Horizon Scanning Research April 2016 & Intelligence Centre

Duvelisib for relapsed chronic lymphocytic leukaemia – second and subsequent line

LAY SUMMARY

Chronic lymphocytic leukaemia is a type of cancer which usually develops very slowly. In people with chronic lymphocytic leukaemia, the body makes too many white blood cells called lymphocytes. These This briefing is based on lymphocytes are abnormal and do not work properly so build up in the information lymph nodes (glands), spleen, bone marrow and blood. Many patients available at the time who have chronic lymphocytic leukaemia are diagnosed when having of research and a a routine blood test and if well, usually do not need to start treatment limited literature straight away. However, if the disease starts to cause symptoms, search. It is not treatment is then required. intended to be a definitive statement Duvelisib is a new type of drug for patients with chronic lymphocytic on the safety, leukaemia given as a tablet twice a day. Some studies have efficacy or suggested duvelisib may be helpful for people whose first treatment effectiveness of the has failed and whose disease has continued to spread. More studies health technology are now aiming to show how well it works and that it is safe to use. covered and should not be used for If duvelisib is licensed for use in the UK, it could be a new treatment commercial option for patients with chronic lymphocytic leukaemia that may reduce purposes or symptoms of the disease and increase survival. commissioning without additional information. NIHR HSRIC ID: 9609

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

• Chronic Lymphocytic Leukaemia (CLL): relapsed – second or subsequent line.

TECHNOLOGY

DESCRIPTION

Duvelisib (NK1197; IPI145) is a small-molecule, selective dual inhibitor of phosphatidylinositol 3 kinase (PI3K) δ and γ isoforms. The PI3K pathway promotes cell proliferation, growth, motility, metabolism and survival. The PI3Kδ/γ isoforms play an important role in immune-receptor signal transduction. Treating cancer cells with a PI3Kδ/γ inhibitor has been shown to block growth and induce cell death. Activity of PI3Kδ (p110δ) is needed for BCR-induced DNA synthesis and phosphorylation of Akt/protein kinase B, forkhead transcription factor/forkhead box O3a (FOXO3a), and p70 S6 kinase. PI3Kδ is also needed for interleukin 4-induced phosphorylation of Akt/PKB and FOXO3a and protection from apoptosis. As such, selective inhibition of PI3Kδ/γ may provide a treatment for various haematological malignancies. Early phase trials have suggested that duvelisib appears safe and has some activity in patients with relapsed CLL. In the phase III clinical trial, duvelisib is administered orally at 25mg twice daily for the first 21-day cycle, and then at 25mg twice daily for subsequent 28-day cycles, for up to 18 cycles1.

Duvelisib does not currently have Marketing Authorisation in the EU for any indication.

Duvelisib is also currently in phase III development for previously treated, indolent, non- Hodgkin lymphoma (as combination therapy with and rituximab). It is in phase II development for previously treated indolent non-Hodgkin lymphoma (as monotherapy), previously untreated follicular lymphoma (as combination therapy with rituximab or obinutuzumab), relapsed follicular lymphoma (monotherapy) and relapsed or refractory indolent non-Hodgkin lymphoma (as combination therapy with rituximab).

INNOVATION and/or ADVANTAGES

If licensed, duvelisib will offer an additional oral treatment option for patients with relapsed CLL.

DEVELOPER

AbbVie; in collaboration with Infinity.

AVAILABILITY, LAUNCH OR MARKETING

In phase III clinical trials.

PATIENT GROUP

BACKGROUND

CLL is a disease affecting the growth and development of B-lymphocytes2. Patients with CLL have abnormal B-cells in their blood as well as in lymph nodes at diagnosis3. The

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disease can also be characterised by abnormal lymphocyte morphology and the accumulation of resting malignant B-cells in the spleen and bone marrow4,5.

The progressive accumulation of monoclonal B-lymphocytes leads to leucocytosis, lymphadenopathy, hepatosplenomegaly, anaemia, thrombocytopenia, neutropenia, bone marrow failure, recurrent infections, and systemic symptoms (fatigue, weight loss, and night sweats)6,7. In contrast to most other leukaemias, patients with CLL are not necessarily treated at diagnosis, but rather after the development of symptomatic or progressive diseasea,6. Whilst around 40% of patients are asymptomatic at diagnosis, the majority will require treatment at some point and as no current treatment option is curative, most patients who are treated will eventually relapse8,9. Expert opinion also notes that in their experience around 50% of patients who have early stage disease at diagnosis eventually require treatment, but this is difficult to measure as early CLL can go undetecteda. An expert estimates that around 80% of patients are asymptomatic at diagnosisa.

