Innovative Therapy in B-Cell Malignancies An Expert Tumor Board on Novel Agent Classes in CLL, FL, and MCL

This activity is an Independent Satellite Symposium on B-cell malignancies, following the adjournment of the first day of the ASH Meeting on Hematologic Malignancies. Disclosures

Nathan H. Fowler, MD, has a financial interest/relationship or affiliation in the form of: Grant/Research Support from AbbVie Inc.; Celgene Corporation; F. Hoffmann-La Roche; Janssen Pharmaceuticals, Inc.; and TG Therapeutics, Inc. Advisory Board for AbbVie Inc.; Celgene Corporation; F. Hoffmann-La Roche; Janssen Pharmaceuticals, Inc.; and TG Therapeutics, Inc.

This CME activity is jointly provided by Penn State College of Medicine and PVI, PeerView Institute for Medical Education. This activity is supported by educational grants from AstraZeneca, Bayer HealthCare Pharmaceuticals, Inc. and Pharmacyclics LLC, an AbbVie Company, Janssen Biotech, Inc., administered by Janssen Scientific Affairs, LLC, and TG Therapeutics, Inc. Disclosures

Matthew S. Davids, MD, MMSc, has a financial Sonali M. Smith, MD, has a financial interest/relationship or affiliation in the form of: interest/relationship or affiliation in the form of: Consultant and/or Advisor for AbbVie Inc.; Consultant and/or Advisor for AbbVie Inc.; AstraZeneca; Celgene Corporation; Genentech, AstraZeneca; Kite Pharma, Inc./Gilead; Inc.; Gilead; Janssen Pharmaceuticals, Inc.; Pharmacyclics LLC; and Seattle Genetics, Inc. Merck & Co., Inc.; Pharmacyclics LLC; TG Therapeutics, Inc.; and Verastem, Inc. Grant/Research Support from AstraZeneca; Bristol-Myers Squibb; Genentech, Inc.; MEI Pharma Inc.; Pharmacyclics LLC; Surface Oncology; and TG Therapeutics, Inc.

This CME activity is jointly provided by Penn State College of Medicine and PVI, PeerView Institute for Medical Education. This activity is supported by educational grants from AstraZeneca, Bayer HealthCare Pharmaceuticals, Inc. and Pharmacyclics LLC, an AbbVie Company, Janssen Biotech, Inc., administered by Janssen Scientific Affairs, LLC, and TG Therapeutics, Inc. Introduction Interpreting the Emergence of New Options in B-Cell Lymphoma Subtypes

Nathan H. Fowler, MD Associate Professor of Medicine, Department of Lymphoma/Myeloma The University of Texas MD Anderson Cancer Center Houston, Texas

Go online to access full [Certification Type] information, including faculty disclosures. In B-Cell Malignancies: A Crowded Clinical Landscape

Obinutuzumab Venetoclax

CLL + chlorambucil, rituximab-refractory FL + BR, then as maintenance, relapsed FL + Del(17p) CLL ≥1 prior therapy bendamustine Axicabtagene ciloleucel Large B-cell lymphomas ≥2 prior therapies Initial rituximab approval (1997) Bendamustine Idelalisib Tisagenlecleucel MCL, CLL, indolent B-cell NHL Relapsed CLL + rituximab, relapsed FL or SLL ≥2nd relapsed/refractory B-ALL Bortezomib (MCL) after ≥2 prior therapies R/R large B-cell lymphoma ≥2 lines of Alemtuzumab (CLL) therapy (DLBCL NOS, high-grade B-cell lymphoma, DLBCL [arising from FL])

Before 2008 2013 2014 2016 2017/2018

Acalabrutinib

Lenalidomide MCL ≥1 prior therapy a Relapsed MCL after ≥2 prior therapies Ibrutinib CLL, del(17p) CLL Copanlisib MCL ≥1 prior therapy Ofatumumab FL ≥2 prior therapy MZL ≥1 prior anti-CD20 therapy CLL+ chlorambucil, relapsed CLL after ≥2 prior therapies, fludarabine/alemtuzumab- refractory CLL a Also approved in WM, including in combination with rituximab. Tonight’s Agenda

1. Progress in CLL, the role of novel agents, and implications for treatment decisions 2. Focus on FL—is R-chemo now just one of many possible treatment options? 3. A look at MCL and the clinical uses and potential of novel therapeutics 4. Each session will open with a tumor board/case review

Be prepared to vote again: Follow-up polling questions will be presented to you via iPad during the scientific sessions this evening Developing Personalized Regimens in CLL A Look at the Role and Clinical Potential of Novel Therapeutics

Matthew S. Davids, MD, MMSc Assistant Professor of Medicine Dana-Farber Cancer Institute Harvard Medical School Boston, Massachusetts

Go online to access full [Certification Type] information, including faculty disclosures. Tumor Board in CLL: An Older Patient With Symptomatic CLL, Unmutated IGHV

David, a 75-year-old Presents with B Results of further male symptoms, other testing features leading to symptomatic CLL dx • Fit with active • Bulky nodes • Flow cytometry lifestyle despite age in neck, axilla confirms diagnosis • Continues to jog 3x • WBC: 88,000 • Marrow is 70% a week and perform (90% lymphocytes) replaced with CLL yard work • Hb: 11.1 g/dL • FISH is normal • PLT: 104,000 • IGHV is unmutated

Tumor Board in CLL: Treatment Pathway

Upfront use of ibrutinib Given this patient’s features and 420 mg daily recommended current evidence … Response achieved with rapid resolution of symptoms

Evidence supports use of venetoclax in this instance Relapse with del(17p) after 2 years of therapy 20 mg once daily for 7 days, → weekly ramp-up to recommended 400 mg daily Tumor Board in CLL: An Alternate Pathway

If this patient had been in poorer health, frail, or had presented Acalabrutinib (off-label) or with history of cardiovascular obinutuzumab events (AFib), potential options could include

Relapse with high-risk features Venetoclax remains an option such as del(17p) in this pathway Evolution of Therapy for CLL

1960s/1970s 1980s 1990s 2000s 2010s

Alkylating agents Next-gen mAbs • Chlorambucil • Ofatumumab (2009) • Cyclophosphamide • Obinutuzumab

Purine nucleosides • Fludarabine • Pentostatin Combination Small molecule inhibitors • Cladribine chemotherapy • BCR pathway (ibrutinib, acalabrutinib; idelalisib) • Alemtuzumab • Bcl-2 (venetoclax) • CD20 mAbs • Bendamustine • Chemoimmunotherapy (FCR) BTK Inhibitors in CLL: Ibrutinib Ibrutinib: A Potent Irreversible BTK Inhibitor1

• Forms a specific and irreversible bond with cysteine-481 in BTK O • Potent and irreversible BTK inhibition with IC50 = 0.5 nM • Blocks BCR signaling; active in canine NH 2 model of spontaneous lymphoma N N • Orally bioavailable with short half-life N N • Alternative irreversible targets could include EGFR, ERBB4, BMX, ITK, TEC, BLK, and N JAK3; many reversible targets O • In CLL: Approved for marketing as initial therapy and for relapsed/refractory patients (full approval)

1. Honigberg LA et al. Proc Natl Acad Sci USA. 2010;107:13075-13080. Ibrutinib: Pivotal Phase 2 Study1-4

132 patients with CLL enrolled into • Median: 4 prior therapies this study • 57% advanced (stage III or IV) disease • 31 pts aged >65 years with symptomatic disease • 35% del(17)(p13.1) but no prior therapy • Dosing 420 mg or 840 • 101 pts of any age with mg QD with similar R/R disease response and PFS (data merged)

1. O’Brien S, Byrd JC. Lancet Oncol. 2014;15:48-58. 2. Byrd JC, O’Brien S. N Engl J Med. 2013;369:32-42. 3. Byrd JC, O’Brien S. Blood. 2015;125:2497-2506. 4. O’Brien S et al. Blood. 2018:131:1910-1919 PCYC-1102-1103: 5-Year Survival Outcomes1

Median PFS, mo 5-Year PFS, % Median OS, mo 5-Year OS, %

TN (n = 31) NR 92 TN (n = 31) NR 92 R/R (n = 101) 52 43 R/R (n = 101) NR 57

1. O’Brien S et al. Blood. 2018:131:1910-1919 Ibrutinib Leads to Durable Response in Most FISH Subgroups1

Progression-Free Survival Overall Survival

100 R/R del(13q) 100 No abnormality R/R del(13q) R/R trisomy 12 80 80 R/R trisomy 12 No abnormality

60 60 R/R del(11q) Free Survival, % Survival, Free - 40 40 R/R del(11)q R/R del(17p) 20 20 R/R del(17p) 0 % Survival, Overall 0 0 6 12 18 24 30 36 42 48 54 60 66 72 0 6 12 18 24 30 36 42 48 54 60 66 72

Progression Time Since Initiation of Ibrutinib, mo Time Since Initiation of Ibrutinib, mo Median PFS 5-y PFS Median OS 5-y OS Del(17p) (n = 34) 26 mo 19% Del(17p) (n = 34) 57 mo 32% Del(11q) (n = 28) 55 mo 33% Del(11q) (n = 28) NR 61% Trisomy 12 (n = 5) NR 80% Trisomy 12 (n = 5) NR 80% Del(13q) (n = 13) NR 91% Del(13q) (n = 13) NR 91% No abnormalitya (n = 16) NR 66% No abnormalitya (n = 16) NR 83% a No del(17p), del(11q), del(13q), or trisomy 12; in hierarchical order for del(17p) and then del(11q). 1. O’Brien S et al. Blood. 2018:131:1910-1919 Ibrutinib Leads to Comparable PFS/OS Regardless of IGHV Status (PCYC-1102 Study)1

