Idelalisib in the Treatment of Chronic Lymphocytic Leukemia

Idelalisib in the Treatment of Chronic Lymphocytic Leukemia Jacqueline C. Barrientos, MD Assistant Professor of Medicine Hofstra North Shore LIJ School of Medicine North Shore LIJ Cancer Institute CLL Research and Treatment Program New Hyde Park, New York

Disclosures Research Funding: Pharmacyclics, Gilead, Abbvie Ad Board: Pharmacyclics, Celgene, Genentech, Gilead

Introduction Idela Monotherapy Idela in Combination with: Rituximab Frontline 2 nd IA Phase III Relapsed Refractory (R/R) Ofatumumab R/R Bendamustine and Rituximab R/R Side Effect Profile Conclusions Overview

Regimens for CLL can have substantial toxicity and generally become less effective with recurrent treatment Hallek, Hematology Am Soc Hematol Educ Program 2009

PI3K Delta Inhibition in B Cell Malignancies PI3K delta critical for activation, proliferation and survival of B lymphocytes Plays a critical role in homing and retention of B cells in lymphoid tissues Is hyperactive in many B cell malignancies and drives proliferation, survival and trafficking to lymphoid tissue Idelalisib Is a targeted, highly selective, oral inhibitor of PI3K delta Inhibits proliferation and induces apoptosis in many B cell malignancies Inhibits homing and retention of malignant B cells in lymphoid tissues reducing B cell survival

PI3Kδ inhibitor idelalisib (GS 1101/CAL 101): MOA

Idelalisib Phase 1 Study Design Patients with previously treated hematologic malignancies Phase 1 Dose Ranging Study Idelalisib, 50 mg to 350 mg BID, Continuous oral dosing Extension Study Idelalisib Continuous oral dosing 48 weeks Until end of benefit Population reported on: 54 patients with CLL Starting dose cohorts 50mg BID, n=5 100mg BID, n=11 300mg QD, n=10 150mg BID, n=11 200mg BID, n=10 350mg BID, n=7 Disease assessments: Weeks 0, 8, 16, 24 Every 12 weeks thereafter Endpoints: Dose selection Safety Pharmacodynamics Pharmacokinetics Efficacy Brown et al., J Clin Oncol 31, 2013 (suppl; abstr 7003)

Patient Characteristics N=54 Gender, male 45 83% Age, median [range], years 63 [37 82] Disease status, n (%) Refractory 38 70% Prior therapies, median [range], n 5 [2 14] Prior therapy type, n (%) Purine analog 54 100% Rituximab 52 96% Alkylating agent 47 87% Alemtuzumab 19 35% Anthracycline/anthracenedione 18 33% Brown et al., J Clin Oncol 31, 2013 (suppl; abstr 7003)

Disease Characteristics N=54 Extent of CLL Bulky lymphadenopathy ( 1 node 5 cm) 43 80% Splenomegaly 20 37% Hepatomegaly 3 6% Thrombocytopenia (platelets < 100K/μL) 34 63% Anemia (hemoglobin < 11g/dL) 25 46% Neutropenia (ANC < 1.5K/μL) 15 28% ALC, median [range], cells, x 1Kμ/L 10.8 [0 185] CLL genetics, n (%) Unmutated IgHV 49 91% Del 17p/TP53 mut 13 24% Del 11q 15 28% NOTCH1 mutation 9 17% Brown et al., J Clin Oncol 31, 2013 (suppl; abstr 7003)

Adverse Events (AEs) and Selected Lab Abnormalities (N=54) AE, n (%) Any Gr. Gr. 3 Fatigue 17 (31.5) 1 ( 1.9) Diarrhea 16 (29.6) 3 ( 5.6) Pyrexia 16 (29.6) 2 ( 3.7) Cough 13 (24.1) 2 ( 3.7) Back pain 12 (22.2) 0 Rash 12 (22.2) 0 URI 12 (22.2) 0 Pneumonia 11 (20.4) 10 (18.5) Night sweats 10 (18.5) 0 Chills 9 (16.7) 0 Headache 7 (13.0) 0 Abdominal pain 6 (11.1) 0 Arthralgia 6 (11.1) 0 Decreased appetite 6 (11.1) 0 Neutropenic fever 6 (11.1) 6 (11.1) Nausea 6 (11.1) 0 Vomiting 6 (11.1) 1 (1.9) Peripheral edema 6 (11.1) 0 Laboratory abnormality, n (%) Any Gr. Gr. 3 AST, increased* 13 (24.1) 1 (1.9) ALT, increased* 10 (18.5) 1 (1.9) *15 subjects total with transaminases elevations Brown et al., J Clin Oncol 31, 2013 (suppl; abstr 7003)