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.

CLINICAL NEED and BURDEN OF DISEASE

CLL is the most common leukaemia in adults4, accounting for around 37% of all leukaemia diagnoses in the UK and 1% of all new cancer cases10. In 2013, 2,982 patients were newly diagnosed with CLL (ICD-10 C91.1) in England11. The risk of developing CLL increases progressively with age8, with around 60% of cases in 2013 diagnosed in people aged 70 and over11. Incidence in men is almost twice that of women8; in 2013, 1,884 males and 1,098 females were diagnosed with CLL in England11. Between 2008 and 2010, relative survival at five years for patients aged 15-64 years was estimated to be around 84%12. However, for patients aged 65 years and over relative survival at five years was approximately 62%12.

In 2014-15, there were 26,918 hospital admissions due to CLL (ICD-10 C91.1) in England, accounting for 27,712 finished consultant episodes and 14,415 bed days13. In 2014, there were 920 deaths from CLL registered in England and Wales14.

PATIENT PATHWAY

RELEVANT GUIDANCE

NICE Guidance

• NICE technology appraisal in development. Leukaemia (chronic lymphocytic) – ibrutinib [ID749]. Expected June 2016. • NICE technology appraisal in development. Leukaemia (chronic lymphocytic, relapsed) – ofatumumab (maintenance) [ID732]. Expected September 2016.

a Expert personal communication.

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• NICE technology appraisal. for previously treated chronic lymphocytic leukaemia (TA359). October 2015. • NICE technology appraisal. Obinutuzumab in combination with for untreated chronic lymphocytic leukaemia (TA343). June 2015. • NICE technology appraisal. Ofatumumab in combination with chlorambucil or bendamustine for untreated chronic lymphocytic leukaemia (TA344). June 2015. • NICE technology appraisal. Bendamustine for the first line treatment of chronic lymphocytic leukaemia (TA216). February 2011. • NICE technology appraisal. Ofatumumab for the treatment of chronic lymphocytic leukaemia refractory to and alemtuzumab (TA202). October 2010. • NICE technology appraisal. Rituximab for the treatment of relapsed or refractory chronic lymphocytic leukaemia (TA193). July 2010. • NICE technology appraisal. Rituximab for the first line treatment of chronic lymphocytic leukaemia (TA174). July 2009. • NICE technology appraisal. Fludarabine monotherapy for the first line treatment of chronic lymphocytic leukaemia (TA119). February 2007. • NICE technology appraisal. Guidance on the use of fludarabine for B-cell chronic lymphocytic leukaemia (TA29). September 2001.

Other Guidance

• British Committee for Standard in Haematology. Inerim statement from the BCSH CLL guidelines panel. 201515. • European Society for Medical Oncology. Chronic lymphocytic leukaemia: ESMO clinical practice guidelines for diagnosis, treatment and follow-up. 201516. • National Comprehensive Cancer Network. NCCN clinical practice guidelines in oncology – non-Hodgkin’s lymphoma. 201517. • British Committee for Standards in Haematology. Guidelines on the diagnosis, investigation and management of chronic lymphocytic leukaemia. 20125. • National Cancer Institute Working Group. Guidelines on the treatment of chronic lymphocytic leukaemia. 1996 (revised 2008)18.

CURRENT TREATMENT OPTIONS

Treatment strategies for CLL, as a disease of the elderly, are highly individualised7. Factors influencing the choice of treatment include an assessment of fitness to tolerate chemotherapy and/or immunotherapy, co-morbidities, TP53 status, previous or current immune cytopenias, and evidence of lymphomatous transformation5. Guidelines recommend the use of chemoimmunotherapy with FCR (fludarabine, and rituximab) for the first line treatment of physically fit patients with CLL5,16, provided that their disease does not exhibit a TP53 deletionb.

In frailer patients and those with relevant co-morbidity, standard first line therapy includes alkylating agents such as chlorambucil (especially for very frail patientsb, in combination with ofatumumab or obintuzumab15) and bendamustine (as monotherapy or ideally in combination with a monoclonal antibody, typically rituximab or obinutuzumab with chlorambucil), and purine analog-based therapies, such as PCR (, cyclophosphamide and rituximab)5. Expert opinion notes that PCR is now rarely used in the UK and would be viewed as a fairly intensive treatmentb.

b Expert personal communication.