Progression-Free Survival Overall Survival

100 100

80 80 R/R mutated IGHV 60 R/R mutated IGHV 60

Free Survival, % Survival, Free R/R unmutated IGHV - 40 40 R/R unmutated IGHV 20 20

0 % Survival, Overall 0 0 6 12 18 24 30 36 42 48 54 60 66 72 0 6 12 18 24 30 36 42 48 54 60 66 72

Progression Time Since Initiation of Ibrutinib, mo Time Since Initiation of Ibrutinib, mo

Median PFS 5-y PFS Median OS 5-y OS Mutated IGHV (n = 16) 63 mo 53% Mutated IGHV (n = 16) 63 mo 66% Unmutated IGHV (n = 79) 43 mo 38% Unmutated IGHV (n = 79) NR 55%

1. O’Brien S et al. Blood. 2018:131:1910-1919 Onset of Most Grade ≥3 Adverse Events Decreased Over Time1

≤1 year >1-2 years >2-3 years >3-4 years >4 years Hypertension Pneumonia Neutropenia Thrombocytopenia Atrial fibrillation Cellulitis Diarrhea Hyperglycemia Sepsis Fatigue Decreased lymphocyte count 0 25 50 75 100 0 25 50 75 100 0 25 50 75 100 0 25 50 75 100 0 25 50 75 100

• Dose reductions and dose discontinuations due to AEs occurred more frequently in R/R patients than in TN patients, and during the first year after treatment versus later

1. O’Brien S, Byrd JC. Blood. 2018:131:1910-1919. Phase 3 RESONATE Study in Relapsed CLL1,2

• Response (42.1% vs 4%, P < .001) Outcome • PFS (median NR vs 8 months; HR 0.22, P < .001) dramatically • At F/U of 44 months: 3-year PFS 59% with ibrutinib vs 3% with ofa improved with ibrutinib • OS (12 mo 90% vs 81%, HR 0.43, P < .005) • 3-year OS is 74% in ibrutinib arm

• Atrial fibrillation (6% vs 1%) > with ibrutinib • Grade 1/2 bleeding/ecchymosis (44% vs 12%) > with ibrutinib Toxicity differs • Rash (8% versus 4%) > with ibrutinib between arms • Blurred vision (10% vs 4%) > with ibrutinib • PN (4% versus 13%) > with ofa; infusion events (0% vs 28%) > with ofa

1. Byrd JC et al. N Engl J Med. 2014;371:213-223. 2. Byrd JC et al. ASCO 2017. Abstract 7510. RESONATE: Extended Follow-Up1,2

Ibrutinib vs Median PFS, mo HR (95% CI) HR (95% CI) Ofatumumab Ibrutinib NE 0.113 (0.099-0.178) No censoring for crossover 0.769 (0.547-1.080) Ofatumumab 8.11 Adjusted for crossover (RPSFTM) 0.371 (0.223-0.618) (RPSFTM)

1. Byrd JC et al. N Engl J Med. 2014;371:213-223. 2. Byrd JC et al. ASCO 2017. Abstract 7510. Ibrutinib in Newly Diagnosed CLL: Phase 3 RESONATE-2 Study1

Treatment-naïve CLL/SLL Ibrutinib 420 mg once daily until with active disease

disease progression or

• Age ≥65 y unacceptable toxicity

• For patients 65-69 y, 1116 comorbidity that may R - preclude FCR 1:1 Chlorambucil 0.5 mg/kg (to max • Del(17p) excluded PCYC • Warfarin use excluded 0.8 mg/kg) d 1 and 15 of 28-d cycle up to 12 cycles • N = 269

PCYC-1116 Extension Study (N = 43): Crossed over to ibrutinib from chlorambucil arm

• Primary endpoint: PFS as evaluated by IRC (2008 IWCLL criteria)2 • Secondary endpoints: OS, ORR, hematologic improvement, safety a Patients with IRC-confirmed PD enrolled in extension Study 1116 for follow-up and second-line treatment per investigator’s choice. 1. Bruger JA et al. N Engl J Med. 2015;373:2425-2437. 2. Hallek M et al. Blood. 2008;111:5446-5456. RESONATE-2: Ibrutinib vs Chlorambucil1

• Phase 3 study in symptomatic, untreated CLL/SLL patients comparing ibrutinib with chlorambucil (crossover allowed) • Eligibility criteria included age of 65 years, ANC >1K, platelets >50K, and no del(17p) • Patient demographics: Median age of 73 years (70% ≥70 years) – 45% advanced Rai stage, 20% del(11)(q22;q23)

• Response: Ibrutinib 86% (4% CR) vs chlorambucil 36% (2% CR) RESONATE-2 • Significant PFS and OS with ibrutinib (despite crossover) Summary • Toxicity similar, except for diarrhea and atrial fibrillation (ibrutinib)

1. Burger JA et al. N Engl J Med. 2015;373:2425-2437. RESONATE-2: 4-Year PFS Update1

Single-agent ibrutinib associated with • 86% risk reduction of PD or death Ibrutinib • Substantially improved PFS in pts with traditional high-risk features del(11q) or UM-IGHV (risk reduction 97% and 91% vs chlorambucil, respectively) • Preservation of PFS in pts with or without del(11q) or UM-IGHV

Safety Chlorambucil Median PFS, mo HR (95% CI) • Discontinuation due to AEs decreased Ibrutinib NR over time, with 65% of ibrutinib pts 0.137 (0.090-0.210) Chlorambucil 15.0 continuing daily treatment

1. Burger JA et al. EHA 2018. Abstract PF343. Ibrutinib-Based Combination Therapy in CLL: HELIOS1

• 578 previously treated CLL pts without del(17p); treatment included BR x 6 + ibrutinib or placebo

Outcome significantly favored ibrutinib + BR • ORR was 82.7% with ibrutinib + BR vs 67.8% with BR (P < .0001) • At median F/U of 17 mo, PFS not reached with ibrutinib + BR vs 13.3 mo with BR alone (HR, 0.203; P < .0001) • OS analysis had trend toward benefit (P = .0598), but confounded by crossover • Toxicity between arms similar except for more mild bleeding events and atrial fibrillation with ibrutinib + BR

1. Chanan-Khan A et al. Lancet Oncol. 2016;17:200-211. Phase 3 Study of Ibrutinib ± Rituximab1

• 206 pts with relapsed or previously untreated del(17)(p13.1) CLL randomized to ibrutinib versus ibrutinib + rituximab (375 mg/m2 weekly x 4 then monthly x 5) • Demographics: Median age, 65 years; 37% with del(17p) or TP53 mutation, 72% IGHV unmutated; and 38% Rai stage 3 or 4

• 26% CR/100% ORR with ibrutinib + R vs CR 21%/ORR 98% with ibrutinib Ibrutinib ± • BM MRD lower in ibrutinib + R (median: 4.9% CLL cells) vs ibrutinib-treated Rituximab: patients (17.1%, P = .002); 5 vs 1 with MRD-CR Efficacy and • Lymphocyte count normalizes faster with ibrutinib + R vs ibrutinib (3.0 vs 8.9 Safety mo, P < .001) and time to best response quicker • No difference in toxicity between regimens, but PFS, OS the same

1. Burger JA et al. ASH 2017. Abstract 427. Ibrutinib vs Ibrutinib + Rituximab: PFS1

n (deaths), 2-y PFS (95% CI)

1. Burger JA et al. ASH 2017. Abstract 427. E1912: FCR Versus Ibrutinib Plus Rituximab as Frontline Therapy in Patients Aged 18-70 Years1

Arm A Ibrutinib 420 mg PO daily, d 1-28, cycles 1-7 Stratification Rituximab 50 mg/m2 IV, d 1, cycle 2, 2 • Age <60 y vs ≥60 y then 325 mg/m IV, day 2, cycle 2 Rituximab 500 mg/m2 IV, d 1, cycles 3-7 • PS 0, 1 vs 2 Subsequent cycles: Ibrutinib 420 mg PO daily, • Stage 3/4 vs 1/2 d 1-28 until disease progression R • Del 11q22.3 (ATM) vs Arm B other 1:1 Rituximab 50 mg/m2 IV, d 1, cycle 1; • Del(17p) excluded 325 mg/m2 IV, d 2, cycle 1; 2 • N = 519 500 mg/m IV, d 1, cycles 2-6 Fludarabine 25 mg/m2 IV, d 1, 2, and 3, x 6 cycles Cyclophosphamide 250 mg/m2, IV, d 1, 2, 3

1. https://clinicaltrials.gov/ct2/show/NCT02048813. Accessed August 28, 2018. Alliance Study: A0412021

Frontline Trial in Patients Arm 1 With CLL Aged ≥65 y Bendamustine 90 mg/m2 IV, cycles 1-6, d 1 and 2 Rituximab 375 mg/m2 IV, cycle 1, d 0 (day before d 1 of cycle 1); 500 mg/m2 IV, cycles 2-6, d 1

Preregistration PD • Zap-70 methylation Arm 2 R (performed centrally) Ibrutinib 420 mg PO daily until disease progression • FISH (performed locally)

