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Obinutuzumab (Gazyvaro) for Indolent Non-Hodgkin Lymphoma – First Line, in Combination with Chemotherapy

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Obinutuzumab (Gazyvaro) for Indolent Non-Hodgkin Lymphoma – First Line, in Combination with Chemotherapy Horizon Scanning Research July 2015 & Intelligence Centre Obinutuzumab (Gazyvaro) for indolent non-Hodgkin lymphoma – first line, in combination with chemotherapy SUMMARY NIHR HSRIC ID: 6813 Obinutuzumab is a humanised and glyco-engineered, type II anti-CD20 monoclonal antibody for the treatment of B-cell malignancies such as This briefing is indolent non-Hodgkin lymphoma (NHL). Such antibodies act by increasing antibody-dependent cellular cytotoxicity, which increases immune-mediated based on target cell death. However, as obinutuzumab specifically targets a CD20 type information II epitope to enhance direct cell death induction, it has lower complement- available at the time dependent cytotoxicity compared with existing type I anti-CD20 antibodies, of research and a such as rituximab and ofatumumab. limited literature search. It is not Indolent NHLs include follicular lymphomas, lymphoplasmacytic intended to be a lymphoma/Waldenstrom macroglobulinemia, small lymphocytic lymphoma definitive statement and marginal zone lymphoma. NHL is the 6th most common cancer in the UK on the safety, with around 12,800 new cases diagnosed annually (2011). For England, the efficacy or crude incidence of NHL was 20.3 per 100,000 population in 2011; the effectiveness of the incidence for follicular lymphoma was 3.4 per 100,000 in England and Wales health technology in 2008. In 2013-14, there were 22,015 admissions for follicular lymphoma in covered and should England, resulting in 14,046 bed days and 22,551 finished consultant not be used for episodes. In 2013, there were 4,151 deaths registered from NHL in England commercial and Wales, of which197 were from follicular lymphoma. purposes or commissioning Indolent NHLs are progressive diseases that are characterised by a without additional relapsing and remitting clinical course; they are highly responsive to standard information. chemotherapy but remain incurable. The main aim of treatment is to increase life expectancy and increase quality of life. Treatment should commence when patients become symptomatic. Current treatment involves chemotherapy in combination with rituximab. Chemotherapy options include chlorambucil, fludarabine, bendamustine, R-CVP (rituximab, cyclophosphamide, vincristine and prednisolone) and R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, prednisolone). Currently, obinutuzumab is in one phase III study comparing its effects on progression free survival against treatment with rituximab (both with chemotherapy). This trial is expected to complete in March 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 Research & Intelligence Centre, University of Birmingham. Email: [email protected] Web: www.hsric.nihr.ac.uk Horizon Scanning Research & Intelligence Centre TARGET GROUP • Non-Hodgkin lymphoma: stage III-IV; indolent – first line; in combination with chemotherapy. TECHNOLOGY DESCRIPTION Obinutuzumab (Gazyvaro; afutuzumab; GA 101; Gazyva; RO5072759; RG 7159) is a humanised and glyco-engineered, type II anti-CD20 monoclonal antibody for the treatment of B-cell malignancies such as indolent non-Hodgkin lymphoma (NHL). Such antibodies act by increasing antibody-dependent cellular cytotoxicity, which increases immune-mediated target cell death. However, as obinutuzumab specifically targets a CD20 type II epitope to enhance direct cell death induction, it has lower complement-dependent cytotoxicity compared with existing type I anti-CD20 antibodies, such as rituximab and ofatumumab1. Obinutuzumab is administered by intravenous (IV) infusion at 1,000mg on days 1, 8 and 15 of cycle 1 and on day 1 of cycles 2-8 (21-day cycles) or cycles 2-6 (28-day cycles), followed by 1,000mg IV every 2 months in responders until disease progression for up to 2 years. Obinutuzumab is intended to be used in combination with chemotherapy. Obinutuzumab is licensed in the EU for the treatment of previously untreated chronic lymphocytic leukaemia (CLL) in adult patients with comorbidities that make them unsuitable for full-dose fludarabine based therapy. Very common (>10%) adverse reactions reported include neutropenia, thrombocytopenia, anaemia, diarrhoea, pyrexia and infusion related reactions. Common reactions (≥1% to <10%) reported included urinary tract infection, nasopharyngitis, oral herpes, rhinitis, pharyngitis, squamous cell carcinoma of skin, leukopenia, tumour lysis syndrome, hyperuricaemia, atrial fibrillation, hypertension, cough, constipation, alopecia, arthralgia, back pain, musculoskeletal chest pain, decreased white blood cell count, decreased neutrophil count, and weight increase2. Obinutuzumab is also currently in phase III clinical trials for diffuse large B cell lymphoma. INNOVATION and/or ADVANTAGES If licensed, obinutuzumab will offer an additional treatment option for patients with indolent NHL. DEVELOPER Roche Product Ltd. AVAILABILITY, LAUNCH OR MARKETING Obinutuzumab is a designated orphan drug in the EU and USA. Obinutuzumab is in phase III clinical trials. 