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.

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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.

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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. The clinical effectiveness and cost effectiveness of rituximab for follicular lymphoma (TA37). March 2002. • NICE clinical guidelines. Non-Hodgkin's lymphoma. Expected date of issue July 2016.

Other Guidance

• European Society for Medical Oncology. Newly diagnosed and relapsed follicular lymphoma: ESMO Clinical Practice Guidelines. September 20149. • American Cancer Society. Non-Hodgkin lymphoma. August 201410. • European Society for Medical Oncology. ESMO Consensus Guidelines: Diffuse large B- cell lymphoma (DLBCL), follicular lymphoma (FL) and chronic lymphocytic leukemia (CLL). 201311. • Anglia Cancer Network Lymphoma Subgroup. Guidelines for the management of Hodgkin’s and non-Hodgkin’s lymphoma. April 201012. • NICE Clinical Knowledge Summary. Haematological malignancy - suspected. June 200913.

CURRENT TREATMENT OPTIONS

Indolent NHLs are progressive diseases that are characterised by a relapsing and remitting clinical course4; they are highly responsive to standard chemotherapy but remain incurable4,9. Median survival has improved over the last decade with 20 year survival reported as high as 44%4. However, advanced stages become increasingly resistant to

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chemotherapy and transfer to high-grade or aggressive lymphomas, such as diffuse large B- cell lymphoma4.

The main aim of treatment is to increase life expectancy and increase quality of life4. Treatment should commence when patients become symptomatic4,5,9. Clinical trials have not found any improvements in disease specific survival or overall survival when early treatment is initiated in asymptomatic patients9. Current treatment involves chemotherapy in combination with rituximab, an anti-CD20 monoclonal antibody4,5. Chemotherapy options include chlorambucil, fludarabine, bendamustine, R-CVP (rituximab, cyclophosphamide, vincristine and prednisolone) and R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone)5. First line therapy involves R-CVP for around two thirds of patients, while 16% receive R-CHOP4. Those with a lower performance status may be offered chlorambucil as single agent chemotherapy4. NICE recommends rituximab for the first line maintenance treatment of follicular NHL after rituximab and chemotherapy4. Treatment for relapsed disease depends on first line treatment used, the duration of response and whether the disease has transformed to aggressive lymphoma4.

Other treatment options that are used occasionally include 90Y-ibritumomab (ibritumomab tiuxetan)5. Some patients may also be offered radiotherapy5. For patients at low risk or with contraindications to more intensive chemoimmunotherapy, antibody monotherapy (rituximab alone or radioimmunotherapy), or chlorambucil plus rituximab are alternative approaches9.

EFFICACY and SAFETY

Trial GALLIUM, NCT01332968, BO21223; GAUDI, NCT00825149, BO21000, 2008- obinutuzumab vs rituximab, both in 001643-19; obinutuzumab in combination combination with chemotherapy, followed with chemotherapy; phase I. by maintenance with obinutuzumab or rituximab; phase III. Sponsor Roche Products Ltd. Roche Products Ltd. Status Ongoing. Ongoing. Source of Trial registry14 and manufacturer. Poster15 and trial registry16. information Location EU (incl. UK), USA, Canada and other EU (incl. UK) and Australia. countries. Design Randomised, active-controlled. Randomised, open-label. Participants n=1,401 (planned); aged ≥18 years; n=137; aged ≥18 years; CD20+ relapsed CD20+ indolent B-cell NHL (follicular or refractory B-cell NHL (max 2 prior lymphoma or splenic, nodal or extranodal chemotherapy regimens) or CD20+ B-cell marginal zone lymphoma); stage III or IV follicular lymphoma with no prior systemic or stage II bulky disease (defined as therapy; ECOG performance status 0-2; tumour diameter ≥7cm); follicular no prior administration of rituximab within lymphoma patients requiring treatment or 8 weeks of study entry or 3 months for symptomatic marginal zone lymphoma any radioimmunotherapy. that is de novo or relapsed following surgery or radiotherapy; Eastern Cooperative Oncology Group (ECOG) performance status 0-2. Schedule Patients randomised to: Randomised to: Arm 1: rituximab 375mg/m2 IV on day 1 of Arm 1: CHOP as prescribed for 8x3 week cycles 1-8 (21-day cycles) or cycles 1-6 cycles; obinutuzumab 400mg IV on days (28-day cycles); followed by 375mg/m2 IV 1 and 8 of first cycle, and on day 1 of every 2 months in responders until each subsequent cycle. disease progression for up to 2 years. Arm 2: fludarabine and

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Arm 2: obinutuzumab 1,000mg IV on cyclophosphamide (FC) as prescribed for days 1, 8 and 15 of cycle 1 and on day 1 6x4 week cycles; obinutuzumab 400mg of cycles 2-8 (21-day cycles) or cycles 2- IV on days 1 and 8 of first cycle, and on 6 (28-day cycles); followed by 1,000mg IV day 1 of each subsequent cycle. every 2 months in responders until disease progression, for up to 2 years. Arm 3: CHOP as prescribed for 8x3 week cycles; obinutuzumab 1,600mg IV on Both administered with background days 1 and 8 of first cycle, followed by chemotherapy: CHOP (6 cycles of 21- 800mg IV on day 1 of each subsequent days), CVP (8 cycles of 21 days), or cycle. bendamustine (6 cycles of 28-days). For patients with follicular lymphoma – Arm 4: FC as prescribed for 6x4 week chemotherapy selected by each study cycles; obinutuzumab 1,600mg IV on site. For patients with non-follicular days 1 and 8 of first cycle, followed by lymphoma – chemotherapy selected by 800mg IV on day 1 of each subsequent the site individually for each patient. cycle.