Del(17p) excluded Arm 2 Ibrutinib 420 mg PO daily until disease progression Rituximab 375 mg/m2 IV, cycle 2, d 1, 8, 15, 22; 375 mg/m2 IV cycles 3-6, d 1

1. https://clinicaltrials.gov/ct2/show/NCT01886872. Accessed August 27, 2018. Discontinuation of Ibrutinib for Intolerance (10%-20%)

Reasons • Atrial fibrillation • Bleeding BTK is a great • Arthralgias/myalgias target that, when WHAT TO DO? • Diarrhea inhibited, promotes • Recurrent erythema durable remissions nodosum • Panniculitis BTK Inhibitors in CLL: Acalabrutinib Acalabrutinib (ACP-196)1

Kinase Inhibition Acalabrutinib is more selective for BTK Average IC50 (nM) with less off-target kinase inhibition compared with ibrutinib in vitro Kinase Acalabrutinib Ibrutinib BTK 5.1 1.5 Acalabrutinib Ibrutinib TEC 126.0 10 ITK >1,000 4.9 BMX 46 0.8 Kinase TXK 368 2.0 Selectivity EGFR >1,000 5.3 Profiling ERBB2 ~1,000 6.4 at 1 M ERBB4 16 3.4 BLK >1,000 0.1 Larger red circles represent stronger inhibition JAK3 >1,000 32

1. Byrd JC et al. N Engl J Med. 2016;374:323-332. Acalabrutinib Phase 1/2 Study in CLL1

• Eligibility includes – R/R CLL, ECOG PS ≤ 2 – Prior exposure to PI3Kδ, Bcl-2 inhibitors allowed, no BTK inhibitor exposure allowed – Pancytopenia, prior BMT allowed

• Multiple cohorts explored; all levels >90% BTK occupancy, but 100 mg BID chosen to get 98%-99% 24-hr occupancy – 134 pts with R/R enrolled with median of 3 prior therapies, 67% Rai advanced disease, 31% del(17p)

• Well tolerated with good safety profile (no atrial fibrillation) and diminished toxicity

1. Byrd JC et al. N Engl J Med. 2016;374:323-332. Time-to-Event Outcomes With Acalabrutinib1,2

N = 134 Median PFS, mo (95% CI) NR (35.7-NR) del(17p) NR (21.4-NR) del(11q) NR (NR-NR) Complex karyotype 27.9 (18.4-NR) No complex karyotype NR (35.7-NR) 18-month PFS, % (95% CI) 90 (83-94) All patients del(17p) 80 (59-91) Del(17p) del(11q) 100 (100-100) Del(11q) No complex karyotype 95 (81-99) With complex karyotype Censored • Median PFS in the overall population was not reached • Median TTR (≥PR) was 5.3 months (95% CI, 1.7-22.4), and median DOR was not reached

1. Byrd JC et al. N Engl J Med. 2016;374:323-332. 2. Byrd JC et al. ASCH 2017. Abstract 498. Acalabrutinib for Ibrutinib Intolerance1,2

• 33-patient cohort enrolled

Safety Other Outcomes

• 21 (64%) patients did not experience a • 81% response recurrence of ibrutinib-related AEs during treatment with acalabrutinib • Higher frequency of development of C481S mutation long term, possibly • 12 patients (36%) had persistent AE due to on and off exposure to ibrutinib − 47% decreased in severity (next study will examine pre-C481S − 41% remained stable mutation clones) − 12% worsened (fatigue—MS patient and ecchymosis)

• Registration follow-up study based upon these data

1. Awan FT et al. ASH 2016. Abstract 638 2. Awan F et al. In submission. Phase 3 Studies With Acalabrutinib in CLL1,2

Elevate CLL TN1 Obinutuzumab + chlorambucil • N = 535 (anticipated) • Patients with newly R Acalabrutinib + obinutuzumab diagnosed CLL Acalabrutinib monotherapy

Elevate CLL R/R2 • N = 500 (anticipated) Acalabrutinib • Patients with previously R treated high-risk CLL (del[17p] or del[11q]) Ibrutinib

1. https://clinicaltrials.gov/ct2/show/NCT02475681. Accessed August 27, 2018. 2. https://clinicaltrials.gov/show/NCT02477696. Accessed August 27, 2018. PI3K Inhibitors: Idelalisib Idelalisib Is Highly Effective in Relapsed/Refractory CLL1

1. Furman RR et al. N Engl J Med. 2014;370:997-1007. Idelalisib Is Highly Effective in Relapsed/Refractory CLL (Cont’d)1

1. Furman RR et al. N Engl J Med. 2014;370:997-1007. Monitoring for Potentially Serious Adverse Events With Idelalisib

• Serious AEs, including infection, have been noted with idelalisib therapy (including in combination with rituximab or regimens such as BR)1

Monitor for  Autoimmune colitis, iwCLL recommendations pneumonitis (2018)  Infection (eg, CMV reactivation, herpes zoster)

1. Hallek M et al. Blood. 2018;131:2745-2760. Another PI3K Option? Duvelisib Improves PFS vs Ofatumumab in Relapsed/Refractory CLL1 Phase 3 DUO Trial (N = 319) PFS per IRC PFS per Investigator Assessment

Median PFS, mo HR 95% CI P Median PFS, mo HR 95% CI P Duvelisib 13.3 12.1-16.8 Duvelisib 17.6 15-22 0.52 <.0001 0.40 <.0001 Ofatumumab 9.9 9.2-11.3 Ofatumumab 9.7 9-11 1. Flinn I et al. ASH 2017. Abstract 493. Another PI3K Option? Umbralisib in R/R CLL1

• Early phase study in patients with relapsed and/or refractory NHL, CLL, HL, or T cell (≥1 prior treatment regimen)

Objective Disease Response, n (%)

CLL (n = 20) 17 (85)

CLL, del(17p)/ 6 (75) del(11q) (n = 8)

FL (n = 17) 9 (53)

DLBCL (n = 13) 4 (31)

1. Burris HA et al. Lancet Oncol. 2018;19:486-496. Next-Generation Antibodies in CLL CLL11: Obinutuzumab or Rituximab + Chlorambucil vs Chlorambucil Alone for Newly Diagnosed CLL1

Obinutuzumab + Chlorambucil Obinutuzumab + Chlorambucil vs Chlorambucil vs Rituximab + Chlorambucil

Obinutuzumab + chlorambucil associated with prolonged PFS vs chlorambucil (left) and rituximab + chlorambucil (right)

1. Goede V et al. N Engl J Med. 2014;370:1101-1110. CLL11: Final Efficacy Analysis (Median Follow-Up, ~5 Years)1

• Median OS not reached with obinutuzumab + chlorambucil compared with 73.1 months for rituximab plus chlorambucil (HR, 0.76; P < .0245)

• Obinutuzumab combination reduced risk of disease progression/death by 51% vs rituximab regimen; median PFS was 28.9 versus 15.7 months, respectively (HR, 0.49; P < .0001)

• Prolonged TTNT with obinutuzumab treatment (56.4 months vs 34.9 months; HR, 0.58; 95% CI, 0.46-0.73; P < .0001); rate of MRD negativity was 24% versus 2%, respectively

1. Goede V et al. EHA 2018. Abstract S151. Ublituximab: Novel Anti-CD20 mAb in B-Cell NHL1

CD20 Antigen Binding Epitope of Ublituximab • Chimeric mAb targeting a unique epitope on the CD20 antigen • Active as single-agent and in combination with PI3K inhibitors in aggressive/indolent NHL2,3

Phase 3 GENUINE study: Ublituximab + ibrutinib more active vs ibrutinib alone in high-risk, relapsed/refractory CLL4

1. Sharman JP et al. Br J Haematol. 2017;176:412-420. 2. O’Connor OA et al. ASCO 2014. Abstract 8524. 3. Lunning M et al. ASH 2016. Abstract 4197. 4. Sharman JP et al. ASCO 2017. Abstract 7504. Next Steps With Ublituximab in CLL

• Early data suggested that the combination of ublituximab + umbralisib (U2) was well tolerated and active in pretreated and high-risk patients with CLL1 • Phase 3 UNITY CLL trial now assessing U2 combination2

• Treatment-naïve or previously treated CLL Ublituximab + umbralisib • ECOG PS 0-2 Primary • No prior tx with a PI3Kδ R endpoint: inhibitor, obinutuzumab, 1:1 PFS or chlorambucil Obinutuzumab + • Planned N = 600 chlorambucil

1. Lunning M et al. ASH 2014. Abstract 801. 2. https://clinicaltrials.gov/ct2/show/NCT02612311. Accessed September 5, 2018. Special Considerations for Use of Novel Anti-CD20 Antibodies1-4

Obinutuzumab Ofatumumab Minimize infusion reactions Initial dosing  Divide initial dose over 2 days  Newly diagnosed CLL: 300 mg on day 1  Premedicate patients with → 1,000 mg on day 8 (cycle 1) steroids/antihistamines  Extended treatment: 300 mg on day 1; Anticipate TLS refractory CLL: 300 mg on day 1  Premedicate patients with TLS antihyperuricemics and adequate  Antihyperuricemic, hydration hydration, especially those with high IRRs tumor burden and/or high circulating lymphocyte count  Premedicate with corticosteroid, acetaminophen, and an antihistamine

