regimens (~15%) have a very poor outcome with no effective treatment optionsa EFFICACY and SAFETY Trial Sponsor Status Source of information Location Design Participants Schedule Follow-up Primary outcomes Secondary outcomes Key results Adverse effects (AEs) Expected reporting date NCT02453594, 3475-087, EudraCT 2014-004482-4, 153005; MK-3475; phase II MSD Ongoing 15 Abstract , trial registry , manufacturer EU (incl UK), USA, Canada and other countries Non-randomised, uncontrolled n=180 (planned); aged 18 years and older; relapsed or refractory de novo classical Hodgkin lymphoma; failed to achieve a response to, progressed after, or be ineligible for ASCT; failed to achieve a response to or progressed after treatment with brentuximab vedotin or brentuximab vedotin naïve; Eastern Cooperative Oncology Group (ECOG) performace status or 1; no immunosuppression or immunosuppressive therapy within days prior to day 1; no prior monoclonal antibody, chemotherapy or targeted small molecular therapy within wks of day 1; no radiation therapy within wks to study day 1; no prior ASCT transplantation; no additional malignancy Participants receive pembrolizumab 200mg IV on day of each 21-day treatment cycle Active treatment for up to 24 mths Safety follow-up 30 days after last dose of study drug Follow-up until death, withdrawal of consent, or the end of the study, whichever occurs first Overall response rate (ORR); safety Complete remission rate; duration of response; progression free survival; overall survival; changes in health-related quality of life Interim results, at time of data cut-off (1 Feb, 2016): 60 pts were evaluable for cohorts (after ASCT and subsequent brentuximab vedotin therapy) and (ineligible for ASCT due to chemo-resistance and BV therapy failure); ORR among 30 pts in cohort is 70% (95% CI, 51-85), CR (complete response) (residual mass permitted if PET negative) achieved in pts (20%), PR (partial response) 15 (50%), and (20%) stable disease as best response; ORR among 30 pts in cohort is 80% (95% CI, 61-92); CR achieved in pts (27%), PR 16 (53%), and stable disease as best response (13%) With a median of treatment cycles, most common treatment-related AEs in the combined cohorts are pyrexia (13%), diarrhoea (8%), fatigue, back pain, platelet count decrease, dry skin, and cough (7% each) The estimated primary completion date is reported as June 2016 ESTIMATED COST and IMPACT COST Pembrolizumab is already marketed in the UK for the treatment of melanoma; a 50mg vial costs £1,315 16 The cost per treatment cycle would be £5,260 Horizon Scanning Research & Intelligence Centre 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: uncertain unit cost compared to existing treatments None identified Other Issues Clinical uncertainty or other research question identified: An expert states that the amplification of chromosome 9p24.1, which includes the genes encoding PDL1 and PDL2, is frequent in classical Hodgkin lymphoma making it a disease that may be particularly 17,b susceptible to PD1 blockade The recognition and management of side-effects associated with PD1 inhibitors is an area that requires education and research Although there are a few review articles and guidelines now discussing this, some hospitals form their own guidelines Other areas that require more work are predictive biomarkers and the frequency and modalities for response assessment of patients on these inhibitors, recognising that delayed responses are not b uncommon None identified REFERENCES ClinicalTrials.gov Study of pembrolizumab (MK-3475) in participants with relapsed or refractory classical Hodgkin lymphoma (MK-3475/KEYNOTE-087) https://clinicaltrials.gov/ct2/show/NCT02453594 Accessed 10 May 2016 electronic Medicines Compendium (eMC) Keytruda 50mg powder concentrate for solution for infusion http://www.medicines.org.uk/emc/medicine/30602 Accessed 10 May 2016 Cancer Research UK Hodgkin Lymphoma http://www.cancerresearchuk.org/aboutcancer/type/hodgkins-lymphoma Accessed 10 May 2016 Orpha.net Hodgkin Lymphoma (ORPHA98293) http://www.orpha.net/consor/cgibin/OC_Exp.php?lng=en&Expert=98293 Accessed 10 May 2016 b Expert personal communication Horizon Scanning Research & Intelligence Centre 10 11 12 13 14 15 16 17 Macmillan Cancer Support What is Hodgkin Lymphoma? www.macmillan.org.uk/information-andsupport/lymphoma/lymphoma-hodgkin/understanding-cancer/what-is-hodgkin-lymphoma.html Accessed 10 May 2016 Office for National Statistics Cancer Registration Statistics, England, 2013 www.ons.gov.uk Cancer Research UK Hodgkin lymphoma statistics www.cancerresearchuk.org/healthprofessional/cancer-statistics/statistics-by-cancer-type/hodgkin-lymphoma#heading-Zero Accessed 10 May 2016 Rancea M, Monsef I, Von Tresckow B et al High-dose chemotherapy followed by autologous stem cell transplantation for patients with relapsed/refractory Hodgkin lymphoma Critical Reviews in Oncology Haematology 2014;91(1):1-10 British Society of Blood and Marrow Transplantation 2013 Activity www.bsbmt.org/2013-activity/ Accessed 10 May 2016 Office for National Statistics Deaths registered in England and Wales (series DR), 2014 www.ons.gov.uk Health & Social Care Information Centre Hospital episode statistics for England Inpatient statistics, 2014-15 www.hscic.gov.uk/hes Follows AG, Ardeshna KM, Barrington SF et al Guidelines for the first line management of classical Hodgkin lymphoma British Journal of Haematology 2014;166:34-49 Eichenauer DA, Engert A and Andre M Hodgkin’s lymphoma: ESMO clinical practice guidelines for diagnosis, treatment and follow-up Annals of Oncology 2014; 23(3):ii7-ii75 Collins GP, Parker AN, Pocock C et al Guidelines on the management of primary resistant and relapsed classical Hodgkin lymphoma British Journal of Haematology 2013;164:39-52 Chen RW, Zinzani PL, Fanale MA et al Pembrolizumab for relapse/refractory classical Hodgkin lymphoma (R/R cHL): phase KEYNOTE-087 study Journal of clinical Oncology 2016; 34, supplement abstract 7555 Joint Formulary Committee British National Formulary BNF June 2016 BMJ Group and Pharmaceutical Press www.medicinescomplete.com Green MR, Monti S, Rodig SJ, et al Integrative analysis reveals selective 9p24.1 amplification, increased PD-1 ligand expression, and further induction via JAK2 in nodular sclerosing Hodgkin lymphoma and primary mediastinal large B-cell lymphoma Blood 2010;116:3268-3277 ... types of lymphoma: Hodgkin lymphoma and non- Hodgkin lymphoma Approximately in of all lymphomas diagnosed are Hodgkin lymphoma Hodgkin lymphoma is a heterogeneous group of malignant lymphoid neoplasms... types of classical Hodgkin lymphoma: nodular sclerosing lymphoma, which accounts for 60% of classical Hodgkin lymphomas, mixed cellularity accounting for 15%, lymphocyte rich which accounts for 20%... Support What is Hodgkin Lymphoma? www.macmillan.org.uk/information-andsupport /lymphoma/ lymphoma -hodgkin/ understanding-cancer/what-is -hodgkin- lymphoma. html Accessed 10 May 2016 Office for National