Best Nodal Response Inevaluable (patients without a follow up tumor assessment) Presence of del17p or TP53 mutation a Criterion for lymphadenopathy response (Hallek 2008) Brown et al., J Clin Oncol 31, 2013 (suppl; abstr 7003)

Nodal and Overall Response Rate 100 Response Rate ±95% CI 80 60 40 20 81% n=44 72% n=39 33% n=18 39% n=21 ALC and Tumor Burden Over Time 0 Lymph Node Overall Response Response Decrease by 50% of nodal SPD PR with lymphocytosis (Cheson 2012) PR by IWCLL criteria (Hallek 2008) ALC (N=54) SPD (N=51) Brown et al., J Clin Oncol 31, 2013 (suppl; abstr 7003)

Progression Free Survival (PFS) and Overall Survival (OS) Median PFS = 17.1 months Median OS not reached 150mg BID, Median PFS = 29 months <150mg BID, Median PFS = 7 months Brown et al., J Clin Oncol 31, 2013 (suppl; abstr 7003)

Improvement of Baseline Cytopenias Brown et al., J Clin Oncol 31, 2013 (suppl; abstr 7003)

Idelalisib + Rituximab in Treatment Naive CLL Subject accrual Oct 2010 through Apr 2012 Primary Study: 101-08 Extension Study: 101-99 Idelalisib (150 mg BID) x 48 wks Rituximab (375 mg/m 2 ) weekly x 8 Therapy continues as long as patient receives benefit Eligibility Disease assessment Age 65 years Treatment naive CLL requiring therapy (IWCLL 2008) No exclusions for cytopenias Investigator determined Weeks 0, 8, 16, 24, 36, 48 and per SOC thereafter Endpoints Primary: ORR (IWCLL 2008) Secondary: DOR, PFS, Safety O Brien et al., J Clin Oncol 31, 2013 (suppl; abstr 7005)

Baseline Characteristics Demographics and Baseline Characteristics Age (yrs), median [range] 71 [65-90] Idelalisib + R N=64 (%) Diagnosis: CLL/SLL 59/5 (92/8) WHO Performance Score 0-1 / 2 63/1 (98/2) Rai Stage I-II / III-IV 33/27 (52/42) Binet Stage A/B/C 14/22/28 (22/34/44) β2 Microglobulin, mg/l, median [range] 4.0 (1.9-15.8) Hematology Parameters Hemoglobin < 11 g/dl 17 (27) Platelets < 100 x10 3 /µl 17 (27) B-symptoms 26 (41) Bulky adenopathy ( 5 cm) 7 (11) IGHV unmutated (n=60) 37 (58) Either Del(17p) or TP53 mutation (n=61) 9 (14)

Idelalisib + Rituximab: Response All Subjects Del(17p) and/or TP53 mutation N=64 n=9 Complete Response 9 (14%) 3 (33%) Partial Response 53 (83%) 6 (67%) Stable Disease 0 0 Progressive Disease 0 0 Not Evaluable 2 (3%) 0 Overall Response 62 (97%) 9 (100%) Med TTR 1.9 mos 24/26 patients with B symptoms resolved by week 16 No on-study progression O Brien et al., J Clin Oncol 31, 2013 (suppl; abstr 7005)

All Cause AEs 25% in Primary and Extension Studies; On Study Lab Abnormalities* Adverse Event n (%) with any Grade n (%) with Grade 3 Diarrhea** 35 (55) 15 (23) Pyrexia 27 (42) 2 (3) Nausea 24 (38) 1 (2) Rash 24 (38) 5 (8) Chills 23 (36) 0 Cough 21 (33) 1 (2) Fatigue 20 (31) 0 Pneumonia 17 (27) 11 (17) ** 10 patients reported as Gr 3 colitis, including 6 lacking any AE report of Gr 3 diarrhea Med time to Gr 3 diarrhea/colitis = 9 mos Lab Abnormality* n (%) with Increase to Grade 3 Transaminase elevations 15 (23) Neutropenia 18 (28) Anemia 2 (3) Thrombocytopenia 1 (2) * Primary study only O Brien et al., J Clin Oncol 31, 2013 (suppl; abstr 7005)

