UNMET NEEDS OF PATIENTS WITH CLL/SLL AND FL. June 6, 2018

UNMET NEEDS OF PATIENTS WITH CLL/SLL AND FL June 6, 2018 0

PRESENTATION OVERVIEW IN CLL/SLL AND FL: Review patient heterogeneity and its connection to unmet needs Explore unmet needs within the CLL/SLL and FL treatment landscapes Discuss how targeted treatment options may address unmet needs and improve treatment outcomes 1 CLL/SLL, chronic lymphocytic leukemia/small lymphocytic lymphoma; FL, follicular lymphoma.

2 PATIENT HETEROGENEITY IN CLL/SLL

CLL/SLL REMAINS AN INCURABLE DISEASE, AND PATIENTS EVENTUALLY RELAPSE OR DEVELOP REFRACTORY DISEASE CLL/SLL The median age of diagnosis is 72 years old 1 10-year relative survival (the ratio of actual survival to expected survival) is 64.6% for those 65 74 years old, which is when most patients are diagnosed with CLL/SLL 2 Therapies that provide durable remission and improve survival are still needed 2 3 1. Gribben JG. Expert Rev Anticancer Ther. 2010;10(9):1389-1394. 2. Pulte D et al. J Hematol Oncol. 2016;9(28):1-8. *10-year-period relative survival for patients with CLL/SLL. Mean survival±se. N=24,771. Relative survival was calculated as the ratio of actual survival to expected survival (based on age, sex, race, and calendar year) to minimize the effect of non-cll-related death. 2

CLL/SLL THE CLL/SLL PATIENT POPULATION IS EXTREMELY HETEROGENEOUS Variable mutation status, disease burden, comorbidities, and performance status all contribute to patient heterogeneity 1,2 This diversity complicates disease management and results in highly variable treatment responses 1,2 Patients with del(17p) respond poorly to front-line chemoimmunotherapy 6 Older patients may not benefit as much as younger patients from front-line chemoimmunotherapy due to comorbidities and reduced organ function (including renal insufficiency) 3,7 As a result, there is no uniform standard of care in CLL/SLL 1 This is particularly evident in the relapsed/refractory setting 8 IGHV, immunoglobulin heavy chain variable; Notch1, Notch homolog 1, translocation-associated (Drosophila); TP53, tumor protein p53. 4 1. Riedell PA et al. Am J Hematol Oncol. 2016;12:15-19. 2. Hallek M. Am J Hematol. 2017;92(9):946-965. 3. Shanafelt T. Hematology. 2013;2013(1):158-167. 4. Thurmes P et al. Leuk Lymphoma. 2008;49(1):49-56. 5. Rossi D et al. Blood. 2013;121(8):1403-1412. 6. Nabhan C, Raca G, Lynn Wang Y. JAMA Oncol. 2015;1(7):965-974. 7. Pulte D et al. J Hematol Oncol. 2016;9(28):1-8. 8. National Comprehensive Care Network. 2018:1-85.

CLL/SLL PATIENT HETEROGENEITY RESULTS IN AREAS OF SIGNIFICANT UNMET NEED Available treatments, such as chemoimmunotherapy, are recommended for a broad range of patients with less consideration towards their heterogeneity 1,2 Multiple factors must be addressed to match treatments best suited for patients with unique biological and clinical challenges 1,2 There remain further opportunities to define specific patient populations who will best benefit from specific treatments 5 1. Castellino A et al. Mediterr J Hematol Infect Dis. 2017;9(1):1-13. 2. Shanafelt T et al. Hematology. 2013;2013(1):158-167. 3. Pulte D et al. J Hematol Oncol. 2016;9(28):1-8. 4. Rossi D et al. Blood. 2013;121(8):1403-1412.

CLL/SLL THE RAI STAGING SYSTEM CLASSIFIES TUMOR BURDEN Disease Burden The Rai staging system comprises stages 0 IV and classifies CLL/SLL according to tumor burden 1,2 Degree of tumor burden is based solely on a physical examination and blood parameters 2 RAI STAGING SYSTEM Rai Stage 0 Rai Stage I & II Rai Stage III & IV Lymphocytosis Lymphocytosis Enlarged lymph nodes Enlarged spleen Enlarged liver Lymphocytosis Disease-related anemia Enlarged lymph nodes Enlarged spleen Enlarged liver Thrombocytopenia 6 1. Hallek M et al. Am J Hematol. 2017;92(9):946-965. 2. NCCN Guidelines Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma. 2018;1-85.