1. National Comprehensive Cancer Network (NCCN) Clinical Practice Guidelines in Oncology. B-Cell Lymphomas. Version 4.2018. 2. Goede V et al. N Engl J Med. 2014;370:1101-1110. 3. GAZYVA (obinutuzumab) Prescribing Information. http://www.gene.com/ download/pdf/gazyva_prescribing.pdf. Accessed August 28, 2018. 4. ARZERRA (ofatumumab) Prescribing Information. http://www.pharma.us.novartis.com/product/pi/pdf/arzerra.pdf. Accessed August 28, 2018. Bcl-2 Inhibitor: Venetoclax Venetoclax1

• BH3 mimetic

• Orally bioavailable

• Selective inhibitor of Bcl-2 that does not target Bcl-xL

• Approved for use in patients with CLL ± del17p who have received at least one prior therapy

1. Souers AJ et al. Nat Med. 2013;19:202-208. Venetoclax in Relapsed CLL: Progression-Free Survival and Duration of Response1

1. Roberts AW et al. N Engl J Med. 2016;374:311-322. M14-032, the First Prospective Study of any Treatment for Patients Progressing on a KI … … found that venetoclax is active post ibrutinib1

* * * * *

• 91 pts progressed after ibrutinib, treated with venetoclax • Median 4 prior therapies (range 1-15), del(17p) in 44% • ORR, 65%; CR/CRi rate, 9% • Peripheral blood MRD rate at 24 weeks (n = 57): 42% • Median follow-up: 14 mo 1. Jones JA et al. Lancet Oncol. 2018;19:65-75. M14-032: Venetoclax Is Also Active for Patients Progressing on Idelalisib1

• 36 pts progressed after idelalisib • Overall response rate: 67% were treated with venetoclax • Median follow-up: 14 mo • Median 3 prior therapies (range 1-11) • Del(17p) in 22%, unmutated IGHV in 88%

1. Coutre S et al. Blood. 2018;131:1704-1711. Phase 3 MURANO: Venetoclax + Rituximab Effective vs BR in Relapsed/Refractory CLL1

Rate of MRD Clearance Over Time

1. Seymour JF et al. N Engl J Med. 2018; 378:1107-1120. Venetoclax Safety

• Most common adverse reactions (≥20%) include neutropenia, diarrhea, nausea, anemia, upper respiratory tract infection, thrombocytopenia, and fatigue

• Anticipate TLS 1. Assess risk in all patients 2. Premedicate with antihyperuricemics and ensure adequate hydration 3. Employ more intensive measures (IV hydration, frequent monitoring, hospitalization) as overall TLS risk increases

• Monitor for neutropenia, with medical management as appropriate Summary Thoughts on Novel Agent Classes in CLL

1. BTK inhibitors: Increasingly an option across the spectrum of CLL treatment settings − Ibrutinib: approved broadly in CLL; combination studies underway − Acalabrutinib: active, potential role in BTK-intolerant CLL; phase 3 studies in newly diagnosed and relapsed settings

2. PI3K inhibitors: Idelalisib approved; duvelisib with phase 3 data; umbralisib emerging

3. Anti-CD20 mAbs: − Obinutuzumab, ofatumumab active in CLL, applications in older patients with comorbid illnesses – Ublituximab being assessed in phase 3 trials

4. Bcl-2: Venetoclax is highly active in relapsed CLL; intriguing combination data

Innovative Therapeutics as the Path Forward in Follicular Lymphoma

Nathan H. Fowler, MD Associate Professor of Medicine, Department of Lymphoma/Myeloma Photo Pending The University of Texas MD Anderson Cancer Center Houston, Texas

Go online to access full [Certification Type] information, including faculty disclosures. Tumor Board in FL: A Woman With Advanced Disease Requiring Treatment

Susan diagnosed After 3 years Susan Results of further with low-grade FL returns to clinic testing and patient at age 59 (age 62) with fatigue, discussion fever, night sweats • CD10+, CD20+, • B symptoms • CBC remains Bcl-2+ • Lymphadenopathy, normal • No B symptoms or with one tumor • Susan very splenomegaly mass of 7 cm concerned about during presentation • Treatment toxicity of standard • W/W approach recommended R-chemotherapy recommended (GELF) • Echocardiogram normal Tumor Board in FL: Treatment Pathway

R-chemo: ↑neutropenia, FN, Susan clearly requires treatment GFS use, nausea, vomiting, now that she has developed B neuropathy, alopecia symptoms and other treatment 2 criteria (GELF) … R : ↑ cutaneous reactions, tumor flare, diarrhea

Based on phase 3 RELEVANCE trial, R2 (chemo- After achieving a response with sparing) regimen an option R2 Susan continues on therapy Addresses some of her with rituximab maintenance concerns over toxicity Be aware of differences in AE profiles & discuss with your patients Guidance for FL Treatment Decisions

GELF Criteria (Indications for Treatment in FL)1 1. Patient comorbidities  Any nodal or extranodal tumor mass ≥7 cm  ≥3 nodal sites, each >3cm 2. Aggressiveness/  Presence of B symptoms grade of disease  Splenomegaly 3. Goals of treatment/  Compression or vital organs compromise patient preference  Significant serous effusions; lymphocyte count >5.0 x 109/L 4. GELF criteria  Cytopenia (granulocyte count <1.0 x 10⁹/L and/or platelets <100 x 10⁹/L)

1. Solal-Celigny P et al. J Clin Oncol. 1998;16:2332-2338 Many Novel Agent Classes Now Included in Recommendations for FL Therapy (NCCN)1

Second-Line or First Line First-Line Consolidation or Extended Dosing Subsequent Therapy

Preferred Preferred Bendamustine + Bendamustine + obinutuzumab or rituximab obinutuzumab or rituximab R-CHOP or G-CHOP R-CHOP or G-CHOP R-CVP or G-CVP Rituximab R-CVP or G-CVP Other recommended Obinutuzumab Lenalidomide ± rituximab Lenalidomide + rituximab RIT (ibritumomab tiuxetan) Rituximab Rituximab Other recommended Alternative strategies Idelalisib available for elderly or infirm Copanlisib if above unlikely to be tolerable Ibritumomab tiuxetan

Options for second-line consolidation or extended dosing include: rituximab, obinutuzumab, HDT + autoSCT, alloSCT for selected patients

1. NCCN Clinical Practice Guidelines in Oncology. B-Cell Lymphomas. Version 4.2018. Next-Generation Antibodies: Obinutuzumab in FL Novel Antibodies: The Next Phase in Targeting CD201-3

• Anti-CD20 antibodies such as rituximab play a key role in augmenting chemotherapy in NHL

Next-generation antibodies represent methods for enhancing antitumor activity via enhanced CDC (ofatumumab) or more potent direct cell death/ADCC (obinutuzumab, ublituximab)

1. Alduaij W et al. Blood. 2011;117:4519-4529. 2. Le Garff-Tavernier M et al. Leukemia. 2014;28:230-233. 3. Lin TS. Pharmacogenomics Pers Med. 2010;3:51-59. GADOLIN: Phase 3 Study of Obinutuzumab + Bendamustine for R/R FL1

Stratified by rituximab-refractory type Maintenancea and number of prior therapies (≤2 vs >2)

Obinutuzumab + bendamustine • Patients with FL who Obinutuzumab did not respond or x 6 cycles CR, PR, SD who progressed within (n = 194) For 2 y or until progression 6 mo of therapy with a R rituximab-containing regimen Bendamustine • N = 396 x 6 cycles (n = 202)

• Primary endpoint: IRC-assessed PFS • Secondary endpoints: Investigator-assessed PFS, best ORR (CR + PR), DOR, OS a Those without disease progression at the end of 6 cycles. 1. Sehn et al. Lancet Oncol. 2016;17:1081-1093. GADOLIN: Interim Analysis Outcomes1

Obinutuzumab + Bendamustine Parametera Bendamustine At 24.1 mo, (n = 166) (n = 155) obinutuzumab + bendamustine IRC PFSb Median NR 13.8 mo followed by Investigator-assessed 29.2 mo 13.7 mo obinutuzumab PFSb reduced risk of death CR 15.5% 18.7% by 38% compared PR 63.2% 56.0% with bendamustine alone DOR Median NR 11.6 mo

• Most common grade 3-4 AEs in obinutuzumab + bendamustine were neutropenia, thrombocytopenia, and infusion reactions a Median follow-up: 21.1 mo. b HR = 0.48; P < .001. 1. Sehn et al. Lancet Oncol. 2016;17:1081-1093. GADOLIN: Extended Follow-Up1

GADOLIN update: Kaplan–Meier A B plots of PFS in (A) the ITT population and in (B) patients with FL

• After median follow-up of 31.8 months, analysis confirms the benefits of obinutuzumab + bendamustine vs bendamustine

• Substantial OS benefit also was Obinutuzumab Outcome, mo Bendamustine HR; P demonstrated in the ITT + Bendamustine population and in patients with FL PFS, ITT 25.8 14.1 0.57; <.001 PFS, FL 25.3 14.0 0.52; <.001

OS, ITT NE NE 0.67; .0269 OS, FL NE 53.9 0.58; .0061

1. Cheson BD et al. J Clin Oncol. 2018;36:2259-2266. GALLIUM: Phase 3 Study of Obinutuzumab vs Rituximab for Previously Untreated FL1 Stratified by chemotherapy, Maintenance Induction FLIPI, and geographic region For 2 y or until progression