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For patients who do not respond to treatment or relapse within 18 months, therapy options have typically included the use of immunotherapy drugs, such as alemtuzumab (with or without corticosteroids)b,19. Expert opinion states that B-cell receptor antagonist drugs, namely ibrutinib and idelalisib, have become standard agents in the relapsed setting and have shown improved outcomes compared to conventional agents in relapsed/refractory patients with CLL, as well as being well toleratedb. Idelalisib is used in combination with rituximab in patients who have relapsed within 24 months of first line therapy. Ibrutinib is also often used for patients for whom treatment or retreatment with purin analog-based therapy is not appropriate20.

Patients who relapse within the first year or whose disease is associated with a TP53 abnormality have very high-risk disease. The recommended treatment approach for patients in this category is either idelalisib (in combination with rituximab) or ibrutinib15, or if this is not available, high-dose corticosteroid and alemtuzumab followed by an allogeneic stem cell transplant19. Idelalisib and ibrutinib show efficacy in patients with TP53 abnormalities although do not completely overcome their poorer prognosisb. The majority of patients who relapse after 2-3 years without a TP53 abnormality will usually respond again to their initial therapy, such as with FCR or bendamusine with rituximab or chlorambucil with obinutuzumabb,19,21. Additional options for patients with relapsed or refractory CLL/SLL include ofatumumab (with chlorambucil or bendamustine), and rituximab with lenalidomideb,22,23. Expert opinion states that ofatumumab and bendamustine are no longer routinely available for the treatment of this indicationb.

Expert opinion notes that in order to try to reduce the frequency and severity of infections, a minority of patients with predominantly advanced stage CLL are given regular intravenous immunoglobulin therapyb.

EFFICACY and SAFETY

Trial NCT02004522, IPI-145-07; duvelisib vs ofatumumab; phase III. Sponsor Infinity Pharmaceuticals. Status Ongoing. Source of Trial registry1, manufacturer. information Location EU (incl UK), USA and other countries. Design Randomised, active-controlled. Participants n=300 (planned); aged 18 yrs or older; chronic lymphocytic leukaemia or small lymphocytic lymphoma; received at least one prior therapy; considered not appropriate for treatment with purine-based analog regimen; no uncontrolled autoimmune haemolytic anaemia or idiopathic thrombocytopenia purpura; not refractory to ofatumumab; no prior allogeneic transplant; no known central nervous system lymphoma or leukaemia. Schedule Randomised to duvelisib oral at 25mg twice daily for a 21-day cycle, and then at 25mg twice daily for subsequent 28-day cycles, for up to 18 cycles; or ofatumumab administered via intravenous (IV) infusion at 300mg as a starting dose, followed by seven weekly doses of 2,000mg, and 2,000mg IV once every month for four mths thereafter. Follow-up Active treatment for up to 18 cycles (72 weeks), follow-up 6 years. Primary Progression-free survival. outcome Secondary Overall response rate, haematological improvements, overall survival, lymph node outcomes response rate, duration of response, treatment-emergent adverse events, , Euro-Qol-5D (EQ-5D) and Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-F) scores.

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Expected Study completion date reported as June 2021. reporting date

ESTIMATED COST and IMPACT

COST

The cost of duvelisib is not yet known. The costs of other selected treatments are shown in the table below24:

Drug Dose 28 day cost Ibrutinib 420mg oral once daily. £4,292 Idelalisib with rituximab Idelalisib 150mg oral twice £4,653c daily in combination with rituximab 500mg/m2 every 28 days.

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  None identified existing treatments. Other Issues

 Clinical uncertainty or other research question  None identified identified: expert opinion states that B-cell receptor antagonists have dramatically altered treatment for patients with CLL and there is a focus now in clinical trials to examine their role in combination with established agents and also at earlier phases in the disease. It is therefore likely that the treatment pathways will continue to evolve with these newer agents. Other novel therapies are also showing impressive efficacy including Bcl-2 antagonists and T cell therapiesd.

c Assuming an average body surface area of 1.88m2 (Health Survey for England 2014). d Expert personal communication.