TUMOR BURDEN AND ASSOCIATED RISK GROUP ARE STRONG INDICATORS OF PATIENT OUTCOMES CLL/SLL Disease Burden Degree of tumor burden and Rai stage correspond to risk categories 1 Rai stage 0: low risk Rai stages I II: intermediate risk Rai stages III IV: high risk At diagnosis, 58% of patients are low risk (Rai stage 0) but may progress to high risk over time 1,2 Risk group at diagnosis is directly related to overall survival time. High-risk patients have poor prognosis 1,3 Higher tumor burden is associated with increased risk of tumor lysis syndrome upon treatment with Bcl-2 inhibitors 4 Bcl-2, B-cell lymphoma 2. 7 1. NCCN Guidelines Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma. 2018;1-85. 2. Thurmes P et al. Leuk Lymphoma. 2008;49(1):49-56. 3. Eichhorst B et al. Ann Onc. 2015;26(5):78-84. 4. Roberts et al. N Engl J Med 2016;374:311-322.

CLL/SLL HIGH-RISK PATIENTS HAVE THE LOWEST OVERALL SURVIVAL, HIGHLIGHTING THE NEED FOR ADDITIONAL TREATMENT OPTIONS Disease Burden Overall survival (OS) differs depending on patient risk category and disease burden Median OS: 5 years for high risk 8 years for intermediate risk 10 years for low risk OS data emphasize the need for additional treatment options in all risk categories *OS stratifying patients by Rai risk scoring. N=347. 8 Thurmes P et al. Leuk Lymphoma. 2008;49(1):49-56.

CLL/SLL PATIENT GENETIC PROFILES ARE VARIABLE AND INFLUENCE PROGNOSIS Genetic Alterations The CLL/SLL genome carries the potential for multiple mutations 1 Among the more common mutations, del(17p), TP53, and del(11q) are associated with poor prognosis 2 Patients with del(17p) showed the worst 10-year OS relative to the general population 2 Del13q and mutated IGHV are associated with an improved patient prognosis compared to other genetic alterations 2,3 *10-year-period relative OS for CLL/SLL patients stratified by genetic mutation. N=1274. 2 9 1. Gaidano G, Rossi D. Hematol Am Soc Hematol Educ Progr. 2017;2017(1):329-337. 2. Rossi D et al. Blood. 2013;121(8):1403-1412. 3. Nabhan C et al. JAMA Oncol. 2015;1(7):965-974.

CLL/SLL GENETIC ALTERATIONS CONTRIBUTE TO CHEMOIMMUNOTHERAPY RESISTANCE, WITH del(17p) SHOWING THE WORST PROGNOSIS Genetic Alterations Patients with a 17p deletion have 1,2 : Highest resistance to chemoimmunotherapy Rapid disease progression Lowest 15-year probability of survival Suboptimal outcomes are also observed in patients with 3 : ZAP70 expression SF3B1 mutations NOTCH1 mutations del(11q) Unmutated IGHV * OS, N=325. 1 10 1. Dohner H et al. N Engl J Med. 2000;343(26):1910-1916. 2. Marcus R et al. Blood. 2005;105(4):1417-1423. 3. Gaidano G, Rossi D. Am Soc Hematol Educ Progr. 2017;2017(1):329-337.

CLL/SLL MULTIPLE COMORBID CONDITIONS ARE COMMON IN NEWLY DIAGNOSED PATIENTS AND INFLUENCE TREATMENT CHOICE Comorbidities Additional comorbidities associated with treatment choice: renal insufficiency, atrial fibrillation, and bleeding 1-4 BPH, benign prostate hyperplasia; CAD, coronary arterial disease; COPD, chronic obstructive pulmonary disease; CVD, cardiovascular disease; PVD, pulmonary vascular disease; TIA, transient ischemic attack. 11 1. Thurmes P et al. Leuk Lymphoma. 2009;49(1):49-56. 2. Goede V et al. Haematologica. 2014;99(6):1095-1100. 3. Kazianka et al. Leukemia. 2017;31,1117-1122. 4. Thompson et al. British Journal of Haematology. 2016;175,462-466.

CLL/SLL THE SUCCESS OF CHEMOIMMUNOTHERAPY IS HINDERED BY UNADDRESSED COMORBIDITIES Comorbidities Chemoimmunotherapy treatment has limited success in elderly, comorbid CLL/SLL patients In patients with 2 comorbidities: Median OS was reduced by 18.5 months (20.5%) Median PFS was reduced by 10.5 months (33.3%) Disease progression is the primary cause of death in patients with at least 2 comorbidities *N=193. PFS, progression-free survival. 12 Goede V et al. Haematologica. 2014;99(6):1095-1100.