• Treatment-naïve adult Obinutuzumab patients with CD20+ + CHOP, CVP, or Obinutuzumab iNHL, including FL bendamustine (n = 539) (grade 1-3)a (n = 601) CR or PR • Stage III/IV or stage II R at EOI visit bulky disease (≥7 cm) Rituximab • ECOG PS 0-2 + CHOP, CVP, Rituximab or bendamustine (n = 527) • N = 1,202 (n = 601) • Primary endpoint: Investigator-assessed PFS in FL patients • Secondary endpoints: IRC-assessed PFS (confirmatory), OS, EFS, DFS, DOR, TTNT, CR/ORR at EOI (±FDG-PET), safety a All data presented for patients with FL though study also enrolled MZL patients (randomized separately). 1. Marcus RE et al. ASH 2016. Abstract 6. GALLIUM: Outcomes1

Primary Endpoint: Obinutuzumab + Rituximab Investigator-Assessed PFS Chemotherapy + Chemotherapy (n = 601) (n = 601)

ORR,a % 88.5 86.9 CR,a % 19.5 23.8 PR,a % 69.1 63.1 3-y PFS,b,c % 81.9 77.9 O-chemo, n = 601 R-chemo, n = 601 3-y OS,d % 94.0 92.1

• Grade 3/4 AEs were more frequent with obinutuzumab, and included infection/infestation, cytopenias, and IRRs a Investigator-assessed by Revised Response Criteria for Malignant Lymphoma. b IRC-assessed. c HR, 0.71; P = .0138. d HR, 0.75; P = .21. 1. Marcus RE et al. ASH 2016. Abstract 6. Can We Consider Chemotherapy-Free Options in FL? MAGNIFY Phase 3b Study: Lenalidomide + Rituximab in Relapsed/Refractory FL1

Lenalidomide + rituximab (R2) induction → R2 vs rituximab maintenance in R/R NHL Subanalysis of FL pts who are double-refractory (DR) or had early relapse (ER) ( <2 y) after initial dx

Best Response in Induction and Maintenance in Evaluable Patients With FL DR ER Overall Response, n (%) n = 28 n = 33 n = 91 ORR 13 (46) 16 (48) 61 (67) CR/CRu 6 (21) 4 (12) 33 (36) PR 7 (25) 12 (36) 28 (31) SD 10 (36) 13 (39) 21 (23) PDa 5 (18) 4 (12) 9 (10)

• Common grade ≥3 TEAEs (DR, ER groups): Neutropenia (53%, 33%), leukopenia (9%, 12%), and lymphopenia (9%, 5%) a Includes PD and/or death prior to response evaluation completion. 1. Andorsky DJ et al. ASCO 2017. Abstract 7502. MAGNIFY: Best Response According to Line of Therapy1

<2L ≥2L Overall Response, n (%) (n = 99) (n = 133) (n = 232)

ORR 69 (70) 88 (66) 157 (68)

CR/CRu 50 (51) 48 (36) 98 (42)

1-y PFS 67 (68) 93 (70) 160 (69)

DOR 76 (77) 108 (81) 184 (79)

1. Andorsky DJ et al. ASCO 2018. Abstract 7516. Lenalidomide + Rituximab for Untreated iNHL: Phase 2 Efficacy Summary

Phase 2 • ORR: 90% (CR 63%, PR 27%) Lenalidomide • FL patients (n = 46) + rituximab – CR: 87%, PR: 11% 1,a (N = 103) – 79% remained in remission at 36 months

Phase 2 • Median PFS: NR vs 2.3 y, HR 0.58; P = .03 SAKK 35/10 Lenalidomide • CR/ CRu duration: NR vs 2.3 y, HR 0.43; P = .04 + rituximab • TTNT: NR vs 2.1 y, HR 0.56; P = .01 (n = 77) • CR/ CRu at 30 mo: 42% vs 19%; P = .001 vs rituximab (n = 76)2,b • 3-y OS: 93% vs 92% a Included patients with newly diagnosed FL, MZL, and SLL. b Started 14 days before the first rituximab treatment, continued until 14 days after the last treatment. 1. Fowler NH et al. Lancet Oncol. 2014;15:1311-1318. 2. Kimby E et al. ASH 2016. Abstract 1099. RELEVANCE: R2 vs R-chemo in Previously Untreated Advanced FL1

a Co-primary endpoints (superiority) Tx Period 1 Tx Period 2 Tx Period 3 • CR/CRu at 120 wk (~6 mo) (~1 y) (~1 y) • PFS

Previously untreated n = 513 R2 R2 Rituximab pts with advanced FL requiring treatment R per GELF 1:1 (N = 1,030) n = 517 R-Chemo Rituximab (R-CHOP, BR, R-CVP)

Stratification • FLIPI score (0-1 vs 2 vs 3-5) Total Treatment Duration: 120 wk • Age (>60 vs ≤60 y) • Lesion size (>6 vs ≤6 cm) a Per central (IRC) review by 1999 IWG with CT. 1. Fowler NH et al. 2018 American Society of Clinical Oncology (ASCO) Annual Meeting (ASCO 2018). Abstract 7500. RELEVANCE Dosing Schedule1

Treatment Period R2 Arm R-Chemo Arm Investigator/patient choice prior to randomization • Lenalidomide: 20 mg/d, d 2-22/28 1 (~6 mo) • R-CHOP (72%) • Rituximab: 375 mg/m2 • BR (23%) • R-CVP (5%) • Lenalidomide: 20 or 10 mg/d 2 (~1 y) per response at 6, 9, or 12 cycles Rituximab: 375 mg/m2 • Rituximab: 375 mg/m2 3 (~1 y) Rituximab: 375 mg/m2 Rituximab: 375 mg/m2 • R2: Lenalidomide 20 mg/d, d 2-22/28 until CR/CRu at 6, 9, or 12 cycles, then 10 mg/d (total 18 cycles); rituximab (R) 375 mg/m2/wk cycle 1 and d 1 and cycles 2-6; continued in responders every 8 wk for 12 cycles • R-CHOP: R 375 mg/m2 IV d 1, cyclophosphamide 750 mg/m2 IV d 1, doxorubicin 50 mg/m2 IV d 1, vincristine 1.4 mg/m2 IV d 1, prednisone 100 mg/d PO d 1-5; every 21 d x 6 and two 21-d cycles R 375 mg/m2 IV d 1 • BR: R 375 mg/m2 IV d 1 and bendamustine 90 mg/m2 IV d 1-2; every 28 d x 6 • R-CVP: R 375 mg/m2 IV d 1, cyclophosphamide 750 mg/m2 IV d 1, vincristine 1.4 mg/m2 IV d 1, prednisone 40 mg/d PO d 1-5; every 21 d x 8 • R maintenance: In responders, 375 mg/m2 IV d 1 of each cycle every 8 wk 1. Fowler NH et al. ASCO 2018. Abstract 7500. RELEVANCE: Response by IRC (ITT)1

Co-Primary Endpoint: Best CR/CRu Best ORR CR/CRu at 120 wk 100% 100% 100% P = .13 89% 90% 90% 90% 84%

80% 80% 80%

70% 70% 67% 70% 59% 60% 53% 60% 60% 50% 48% 50% 50%

40% 40% 40%

Response, % Response, % Response, 30% % Response, 30% 30% 20% 20% 20% 10% 10% 10% 0% 0% 0% R2 R-chemo R2 R-chemo R2 R-chemo (n = 513) (n = 517) (n = 513) (n = 517) (n = 513) (n = 517)

• 3-y DOR was 77% for R2 vs 74 for R-chemo (IRC) • Investigator results were consistent with IRC

1. Fowler NH et al. ASCO 2018. Abstract 7500. RELEVANCE: Interim PFS and OS1

R2 (n = 513) R-Chemo (n = 517) R2 (n = 513) R-Chemo (n = 517)

Events, n (%) 119 (23) 111 (21) Events, n (%) 38 (7) 31 (6)

3-y PFS (95% CI) 77% (72%-80%) 78% (74%-82%) 3-y OS (95% CI) 94% (91%-96%) 94% (91%-96%) HR (95% CI) 1.10 (0.85-1.43) P 0.48 HR (95% CI) 1.16 (0.72-1.86)

Data cutoff: May 31, 2017. 1. Fowler NH et al. ASCO 2018. Abstract 7500. RELEVANCE: Treatment-Emergent AEs1

R-Chemo (n = 503), %

Data cutoff: May 31, 2017. Includes any-grade TEAEs (≥15%) and select AEs of interest as assessed per NCI CTCAE v4.03. a Hematologic AEs were based on laboratory tests; all anemia events were grade 1. Cutaneous reactions include preferred terms from skin and subcutaneous tissue disorders (including rash), GI disorders, general disorders and administration-site conditions, infections and infestations, and reproductive system and breast disorders. 1. Fowler NH et al. ASCO 2018. Abstract 7500. Neutropenia and Neutropenic Complications (Entire Treatment Period)1

Patients, n (%) R2 (n = 507) R-chemo (n = 503) Grade 3/4 neutropeniaa 160 (32) 252 (50) Grade 4 neutropenia 41 (8) 154 (31) Nadir ANC <100/mcL 5 (1) 32 (6) Median time to onset of first grade 3/4 lab 3.7 mo 0.6 mo neutropenia Grade 3/4 infections associated with grade 3/4 10 (2) 20 (4) neutropenia Febrile neutropeniaa 11 (2) 34 (7) Febrile neutropenia requiring hospitalization 8 (2) 26 (5) Infections requiring hospitalization 46 (9) 60 (12) Received growth factors 117 (23) 340 (68)