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REFERENCES

1 ClinicalTrials.gov. A phase 3 study of duvelisib versus ofatumumab in patients with relapsed or refractory CLL/SLL (DUO). www.clinicaltrials.gov/ct2/show/NCT02004522 Accessed 21 April 2016. 2 Leukaemia Care. Small lymphocytic lymphoma. www.leukaemiacare.org.uk/small-lymphocytic- lymphoma Accessed 21 April 2016. 3 MacMillan Cancer Support. How chronic lymphocytic leukaemia is diagnosed. www.macmillan.org.uk/Cancerinformation/Cancertypes/Leukaemiachroniclymphocytic/Symptoms diagnosis/Diagnosis.aspx Accessed 21 April 2016. 4 Rooij M, Kuil A, Geest C et al. The clinically active BTK inhibitor PCI-32765 targets B-cell receptor- and chemokine-controlled adhesion and migration in chronic lymphocytic leukaemia. Blood 2012;199(11):2590-2594. 5 Oscier D, Dearden C, Eren E et al. Guidelines on the diagnosis, investigation and management of chronic lymphocytic leukaemia. British Journal of Haematology 2012;159(5):541-564. 6 Zenz T, Mertens D, Küppers R et al. From pathogenesis to treatment of chronic lymphocytic leukaemia. Nature Reviews Cancer 2010;10:37-50. 7 NIHR Horizon Scanning Research and Intelligence Centre. Idelalisib with rituximab for chronic lymphocytic leukaemia. University of Birmingham, July 2013. www.hsc.nihr.ac.uk/ 8 Macias-Perez I and Flinn I. GS-1101: a delta-specific PI3K inhibitor in chronic lymphocytic leukemia. Current Hematologic Malignancy Reports 2013;8:22-27. 9 National Institute for Health and Clinical Excellence. Ofatumumab for the treatment of chronic lymphocytic leukaemia refractory to fludarabine and alemtuzumab. Technology appraisal. TA202. London: NICE; October 2010. 10 Cancer Research UK. Chronic lymphocytic leukaemia (CLL) incidence statistics. www.cancerresearchuk.org/health-professional/chronic-lymphocytic-leukaemia-cll-incidence- statistics#ref-0 Accessed 21 April 2016. 11 Health & Social Care Information Centre. Cancer registration statistics, England, 2013. www.hscic.gov.uk/hes 12 National Cancer Intelligence Network. Trends in incidence and outcome for haematological cancers in England: 2001-2010. www.ncin.org.uk/cancer_type_and_topic_specific_work/cancer_type_specific_work/haematologic al_cancers/ Accessed 21 April 2016. 13 Health & Social Care Information Centre. Hospital episode statistics for England. Inpatient statistics, 2014-15. www.hscic.gov.uk/hes 14 Office for National Statistics. Mortality statistics: deaths registered in England and Wales, series DR, 2014. www.ons.gov.uk 15 BCSH Guidelines. Interim statement from the BCSH CLL guidelines panel. www.bcshguidelines.com/documents/Interim_statement_CLL_guidelines_version6.pdf Accessed 21 April 2016. 16 Eichhourst B, Robak T, Montserrat E et al. Chronic lymphocytic leukaemia: ESMO clinical practice guidelines. Annals of Oncology 2015;26(5):78-84. 17 National Comprehensive Cancer Network. NCCN clinical practice guidelines in oncology – non- Hodgkin’s lymphomas 2015. www.tri-kobe.org/nccn/guideline/hematologic/nhl/english/ptld.pdf Accessed 21 April 2016. 18 Hallek M, Cheson B, Catosky D et al. Guidelines for the diagnosis of chronic lymphocytic leukaemia: a report from the International workshop on chronic lymphocytic leukaemia (IWCLL) updating the National Cancer Institute working group (NCI-WG) 1996 guidelines. Blood 2008;112(13):5259. 19 Cuthill K and Devereux S. How I treat patients with relapsed chronic lymphocytic leukaemia. British Journal of Haematology 2013;163(4):423-435. 20 National Institute for Health and Clinical Excellence. Idelalisib for treating chronic lymphocytic leukaemia. Technology appraisal TA359. London: NICE; October 2015. 21 National Institute for Health and Clinical Excellence. Rituximab for the treatment of relapsed or refractory chronic lymphocytic leukaemia. Technology appraisal. TA193. London: NICE; July 2010.

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22 Cancer Research UK. Biological therapy for chronic lymphocytic leukaemia. www.cancerresearchuk.org/about-cancer/type/cll/treatment/biological-therapy-for-chronic- lymphocytic-leukaemia Accessed 21 April 2016. 23 electronic Medicines Compendium (eMC). Arzerra 100mg & 1000mg concentrate for solution for infusion. www.medicines.org.uk/emc/medicine/23022 Accessed 21 April 2016. 24 Joint Formulary Committee. British National Formulary. BNF April 2016. BMJ Group and Pharmaceutical Press. www.medicinescomplete.com

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