Arm 5: CHOP as prescribed for 8x3 week cycles; obinutuzumab 1,000mg IV on days 1 and 8 of first cycle, and on day 1 of each subsequent cycle.

Arm 6: bendamustine as prescribed for 6x4 week cycles; obinutuzumab 1,000mg IV on days 1 and 8 of first cycle, and on day 1 of each subsequent cycle.

Patients with complete response or partial response after completion of 1st line obinutuzumab in combination with chemotherapy may receive maintenance treatment with obinutuzumab every 3 months for 2 years or until disease progression. Follow-up Active treatment up to 2.5 years. Follow- Primary outcomes and progression-and up to 7.5 years; overall survival (OS) event-free survival followed up to 6 years. followed up to 10.7 years. Other secondary outcomes followed for up to 27 months. Primary Progression-free survival (PFS) in Safety: incidence of adverse events outcome/s patients with follicular lymphoma, (AEs). investigator assessed according to the Revised Response Criteria for Malignant Lymphoma. Secondary PFS (investigator and independent ORR assessed according to criteria for outcome/s review committee assessed), OS, overall evaluation of response in NHL; complete response rate (ORR) and complete response rate assessed according to the response rate (both responses assessed criteria for evaluation of response in NHL; by investigator and independent review progression-and event-free survival; committee), disease free survival, event pharmacokinetics; pharmacodynamics: free survival, duration of response, time peripheral blood B-cell depletion and to next anti-lymphoma treatment, safety, recovery. medical resource utilisation, patient reported outcomes (Functional assessment of Cancer Therapy for Lymphoma scale and EuroQol EQ questionnaire). Key results - 17/72 patients (24%) discontinued treatment, due to an AE/inter-current illness (n=9), insufficient therapeutic

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response (n-5), administrative/other reason (n=2) or death (n=1). At the end of maintenance, all pts with available data (obinutuzumab-bendustine [O-B], n=41; O-CHOP, n=39) had experienced B-cell depletion (<0.07x109 cells/L). At data cut- off, 22 pts (28%) had a B-cell assessment within 6-9 months of follow up after the end of the maintenance treatment; all remained B-cell depleted. But 6/12 pts (O-B, n=2; O-CHOP, n=4) had recovered by 9-24 months post maintenance treatment (>0.07x109 cells/L). Median IgG remained normal during maintenance. Complete response (CR) rate as best overall response increased from end of induction (O-B: 37%; O-CHOP: 35%) to end of maintenance (O-B: 61%; O-CHOP: 70%). PFS at 32 months was 92% (O-B) and 84% (O-CHOP). Median PFS was not reached; 10 pts (O-B: n=4; O-CHOP: n=6) had progressive disease, including one transformation to diffuse large B-cell lymphoma. Adverse - Most patients had AEs: O-B, 100% (44% effects (AEs) grade ≥3) and O-CHOP, 78% (31% grade ≥3). The most common AE was cough (O-B 17%; O-CHOP 11%). Grade ≥3 AEs were mainly infections and cytopenias. 6 O-B pts (17%) experienced 7 grade ≥3 infections; 4 were treatment related (genital infection, oral herpes, Klebsiella pneumonia, neutropenic infection). 5 O- CHOP pts (14%) had one grade ≥3 infection each; 4 were considered treatment related (viral meningitis, respiratory tract infection [RTI], bacterial pneumonia). 6 O-B pts (17%) experienced 10 grade ≥3 cytopenic AEs; 7 were considered treatment related (anaemia, febrile neutropenia, pancytopenia, neutropenia, thrombocytopenia). No O-CHOP pt experienced grade ≥3 cytopenic AE. 3 pts (O-B, n=1; O-CHOP, n=2) had treatment related AEs during or within 24 hours of infusion (all grade 1-2). 2 deaths (both O- CHOP) occurred during maintenance or maintenance follow up; 1 due to O- related AE (RTI leading to fatal lactic acidosis). Expected Study completion date reported as Mar Study completion date reported as Oct reporting 2017. 2015. date

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ESTIMATED COST and IMPACT

COST

Obinutuzumab is already marketed in the UK for CLL; a 40mg vial (25mg/mL) costs £3,312. A 50mL vial (10mg/mL) of rituximab costs £873.1517.