• Per protocol, patients in the R2 arm had more frequent laboratory assessments than the R-chemo arm a Including 4 cases of febrile bone marrow aplasia (all in the R-chemo arm). 1. Fowler NH et al. ASCO 2018. Abstract 7500. RELEVANCE: Summary1

• R2 is not superior to R-chemo (based on PFS and mature CR data at 120 weeks) – Similar efficacy results between R2 and R-chemo

• Safety differences between treatment arms – R-chemo: More frequent neutropenia, FN, growth factor usage, nausea, vomiting, neuropathy, alopecia – R2: More frequent cutaneous reactions, tumor flare, diarrhea

• Results show that R2 is a potential first-line option in patients with FL requiring treatment

1. Fowler NH et al. ASCO 2018. Abstract 7500. PI3K Inhibitors in Relapsed/Refractory FL PI3K Inhibitors Inhibit Different PI3K Isoforms

Idelalisib Duvelisib Copanlisib Umbralisib 1 2 3 4 Isoform (IC50-nM) (IC50-nM) (IC50-nM) (IC50-nM) (Oral) (Oral) (IV) (Oral) P110α 20,000 1,410 0.4-1 10,000 P110β 1,900 26.2 10-18 800 P110γ 3,000 19.6 93 400 P110δ 8 0.36 3-10 24

1. Meadows SA et al. Blood. 2012;119:1897-1900. 2. Winkler DG et al. Chem Biol. 2013;20:1364-1374. 3. Haike K et al. ASH Meeting on Lymphoma Biology 2014. Abstract 48. 4. Vakkalanka S et al. American Association for Cancer Research Annual Meeting 2014 (AACR 2014). Poster 3741. Efficacy of Idelalisib in Relapsed Indolent Lymphoma1

1. Gopal AK et al. N Engl J Med. 2014;370:1008-1018. Efficacy of Idelalisib in Relapsed Indolent Lymphoma (Cont’d)1

1. Gopal AK et al. N Engl J Med. 2014;370:1008-1018. CHRONOS-1: Copanlisib in Patients With Relapsed, Indolent, or Aggressive NHL1

Phase 2 study • 142 patients with relapsed or Copanlisib 60 mg intravenously on refractory indolent days 1, 8, and 15 of a 28-day cycle lymphoma after ≥2 lines of therapy

Primary end point was ORR; secondary end points included duration of response, PFS, OS; in addition, safety and gene expression were evaluated

1. Dreyling M et al. J Clin Oncol. 2017;35:3898-3905. Efficacy of Copanlisib in R/R Indolent Lymphoma1

1. Dreyling M et al. J Clin Oncol. 2017;35:3898-3905. Efficacy of Copanlisib in R/R Indolent Lymphoma (Cont’d)1

Median, mo 11.2 Median, mo NR Range 0.2-24.0 Range 0-30.3 95% CI 8.1-24.0 95% CI ̶

1. Dreyling M et al. J Clin Oncol. 2017;35:3898-3905. Updates from ASH 2017: Copanlisib in Relapsed/Refractory Indolent NHL1

Updated analyses reaffirmed efficacy Low rate of individual severe toxicities of copanlisib in this setting overall, lack of late-onset toxicities with long-term follow up (29.6% with >1 year) • ORR of 58.5% and median DOR >1 y suggests that intermittent IV dosing may • Median PFS of 11.3 mo contribute to favorable safety profile for copanlisib

• SAEs: Pneumonia 11.3%, hyperglycemia 4.9%, pneumonitis 4.2%, neutropenia 2.8%, diarrhea 2.8%

1. Dreyling M et al. ASH 2017. Abstract 2777. Future Directions With Copanlisib

• Copanlisib to be further evaluated in phase 3 CHRONOS-3 (NCT02367040) and CHRONOS-4 trials (NCT02626455)

• Trials will assess copanlisib + R or standard immunochemotherapy regimens in FL, SLL, LPL, WM, and MZL

Novel PI3K Inhibitor Umbralisib in R/R Lymphoma1

• Early phase study in patients with relapsed and/or refractory NHL, CLL, HL, or T cell (≥1 prior treatment regimen)

Objective Disease Response, n (%)

CLL (n = 20) 17 (85)

CLL, del(17p)/ 6 (75) del(11q) (n = 8)

FL (n = 17) 9 (53)

DLBCL (n = 13) 4 (31)

1. Burris HA et al. Lancet Oncol. 2018;19:486-496. Is There a Role for BTK Inhibitors in FL? The Ibrutinib Experience in FL

DAWN Trial in Relapsed/Refractory FL (Single Agent)1 Ibrutinib + R Combination in Treatment-Naïve FL2

Efficacy Data 18% ORR 20.9% 27% CR Median DOR 19.4 mo PR Median TTNT 16 mo SD 55% Median PFS 4.6 mo NR Median OS (median follow-up = 27.7 mo) ORR, 82% (27% CR + 55% PR) 24-month OS 63% (95% CI, 0.53-0.72)

Percent Change in Tumor Size Effect of Ibrutinib + R on Tumor Size

200 100 (IRC-Assessed, ITT Population) X 150 X 50 100 X X X X X X X X X X 50 X X X X X 0 X X X X X X X X X Z X X X X X Z X Z X 0 X Z Z Z X Z Z X X Z Z Z X X Z X Z Z Z Z Z Z Z X Z Z X Z Z Z Z X Z Z Z Z Z Z X Z X X -50 -50 X O Y Y Z O Y Z Y Y Z Y Y O O Y Y O O Y O O O O O O -100 Y % SPD, Baseline From Maximum Improvement Improvement Maximum N = 60 -100 Change From Baseline, % Baseline, From Change -150 Median target lesion SPD at baseline was 24 cm2 (range, 2.2-135.5) 1. Gopal AK et al. J Clin Oncol. 2018;36:2405-2412. 2. Fowler N et al. ASH 2015. Abstract 470. Acalabrutinib ± Rituximab in FL1

Acalabrutinib dosing: 100 mg PO BID (2 patients received 200 mg QD) until PD or intolerance

• Phase 1b study evaluated TN Combo R/R Combo R/R Mono a acalabrutinib ± rituximab in (n = 13) (n = 13) (n = 12) patients with TN or R/R FL ORRb (≥ PR), n (%) 12 5 4

• Single-agent and combination 95% CI 64-100 14-68 10-65 therapy well-tolerated, with promising response rates in FL CR 4 (31) 1 (8) 1 (8)

• Results support further evaluation Median DOR, mo NR NR NR of acalabrutinib in FL Rangec 12.1 to 20.5+ 10.8+ to 20.5+ 0.03+ to 18.7+

a The 2 patients dosed at 200 mg once daily are not included (1 SD, 1 PD). b Investigator assessed using Cheson 2014 criteria. c “+” indicates ongoing response. 1. Fowler NH et al. EHA 2018. Abstract PF438. Summary Thoughts

• Multiple new novel agents have activity in untreated and relapsed follicular lymphoma

• Individualization of therapy is becoming more and more relevant and should include discussions on: – Goals and length of therapy – Toxicity/efficacy tradeoffs – Patient preferences and $

• Next generation of studies will focus on personalization of therapy and combination regimens ... stay tuned Insights on Treatment Choices in Mantle Cell Lymphoma Moving Beyond Conventional Care

Sonali M. Smith, MD Elwood V. Jensen Professor in Medicine Director, Lymphoma Program The University of Chicago Medicine Chicago, Illinois

Go online to access full [Certification Type] information, including faculty disclosures. Tumor Board in MCL: A Patient Relapsing After Upfront Immunochemotherapy and ASCT

66 year old male Presents now with Results of further with MCL s/p anemia and fatigue testing intensive CIT plus ASCT in 2009 • Induction chemo- • Patient has iron • Marrow has 30% immunotherapy was deficiency anemia involvement by maxi-R-CHOP • Colonoscopy shows MCL +cytarabine/etoposide scattered ulcerated • PET/CT with diffuse • Patient is a recovered nodules adenopathy, largest alcoholic but no other • Biopsy with lesion 3 cm medical comorbidities recurrent classic MCL, Ki67 25%, FISH with t(11;14) Tumor Board in MCL: Treatment Pathway

Chemoimmunotherapy Given this patient’s features and current evidence, options Ibrutinib ± rituximab available for treatment Acalabrutinib include … Lenalidomide + rituximab

PET/CT scan after 3 months Patient starts ibrutinib shows complete metabolic monotherapy 560 mg daily response Tumor Board in MCL: An Alternate Pathway

Alternatively, if this patient had been frail/elderly and with history Venetoclax of uncontrolled atrial fibrillation, Lenalidomide + rituximab history of subdural hematoma, Acalabrutinib potential options could include ...