CLL/SLL PATIENTS WHO RECEIVE FRONT-LINE CHEMOIMMUNOTHERAPY (FCR) HAVE A GREATER RISK OF SECONDARY MALIGNANCIES After front-line chemoimmunotherapy, patients with CLL have 2.38 times higher risk of secondary cancer than the general population The risk of AML and MDS is higher after chemoimmunotherapy-based therapy (5.1% during follow-up period of 4.4 years) AML, acute myeloid leukemia; FCR, fludarabine, cyclophosphamide, and rituximab; MDS, myelodysplastic syndrome. 13 Benjamini O et al. Leuk Lymphoma. 2015;56(6):1643-1650.

14 HOW SHOULD HETEROGENEITY FACTORS IMPACT TREATMENT STRATEGY IN CLL/SLL?

CLL/SLL CATEGORIZING PATIENTS BY BIOMARKER STATUS MAY HELP INFORM PHYSICIANS ON APPROPRIATE TREATMENT OPTIONS Genetic Alterations CLL/SLL genetic alterations can serve as prognostic biomarkers 1 Del(17p) and TP53 mutation are considered the most important in predicting prognosis 2 In high-risk CLL patients who carry del(17p), agents targeting the B-cell receptor pathway have shown significant activity 2 Bcl-2 inhibitors are not approved outside of del(17p) patients 3 CLL patients with NOTCH1 mutation may not respond well to anti-cd20 based therapies 2 Research is ongoing to identify biomarkers of resistance/sensitivity 2 CD, cluster of differentiation; FISH, fluorescent in situ hybridization. 15 1. Gaidano G, Rossi D. Hematol Am Soc Hematol Educ Progr. 2017;2017(1):329-337. 2. Nabhan C et al. JAMA Oncol. 2015;1(7):965-974; 3. VENCLEXTA Prescribing Information 2017.

CLL/SLL TREATMENT STRATEGY SHOULD BE BASED ON AGE, GENETIC ALTERATIONS, AND PATIENT COMORBIDITIES Patient genetic profiles, particularly Del(17p)/TP53, and comorbidities should directly impact treatment strategy 1,6 Disease State Del(17p) mutation determines sequence of first-line treatment 1 Chronic Lymphocytic Leukemia Del(17p)/TP53 mutation status + - First Line BTK inhibitors High-dose corticosteroid Anti-CD20 & anti-cd52 antibodies Unfit/Frail, Age 65 Patient Alkylating agent CIT Fit Patient Purine analog CIT Relapsed/Refractory BTK inhibitors PI3K inhibitors Bcl-2 inhibitors Thalidomide analog CIT Anti-CD20 antibodies Reduced dose CIT BTK inhibitors PI3K inhibitors Bcl-2 inhibitors Alternative CIT Mutations (BTK-C481S and PLCγ2) can drive resistance to BTK inhibitors 2 Discontinuation due to acquired mutations can cause rapid progression of disease 3 If this occurs, PI3K inhibitors or targeting other pathways may be suitable alternatives 1,4 Comorbid patients 65 years old and unfit/frail are suited for chemoimmunotherapy with alkylating agents instead of toxic purine analogs 5 BCR, B-cell receptor; BTK, Bruton s tyrosine kinase; CIT, chemoimmunotherapy; PI3K, phosphoinositide 3-kinase. 16 1. Wierda WG et al. J Natl Compr Canc Netw. 2017;15(3):293-311. 2. Gaidano G, Rossi D. Hematol Am Soc Hematol Educ Progr. 2017;2017(1):329-337. 3. Chiron D et al. Cancer Discov. 2014;4(9):1022-1035. 4. Maddocks KJ et al. JAMA Oncol. 2015;1(1):80. 5. Gribben JG. Expert Rev Anticancer Ther. 2010;10(9):1389-1394. 6. National Comprehensive Cancer Network, Inc. CLL/SLL Guidelines, Version 5.2018.