2 Horizon Scanning Research & Intelligence Centre PATIENT GROUP BACKGROUND Indolent NHLs include follicular lymphomas, lymphoplasmacytic lymphoma/Waldenstrom macroglobulinemia, small lymphocytic lymphoma and marginal zone lymphoma, which itself consists of splenic marginal zone lymphoma (SMZL), primary nodal marginal zone lymphoma (NMZL) and marginal zone lymphoma of mucosa associated lymphoid tissue (MALT)3. Follicular lymphoma is the second most common subtype of NHL, followed by MALT3. Other subtypes of indolent NHL are rare and referred to as indolent non-follicular lymphoma3. Indolent NHL are slow growing, low-grade histological subtypes which may go undetected for many years3,4. Follicular lymphoma can be classified into four stages (I-IV) using the Ann Arbor staging system6 (along with FLIPI – the Follicular Lymphoma International Prognostic Index)a, which reflects both the number of sites involved and the presence of disease above or below the diaphragm4. Only about 10-15% of follicular lymphomas are detected at an early stage; the vast majority are identified at advanced stages (III-IV)4. Typical symptoms of follicular lymphoma include painless, swollen lymph nodes in the neck, armpit or groin4. Systemic symptoms are rare, but may include fever, fatigue, night sweats, and unexplained weight loss4,5. NHS or GOVERNMENT PRIORITY AREA This topic is relevant to: • Improving Outcomes: A Strategy for Cancer (2011). • 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. • NHS England. Clinical Commissioning Policy: Haematopoietic Stem Cell Transplantation. NHSCB/B04/P/a. April 2013. • NHS England. Clinical Commissioning Policy: Haematopoietic Stem Cell Transplantation (HSCT) (All Ages): B04/P/a. Revised January 2015. • NHS England. Clinical Commissioning Policy: Use of Plerixafor for Stem Cell Mobilisation (Update). B04/P/b. January 2015. CLINICAL NEED and BURDEN OF DISEASE NHL is the 6th most common cancer in the UK with around 12,800 new cases diagnosed annually (2011)6. For England, the crude incidence of NHL was 20.3 per 100,000 population in 20116; the incidence for follicular lymphoma was 3.4 per 100,000 in England and Wales in 20084. Follicular lymphoma, which is the most common indolent NHL, makes up about 25% of newly diagnosed cases of NHL followed by MALT at 7%3. Follicular lymphoma is predominantly detected at stages III (22%) and IV (41%)6. For those diagnosed during 2004- 2011, the five year crude survival rates for stages III and IV follicular lymphoma in England were approximately 78% and 79%, respectively, for all ages6. a Expert personal communication. 3 Horizon Scanning Research & Intelligence Centre In 2013-14, there were 22,015 admissions for follicular lymphoma (ICD-10 C82) in England, resulting in 14,046 bed days and 22,551 finished consultant episodes7. In 2013, there were 4,151 deaths registered from NHL (ICD-10 C82-85) in England and Wales, 197 deaths of those were from follicular lymphoma (ICD-10 C82)8. PATIENT PATHWAY RELEVANT GUIDANCE NICE Guidance • NICE Technology Appraisal in development. Bendamustine in combination with rituximab for the first-line treatment of advanced indolent non-Hodgkin's lymphoma (ID434). Expected date of issue to be confirmed. • NICE technology appraisal. Obinutuzumab in combination with chlorambucil for untreated chronic lymphocytic leukaemia (TA343). June 2015. • NICE technology appraisal. Pixantrone monotherapy for treating multiply relapsed or refractory aggressive non-Hodgkin's B‐cell lymphoma (TA306). February 2014. • NICE technology appraisal. Rituximab for the first-line treatment of stage III-IV follicular lymphoma (TA243). January 2012. • NICE technology appraisal. Rituximab for the first-line maintenance treatment of follicular non-Hodgkin's lymphoma (TA226). June 2011. • NICE technology appraisal. Rituximab for the treatment of relapsed or refractory stage III or IV follicular non-Hodgkin's lymphoma: Review of technology appraisal guidance 37 (TA137). February 2008. • NICE technology appraisal. Rituximab for aggressive non-Hodgkin's lymphoma (TA65). September 2003. • NICE technology appraisal.
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