Need to monitor for TLS Need to consider prophylaxis with venetoclax for VTE with lenalidomide A Snapshot of MCL Pathogenesis: Two Biologic Variants1

Typically positive Aggressive 90% extranodal for CD5, CD20 presentation involvement; Leukemic Cyclin D1 positivity with B symptoms adenopathy non-nodal MCL a hallmark of MCL in <50% of cases 70%-90%

Naïve B Cell Early MCL Classical MCL Blastoid MCL • Memory B-cell like • Germinal center Germline experienced ATM • Indolent clinical CHK2 course T(11;14) ATM INK4A/CDK4/RB1 • SOX11 negative Cyclin D1 CHK2 ARF/MDM2/p53

RB1 p27 Complex High karyotypes proliferation

1. Puente XS et al. Blood. 2018;131:2283-2296. To Date, Most Novel Agents Have Applications as Second-Line Therapy in MCL (NCCN)1

Induction Therapy Second-Line Therapy

Aggressive Less Aggressive Short response after Extended response • CALGB regimen • BR prior therapy after prior therapy • Acalabrutinib • BRa • Hyper-CVAD + rituximab • R-CHOP → consolidation • Ibrutinib ± rituximab • Bortezomib • NORDIC regimen with rituximab maintenance • Lenalidomide ±rituximab • Lenalidomide + rituximab • Sequential R-CHOP/RICE ± rituximab • Small molecule • Alternating R-CHOP/R- • VR-CAP • Venetoclax inhibitors DHAP • Modified hyper-CVAD + • Ibrutinib + rituximab • Bendamustine, rituximab → rituximab + lenalidomide bortezomib, maintenance (age >65 y) rituximab a • RBAC • R-CHOP, VR-CAP, or PEPC

• First-line consolidation: HDT + autologous stem cell rescue • Second-line consolidation: alloSCT or rituximab if not eligible for SCT (myeloablative or nonmyeloablative) a If not previously given 1. NCCN Clinical Practice Guidelines in Oncology. B-Cell Lymphomas. Version 4.2018. BTK Inhibitors: Ibrutinib and Acalabrutinib Targeting BCR Signaling Bruton’s Tyrosine Kinase (BTK)

• Member of the Tec family of kinases • Roles in signaling (eg, BCR, TLR), as well as transcription • Leads to activation of PI3K, PLCγ2, MAPK, and NFκΒ pathways • BTK-deficient models predominantly have a B-cell phenotype – XID (BTK mutant) mouse: Diminished B cells, B1 lymphocytes, and impaired BCR signaling. Modest effect on other immune effector cells (NK, monocyte, macrophage, dendritic cells) due to redundancy of TEC family members – BTK knockout mouse: More profound B-cell defect due to loss of chaperone and transcriptional function • BTK mutations in humans give rise to X-linked agammaglobulinemia, an inherited disorder with decreased IgG and an absence of B cells Ibrutinib Pivotal Phase 2 Study of Ibrutinib in MCL1,2

• 111 pts with relapsed or refractory MCL received ibrutinib 560 mg/day (dose differs from that used in CLL) • Demographics: Median age of 68 years; 3 prior therapies

• Most common AEs: Diarrhea, fatigue, and nausea, with grade 3 hematologic toxicity uncommon (<20%) Ibrutinib in MCL: • ORR was 67%, with 23% attaining a CR by Cheson criteria Efficacy • Median treatment duration was 8.3 months; median and Safety duration of response of 17.5 months • At a median follow-up of 26.7 months, median PFS is 13 months and median OS is 22.5 months

1. Wang ML et al. Blood. 2015;126:739-745. 2. Wang ML et al. N Engl J Med. 2013;369:507-516. Outcome of Pivotal Study of Relapsed Mantle Cell Lymphoma1,2

1. Wang ML et al. Blood. 2015;126:739-745. 2. Wang ML et al. N Engl J Med. 2013;369:507-516. Phase 3 Study of Ibrutinib vs Temsirolimus in Relapsed MCL1,2

Ibrutinib Temsirolimus Ibrutinib Temsirolimus (n = 139) (n = 141) (n = 139) (n = 141) Median PFS, mo 15.6 6.2 Median PFS, mo 30.3 23.5 HR 0.45 HR 0.74 95% CI 0.35-0.60 95% CI 0.54-1.02 Log-rank P <.0001 Log-rank P <.0621

1. Rule S et al. Leukemia. 2018 Feb 2 [Epub ahead of print]. 2. Dreyling M et al. Lancet. 2016;387:770-778. Ibrutinib Combinations in MCL

Rituximab: Higher response rate; long-term benefit in low Tam et al: Ibrutinib + Venetoclax in MCL4 proliferative rate disease1 Response at 16 Without PET With PET weeks, % (N = 24) (n = 24) R2: High response rate in relapsed MCL, justifying CR 42 62 phase 3 trial2 Ibrutinib CRu 17 ̶ + BR: Can be safely PR 17 8 combined, and multicenter phase 3 trial SD 8 4 completed enrollment with final results Best CR = 67% without PET, 71% with PET pending3

Venetoclax: High CR rate (42%) in relatively high-risk pts, but short follow-up4

1. Jain P et al. Br J Haematol. 2018 May 22 [Epub ahead of print]. doi:10.1111/bjh.15411. 2. Jerkeman M et al. Lancet Haematol. 2018;5:e109-e116. 3. https://clinicaltrials.gov/ct2/show/NCT01776840. 4. Tam CS et al. N Engl J Med. 2018;378:1211-1223. Acalabrutinib Background on Acalabrutinib in MCL1

• Led to phase 2 Acalabrutinib Ibrutinib Acalabrutinib: More selective ACE-LY-004 trial in for BTK with less off-target relapsed/refractory MCL Kinase kinase inhibition compared Selectivity with ibrutinib in vitro • Tested 100 mg twice- Profiling daily dose and schedule at 1 M

Phase 1/2 ACE-CL-001 Larger red circles represent stronger inhibition trial in CLL provided evidence for activity in B-cell malignancies

1. Byrd JC et al. N Engl J Med. 2016;374:323-332. Acalabrutinib in Relapsed/Refractory MCL1

• Phase 2 study of 124 patients with relapsed or refractory disease treated with acalabrutinib 100 mg BID until progression • Demographics include: Median age of 68 years; 2 prior therapies

• ORR was 81% with 40% attaining a CR • The median duration of treatment was 13.8 months with 31% Acalabrutinib in R/R D/C due to PD and 6% from AEs MCL: • Common AEs include headache (38%), diarrhea (31%), fatigue Efficacy and Safety (27%), and myalgia (21%) • Common grade ≥3 AEs include neutropenia (10%), anemia (9%), and pneumonia (5%), with no cases of atrial fibrillation

1. Wang M et al. Lancet. 2018;391:659-667. Acalabrutinib in Relapsed/Refractory MCL: Response Summary1

• Maximum change from baseline in the SPD of target lesions for all treated patients with baseline and one or more post-baseline lesion measurements • Percentage change in SPD is shown by best response achieved in each patient

1. Wang M et al. Lancet. 2018;391:659-667. Acalabrutinib in Relapsed/Refractory MCL: PFS and OS1

NR

NR

1. Wang M et al. Lancet. 2018;391:659-667. Phase 3 ACE-LY-308 Study: Acalabrutinib + BR in Newly Diagnosed MCL1

• Patients with newly Acalabrutinib administered twice per day orally diagnosed MCL + bendamustine on days 1 and 2 and rituximab on day 1 • ≥65 years of age cycles are repeated every 28 days • Pathologically confirmed MCL requiring tx; no prior R systemic therapies Placebo • ECOG PS ≤2 + bendamustine on days 1 and 2 and rituximab on day 1 • Estimated N = 546 cycles are repeated every 28 days

• Primary endpoint: Progression-free survival per the Lugano classification for NHL in Arm 1 vs Arm 2 a Agreement to use highly effective forms of contraception during the study and 90 days after the last dose of acalabrutinib, 6 months after the last dose of bendamustine, or 12 months after the last dose of rituximab, whichever is longest. 1. https://clinicaltrials.gov/ct2/show/NCT02972840. Accessed September 5, 2018. Take-Homes: BTK Inhibitor Therapy in MCL

Ibrutinib and acalabrutinib are both FDA approved for ≥2nd-line therapy

• Considerations when selecting treatment with BTK inhibitors

 Ibrutinib clinical trial patients more heavily pretreated (3 vs 2 prior tx)  Different response criteria used to judge CR  Differing adverse event profiles  Weigh patient characteristics (eg, history of cardiac events, AFib) and prior treatment when deciding on therapy Immunomodulatory Agent: Lenalidomide Immunomodulatory Agents for MCL: Lenalidomide

• Lenalidomide, approved for use in MCL that has relapsed or progressed after 2 prior therapies (one of which included bortezomib), has shown efficacy as monotherapy and in combination with rituximab

Lenalidomide + Lenalidomide Lenalidomide Rituximab Phase 2 EMERGE Phase 1/2 Study2 MCL-004 Study3,a Efficacy Outcomes Study1 N = 52 N = 30 N = 134 ORR, % 28 57 27 • Relapsed/progressed on Median DOR, mo 16.6 18.9 ibrutinib: 4.1 • Ibrutinib refractory: 2.5 Median PFS, mo 4.0 11.1 − a Patients failing ibrutinib therapy. 1. Goy A et al. Br J Haematol. 2015;170:496-503. 2. Wang M et al. Lancet Oncol. 2012;13:716-723. 3. Wang M et al. ASH 2016. Abstract 1786. SPRINT: Lenalidomide vs Investigator’s Choice for Relapsed/Refractory MCL1

Median Follow-Up: Lenalidomide ICa 15.9 mo (n = 170) (n = 84) Median PFS, mo (95% CI) 8.7 (5.5-12.1) 5.2 (3.6-6.9) HR 0.61; P = .004

Lenalidomide reduced the risk of PD or death by 39% vs IC, reflected as an estimated improvement in median PFS of 3.5 mo