CLL/SLL TARGETED THERAPIES CAN BE AN ALTERNATIVE FOR PATIENTS NOT IDEALLY SUITED FOR CHEMOIMMUNOTHERAPY Targeted therapies regulate key signaling pathways tied to growth and survival and may also target the tumor microenvironment Targeted therapies include BTK inhibitors, PI3K inhibitors, and Bcl-2 inhibitors Targeted therapies can achieve a durable remission for relapsed/refractory patients Targeted therapies are also effective in high-risk disease, can be used in a personalized medicine approach, and provide an alternative to treatments that are associated with secondary malignancies This approach provides a paradigm shift towards an all-inclusive therapy for patients regardless of fitness level, comorbidity status, and genetic profile 17 Frustaci AM et al. Expert Rev Hematol. 2016;9(7):679-693.

CLL/SLL WHEN BTK INHIBITORS BECOME INEFFECTIVE OR NOT TOLERATED, PI3K INHIBITORS PROVIDE A VIABLE ALTERNATIVE Patients may experience intolerance or develop resistance to BTK inhibitors 1,2 In a retrospective analysis, 24% of patients discontinued treatment with a BTK inhibitor within 6.5 months, with toxicity being the most common reason for discontinuation 3 An oral PI3K inhibitor is a rational next step following an oral BTK inhibitor 2 18 1. Mato AR et al. Haematologica. 2018;103:1-20. 2. Frustaci AM et al. Expert Rev Hematol. 2016;9(7):679-693. 3. Mato AR et al. Front-line ibrutinib therapy for chronic lymphocytic leukemia (CLL) in the real world: responses, toxicity, outcomes and subsequent therapies. Blood. 2017;130:3011.

19 PATIENT HETEROGENEITY IN FL

FL FL IS AN INCURABLE NHL, AND RELAPSE OCCURS FREQUENTLY AFTER FRONT-LINE THERAPY FL is the most common subtype of indolent NHL 1 35% of all NHL and 70% of indolent lymphomas The median age of diagnosis is 65 years old 2 FL remains incurable, even with an initial durable response to chemoimmunotherapy 3 Chronic nature of the disease highlights the continuous need for new therapies 5 High-risk patients, in particular, experience treatment failure and early POD with currently available therapies 6,7 NHL, Non-Hodgkin s lymphoma; POD, progression of disease. 20 1. Freedman A et al. Am J Hematol. 2015;90(12):1171-1178. 2. Castellino A, Santambrogio E, Nicolosi M, et al. Follicular lymphoma: the management of elderly patient. Mediterr J Hematol Infect Dis. 2017; 9(1):1-13. 3. Maddocks et al. J Natl Cancer Inst. 2017;109(3):1-8. 4. Federico M et al. J Clin Oncol. 2013;31(12):1506-1513. 5. Sorigue M et al. Expert Rev Hematol. 2017:1747-4086. 6. Jurinovic V et al. Blood. 2016;128(8):1112-1120. 7. Kahl BS et al. Blood. 2016;127(17):2055-2063.

FL PATIENTS WHO RELAPSE FOLLOWING FRONT-LINE CHEMOIMMUNOTHERAPY NEED ALTERNATIVE TREATMENT OPTIONS Despite treatment advances and a range of chemoimmunotherapy options, many FL patients experience frequent relapses and shorter remissions with front-line chemoimmunotherapy High rates of treatment failure with front-line chemoimmunotherapy demonstrate a need for alternative treatments High rates of 3-year treatment failure, up to 62%, occur with R-CVP, R-CHOP, and R-FM 3-year PFS rates: 52% (R-CVP), 63% (R-FM), and 68% (R-CHOP) Patients who relapse on front-line chemoimmunotherapy can develop secondary malignancies for a range of cancers, including colon, breast, prostate, lung, cervical, and uterine Patient risk level and disease characteristics play a role in treatment outcomes 21 R-CVP, rituximab plus cyclophosphamide, vincristine, prednisone; R-CHOP, rituximab plus cyclophosphamide, doxorubicin, vincristine, prednisone; R-FM, rituximab plus fludarabine and mitoxantrone. Federico M et al. J Clin Oncol. 2013;31(12):1506-1513.