IMPACT - SPECULATIVE

Impact on Patients and Carers

 Reduced mortality/increased length of  Reduced symptoms or disability survival: expert opinion notes that there is data to suggest obinutuzumab has a therapeutic advantage but is also associated with increased toxicityb.

 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: frequency of  Other reduction in costs: outpatient attendance; likely increase in inpatient care for side effects (greater number of infections requiring inpatient care)b.

 Other:  None identified

Other Issues

 Clinical uncertainty or other research question  None identified identified: use of obinutuzumab dependent on the outcomes of GALLIUM study: if it shows an advantage over rituximab then it is likely to become the dominant antibody therapy in follicular lymphoma. If the study shows an advantage, the majority, though not all, patients receiving rituximab will move to obinutuzumab.

However, it is more toxic and there may emerge additional criteria regarding which patients will most benefit and those most at risk - there is likely to be a residuum of patients who will continue to receive rituximab. It is also more difficult to administer. It causes more infusion problems and is given at a greater dose and frequency than b Expert personal communication.

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rituximab with a cost and capacity consequence for outpatient careb.

REFERENCES

1 Morschhauser F, Cartron G, Thieblemont C et al. Encouraging activity of Obinutuzumab (GA101) monotherapy in relapsed/refractory aggressive non-Hodgkin's lymphoma: Results from a phase II study (BO20999). Blood (ASH Annual Meeting Abstract) 2011;118(21):3655. 2 electronic Medicines Compendium. Gazyvaro 1,000mg concentrate for solution for infusion. http://www.medicines.org.uk/emc/medicine/29057 Accessed 3 June 2015. 3 Merli M, Ferrario A, Basilico C et al. Novel agents in indolent lymphomas. Therapeutic Advances in Hematology 2013;4(2):133-148. 4 National Institute of Health and Clinical Excellence. Rituximab for the first-line treatment of stage III-IV follicular lymphoma: (review of NICE technology appraisal guidance 110). Technology appraisal TA243. London: NICE; January 2012. 5 Macmillan. Follicular Lymphoma. http://www.macmillan.org.uk/information-and- support/lymphoma/lymphoma-non-hodgkin/types-of-non-Hodgkin-lymphoma/follicular- lymphoma.html Accessed 9 June 2015. 6 Cancer Research UK. Non-Hodgkin lymphoma statistics. http://www.cancerresearchuk.org/health-professional/cancer-statistics/statistics-by-cancer- type/non-hodgkin-lymphoma#heading-Zero Accessed 5 June 2015. 7 Health and Social Care Information Centre. Hospital episode statistics, admitted patient care, England - 2013-14: Diagnosis. http://www.hscic.gov.uk 8 Office for National Statistics. Deaths registered in England and Wales (Series DR), 2013. http://www.ons.gov.uk 9 Dreyling M, Ghielmini M, Marcus R et al. Newly diagnosed and relapsed follicular lymphoma: ESMO Clinical Practice Guidelines. Annals of Oncology 2014;25(suppl 3):iii76-iii82. 10 American Cancer Society. Non-Hodgkin Lymphoma. http://www.cancer.org/acs/groups/cid/documents/webcontent/003126-pdf.pdf Accessed 10 June 2015. 11 Ghielmini M, Vitolo U, Kimby E et al. ESMO Consensus Guidelines: Diffuse large B-cell lymphoma (DLBCL), follicular lymphoma (FL) and chronic lymphocytic leukemia (CLL). Annals of Oncology 2013;24(3):561-576. 12 Bulusu R, Follows G, Crawley C et al. Guidelines for the management of Hodgkin’s and non- Hodgkin’s lymphoma. Anglia: Anglia Cancer Network Lymphoma Subgroup; April 2010. 13 NICE Clinical Knowledge Summary. Haematological malignancy - suspected. London: NICE; June 2009 14 ClinicalTrials.gov. A study of Obinutuzumab (RO5072759) plus chemotherapy in comparison with MabThera/Rituxan (Rituximab) plus chemotherapy followed by GA101 or MabThera/Rituxan maintenance in patients with untreated advanced indolent non-Hodgkin's lymphoma (GALLIUM). https://clinicaltrials.gov/ct2/show/study/NCT01332968?term=nct01332968&rank=1#locn Accessed 5 June 2015. 15 Dyer MJS, Grigg AP, Diaz MG et al. Obinutuzumab (GA101) in combination with CHOP (cyclophosphamide, doxorubicin, vincristine and prednisone) or Bendamustine for the first-line treatment of follicular non-Hodgkin lymphoma: final results from the maintenance phase of the phase Ib GAUDI study. 56th ASH Annual Meeting and Exposition. December 2014. Abstract Number 1743. Poster. 16 ClinicalTrials.gov. A study of RO5072759 in combination with chemotherapy in patients with CD20+ B-cell follicular non-Hodgkin's lymphoma (GAUDI). https://www.clinicaltrials.gov/ct2/show/study/NCT00825149#locn Accessed 25 June 2015. 17 Joint Formulary Committee. British National Formulary. BNF July 2015. BMJ Group and pharmaceutical Press. www.medicinescomplete.com

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