Approved in relapsed/refractory MCL Recommended starting dose: 25 mg/d orally, days 1-21 a Commonly used chemotherapy regimens for MCL. 1. Trneny M et al. Lancet Oncol. 2016;17:319-331. Phase 2 Study of Lenalidomide + Rituximab as Initial and Maintenance Therapy in MCL: 5-Year F/U1

• Median follow-up: 61 mo Efficacy Evaluable Outcome, % Endpoint, % 36 mo 48 mo (n = 36) (95% CI) ORR 92 80.3 70.6 PFS rate CR 64 (63.0-90.1) (52.0-83.1) PR 28 SD 3 91.9 83.0 OS rate PD 6 (76.9-93.7) (65.9-92.0) • 22 of 33 pts in maintenance phase have ongoing response • 8 of 9 pts (89%) with CR who completed ≥ 35 mo of study therapy achieved MRD-negative peripheral blood • OS rate significantly higher with low/intermediate-risk vs high-risk MIPI score (91.4% vs 65.6%; log-rank P = .02) 1. Ruan J et al. ASH 2017. Abstract 154. First-Line Lenalidomide + Rituximab in MCL: Safety Summary1

AEs in >15% of Patients Hematologic Induction Maintenance AEs, % ≥Grade 3 ≥Grade 3 Fatigue Rash Fever Neutropenia 68 42 66 42 Cough Diarrhea Induction Grade 1/2 Grade ≥3 Hyperglycemia Anemia 47 8 32 3 Constipation Maintenance Grade 1/2 Grade ≥3 Edema Tumor Flare Thrombocytopenia 29 11 37 5 Infusion Rxn Nausea Febrile neutropenia 3 3 5 5 Anorexia Dyspnea Hyponatremia Elev ALT Elev AST • Continued treatment not associated Arthralgia with notable cumulative toxicity Elev Alk Phos Headache Dizziness • Further study of outpatient upfront Hypothyroid lenalidomide + rituximab Myalgia Neuropathy in MCL warranted 0 10 20 30 40 50 60 70 80 90 100 Patients, %

1. Ruan J et al. ASH 2017. Abstract 154. Clinical Considerations With IMiDs (Lenalidomide)1

 Be aware of TLS; thromboprophylaxis recommended AEs  Patient education and supportive care for AEs such as fatigue, rash, neutropenia, and GI events

 Starting dose 20-25 mg/day PO, days 1-21 (28-day schedule) in MCL Dosing  Dose modification recommended to manage grade 3/4 neutropenia or thrombocytopenia; initial dose adjustments recommended in cases of renal impairment

1. NCCN Clinical Practice Guidelines in Oncology. B-Cell Lymphomas. Version 3.2017. Sequencing With Novel Agents: Venetoclax After BTK Inhibitor Therapy Venetoclax After BTK inhibition in Relapsed MCL1

Progression-Free Survival Overall Survival • Venetoclax monotherapy was associated with an ORR of 60% in patients with poor-risk R/R MCL previously treated with a BTK inhibitor

• It was reported that 20% Duration of Response Progression-Free Survival of patients had a CR (PR/CR vs Non-Responders; P = .001) by Prior Ibrutinib Response (P = .558)

1. Eyre T et al. EHA 2018. Abstract S855. Phase 3 Study of Ibrutinib in Combination With Venetoclax in MCL (SYMPATICO)1 Safety run-in period: Participants are enrolled into the open-label safety run-in period to evaluate the occurrence of TLS and DLTs with the concurrent administration of ibrutinib and venetoclax

Patients with pathologically confirmed MCL and:  At least 1 measurable site of disease on Ibrutinib + venetoclax cross-sectional imaging (CT/PET)  At least 1, but no more than 5, prior treatment regimens for MCL  Failure to achieve at least PR with, or documented PD after the most recent Ibrutinib + placebo treatment regimen Estimated N = 287

• Primary endpoints: Occurrence of TLS, DLT (run-in phase); PFS

1. https://clinicaltrials.gov/ct2/show/NCT03112174. Accessed August 27, 2018. Summary: Role of New Agent Classes in Relapsed/Refractory MCL Treatment

• New era of targeted and/or biologic agents available for patients – Two options for BTK inhibition: Ibrutinib and acalabrutinib – Venetoclax – Lenalidomide + rituximab

• MCL remains incurable – Combinations need rapid testing and evaluation – Limited duration treatment would be ideal – Use of MRD testing to determine options under evaluation Audience Q&A Please remember to complete and submit your Post-Test and Evaluation for CME credit. Missed anything?

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Thank you and good evening. Abbreviations

ADCC: antibody-dependent cell-mediated cytotoxicity CALGB: Cancer and Leukemia Group B AE: adverse event CD: cluster of differentiation AFib: atrial fibrillation CDC: complement-dependent cytotoxicity alloSCT: allogeneic hematopoietic stem cell transplantation Chemo: chemotherapy ANC: absolute neutrophil count CHOP: cyclophosphamide, doxorubicin hydrochloride, vincristine sulfate, and prednisone autoSCT: autologous stem cell transplantation CIT: chemoimmunotherapy B-ALL: B-cell acute lymphoblastic leukemia Clb: chlorambucil BCR: B-cell receptor CLL: chronic lymphocytic leukemia BCRi: B-cell receptor inhibitor CR: complete response BID: twice a day CRi: complete remission with incomplete hematologic recovery BLK: B-lymphocyte kinase CRu: complete remission/unconfirmed BM: bone marrow CT: computed tomography BMT: bone marrow transplant CTCAE: Common Terminology Criteria for Adverse Events BR: bendamustine and rituximab CVAD: cyclophosphamide, vincristine, doxorubicin, and BTK: Bruton tyrosine kinase dexamethasone

Abbreviations

CVP: cyclophosphamide, vincristine, and prednisolone FDG-PET: fluorodeoxyglucose-positron emission tomography DAG: diglyceride FISH: fluorescence in situ hybridization DFS: disease-free survival FL: follicular lymphoma DHAP: dexamethasone, high-dose cytarabine, and cisplatin FLIPI: Follicular Lymphoma International Prognostic Index DLBCL: diffuse large B-cell lymphoma FN: febrile neutropenia DLT: dose-limiting toxicity G-CHOP: obinutuzumab, cyclophosphamide, doxorubicin hydrochloride, vincristine sulfate, and prednisone DOR: duration of response G-CVP: obinutuzumab, cyclophosphamide, vincristine, and DR: double-refractory prednisolone ECOG: Eastern Cooperative Oncology Group GELF: Groupe d'Etude des Lymphomes Folliculaires EFS: event-free survival GFS: Growth Factor Signature EGFR: epidermal growth factor receptor HDT: high-dose therapy EOI: end of induction HL: Hodgkin lymphoma ER: early relapse IC: investigator’s choice F/U: follow-up IC50: half maximal inhibitory concentration FCR: fludarabine, cyclophosphamide, and rituximab IgG: immunoglobulin G

Abbreviations

iNHL: indolent non-Hodgkin lymphoma MCL: mantle cell lymphoma Inv: investigator MIPI: Mantle Cell Lyphoma International Progrnostic Index IP3: inositol triphosphate MRD: minimal residual disease IRC: independent review committee MS: multiple sclerosis IRR: infusion-related reaction MZL: marginal zone lymphoma ITK: interleukin-2-inducible T-cell kinase NCCN: National Comprehensive Cancer Network iwCLL: International Workshop on Chronic Lymphocytic Leukemia NCI: National Cancer Institute IWG: International Working Group NE: nonevaluable JAK3: Janus kinase 3 NFκB: nuclear factor kappa B KI: kinase inhibitor NHL: non-Hodgkin lymphoma LDH: lactate dehydrogenase NK: natural killer LOT: line of therapy NOS: not otherwise specified LPL: lymphoplasmacytic lymphoma nPR: nodular partial response mAb: monoclonal antibody NR: not reached MAPK: mitogen-activated protein kinase O: obinutuzumab

Abbreviations

Ofa: ofatumumab R2: rituximab and lenalidomide ORR: overall response rate RBAC: rituximab, bendamustine, and cytarabine PB: peripheral blood R-chemo: rituximab and chemotherapy PD: progressive disease R-CHOP: rituximab, cyclophosphamide, doxorubicin hydrochloride, vincristine sulfate, and prednisone PEPC: prednisone, etoposide, procarbazine, and cyclophosphamide R-CVP: rituximab, cyclophosphamide, vincristine, and prednisolone PI3K: phosphoinositide 3-kinase RICE: rituximab, ifosfamide, carboplatin, and etoposide PIP2: phosphatidylinositol 4,5-bisphosphate RIT: radioimmunotherapy PIP3: phosphatidylinositol 3,4,5-trisphosphate RPSFTM: rank-preserving structural failure time PLCγ2: phospholipase gamma 2 RT: radiotherapy PN: peripheral neuropathy s/p: status post PR: partial response SAE: serious adverse event PS: performance status SCT: stem cell transplant QD: every day SD: stable disease R/R: relapsed/refractory SLL: small lymphocytic lymphoma R: rituximab

Abbreviations

SPD: sum of the products of the greatest perpendicular diameters TEAE: treatment-emergent adverse event TLR: toll-like receptor TLS: tumor lysis syndrome TN: treatment-naïve TTNT: time to next treatment TTR: time to respond UM: unmutated VR-CAP: bortezomib, rituximab, cyclophosphamide, doxorubicin, and prednisone VTE: venous thromboembolism W/W: watch and wait WM: Waldenstrom macroglobulinemia