FL THE PATIENT POPULATION IS HIGHLY HETEROGENEOUS, COMPLICATING DISEASE MANAGEMENT Variability in treatment success is due to heterogeneity of the disease state 1 Certain subgroups of patients are at higher risk of early progression of disease and relapse due to their clinical and molecular disease heterogeneity 1,2 Optimal sequence of therapy remains undefined as a result of patient heterogeneity 3 ARID1A, AT-rich interactive domain-containing protein 1A; CARD11, caspace recruitment domain-containing protein 11; CREBBP, CREB (camp response element-binding protein)-binding protein; ECOG, Eastern Cooperative Oncology Group; EP300, histone acetyltransferase p300; EZH2, enhancer of zeste homolog 2; FLIPI, Follicular Lymphoma International Prognostic Index; MEF2B, myocyte enhancer binding factor 2B. 22 1. Maddocks K et al. J Natl Cancer Inst. 2017;109(3):1-8. 2. Kritharis A et al. Cancer Treat Res. 2015;165:197-226. 3. Solal-Celigny P et al. Blood. 2004;104(5):1258-1265. 4. Jurinovic V et al. Blood. 2016;128(6):1112-1120.

FL HETEROGENEITY INFLUENCES PATIENT PROGNOSIS The Follicular Lymphoma International Prognostic Index (FLIPI) is a clinical index to assess risk in patients with FL There remains an unmet need in all risk groups LDH, lactate dehydrogenase; ULN, upper limit of normal. 23 1. Solal-Celigny P et al. Blood. 2004;104:1258-1265. 2. Kahl BS, Yang DT. Blood. 2016;127(17):2055-2063.

24 PATIENT HETEROGENEITY AND UNMET NEEDS IN FL

EARLIER PROGRESSION OF DISEASE (POD) DEFINES A HIGH-RISK PATIENT GROUP IN FL FL High-risk patients may experience disease progression within 24 months of diagnosis (POD 24) and initial chemoimmunotherapy 1 POD 24 is associated with poor outcomes and a higher chance of premature death 2 High-risk patients therefore present an unmet need in FL, where currently available treatment strategies are not effective 1 25 1. Kahl BS, Yang DT. Blood. 2016;127(17):2055-2063. 2. Sorigue M et al. Expert Rev Hematol. August 2017:1-2. 3. Kridel R. et al. Blood. 2017;130(3)258-266.

FL POD 24 IS ALSO LINKED TO HISTOLOGICAL TRANSFORMATION Histological transformation is the changing of FL cells on multiple levels through 1 : Change in tumor grade Increased connections to the tumor microenvironment Greater number of genetic alterations Histological transformation is associated with shortened survival time 1 Approximately 30% of patients will transform to a more aggressive histology at some point in their disease 2 There are no treatment strategies that fully address the challenge of histological transformation 1 26 1. Kridel R et al. Blood. 2017;130(3):258-266. 2. Maddocks K et al. J Natl Cancer Inst. 2017;109(3):1-8.

FL ALTERNATIVE TREATMENT OPTIONS ARE NEEDED FOR PATIENTS WITH FOLLICULAR LYMPHOMA Disease State Follicular Lymphoma (Advanced stage, Grade 1-3) Symptoms Asymptomatic Symptomatic Tumor Burden Low High Low High First Line Watch and Wait* *Anti-CD20 antibodies *Patient Preference Anti-CD20 antibodies CIT Fit/young: Purine analog Unfit/elder: Alkylating Relapsed/Refractory PI3K inhibitors CIT Anti-CD20 antibodies Treatment in a relapsed/refractory setting is guided by success of early regimen, disease histology, and patient fitness 3 27 Kahl BS et al. Blood. 2016;127(17):2055-2063.

28 HOW SHOULD HETEROGENEITY FACTORS IMPACT TREATMENT STRATEGY IN FL?

FL TARGETED THERAPIES ARE A PROMISING STRATEGY FOR IMPROVED DISEASE CONTROL IN DIFFICULT-TO-TREAT PATIENTS Improved understanding of the biology of FL has led to increased use of novel targeted therapies Therapies that target the BCR pathway are rationally designed to induce a durable response for early-relapse patients independent of established risk factors 29 Maddocks K et al. J Natl Cancer Inst. 2017;109(3):1-8.

KEY TAKEAWAYS CLL/SLL and FL remain incurable, and current treatments only delay disease progression Available CLL/SLL and FL treatments do not adequately address all unmet needs of patients Optimal management of CLL/SLL and FL is complicated by the presence of heterogeneity-related factors, including disease burden, genetic alterations, and comorbidities Patients with CLL/SLL and FL may benefit from novel treatment strategies, such as targeted agents BTK inhibitors and Bcl-2 inhibitors have shown limited efficacy and are not approved for the treatment of FL 1,2 PI3K inhibitors are approved for FL in the relapsed/refractory setting 3 30 1. IMBRUVICA Prescribing Information 2018. 2. VENCLEXTA Prescribing Information 2017. 3. ZYDELIG Prescribing Information 2018.