Progression Free Survival* 100 Idelalisib + R (N=64) Probability of PFS 80 60 40 20 All Patients N=64 TP53 mutation/ Del (17p) N=9 PFS at 24 months: 93% 0 BL 5 10 15 20 25 30 Months * ITT analysis of primary + extension study Extension study assessments based on standard of care O Brien et al., J Clin Oncol 31, 2013 (suppl; abstr 7005)

Phase III Rituximab +/ Idelalisib Primary Study 116 Extension Study 117 Double-Blind Initial Therapy Rituximab (6 months) Double-Blind Continuous Therapy Blinded Dose Open-Label Screen Idelalisib (150 mg BID) Placebo (BID) Disease Progression Idelalisib (300 mg BID) Idelalisib (150 mg BID) Randomization and Stratification Rituximab (6 months) Blinded, Independent Review Interim Analyses and Unblinding Independent Review Primary Endpoint: PFS; Secondary: ORR, LNR, OS IAs planned at 50% and 75% of total events, DMC recommended early study stop after 1st IA (Furman et al., NEJM 2014) 2nd IA conducted at end of the blinded phase according to amendment (data cut off 09 October 2013 with 63% of total PFS events) BID, twice daily; DMC, data monitoring committee; IA, interim analysis; LNR, lymph node response; N, number of patients; ORR, overall response rate; OS, overall survival; PFS, progression free survival. Coutre et al., J Clin Oncol 32:5s, 2014 (suppl; abstr 7012)

Key Eligibility Relapsed CLL Criteria Lymphadenopathy Prior therapies Appropriate for non cytotoxic therapy Bone marrow function Karnofsky score Requirement CLL progression <24 months since last therapy Treatment warranted according to IWCLL criteria Presence of 1 measurable nodal lesion 1 anti CD20 antibody containing therapy or 2 prior cytotoxic therapies CIRS score >6 or creatinine clearance <60 ml/min ( 30 ml/min) or Grade 3/4 neutropenia or thrombocytopenia due to prior myelotoxicity Any grade anemia, neutropenia or thrombocytopenia allowed 40 CIRS, cumulative illness rating scale; IWCLL, international workshop on chronic lymphocytic leukemia. 22 Coutre et al., J Clin Oncol 32:5s, 2014 (suppl; abstr 7012)

Progression Free Survival: All Patients 100 Progression free Survival (%) 80 60 40 20 HR=0.18 95% CI (0.10, 0.32) P <0.0001 0 0 2 4 6 8 10 12 14 16 18 Idelalisib + Rituximab Median PFS: Not reached Placebo + Rituximab Median PFS: 5.5 months N at risk (Events) Idelalisib + R Placebo + R Time (Months) 110 (0) 87 (3) 54 (7) 35 (8) 30 (10) 17 (14) 7 (15) 2 (16) 1 (16) 0 (16) 110 (0) 69 (21) 37 (37) 19 (44) 14 (49) 6 (54) 3 (56) 1 (58) 0 (59) 0 (59) CI, confidence interval; HR, hazard ratio; PFS, progression free survival; R, rituximab. 23 Coutre et al., J Clin Oncol 32:5s, 2014 (suppl; abstr 7012)

Progression Free Survival: Patient Subgroups Del(17p) and/or TP53 Mutation IGHV Unmutated Progression free Survival (%) 100 80 60 40 20 N at risk (Events) Idelalisib + R46 (0) Placebo + R 49 (0) Idelalisib + Rituximab Median PFS: Not reached Placebo + Rituximab Median PFS: 4.0 months HR=0.16 HR=0.14 95% CI (0.07, 0.37) 95% CI (0.07, 0.27) 0 0 2 4 6 8 10 12 14 16 18 0 0 2 4 6 8 10 12 14 16 18 Time (Months) Time (Months) 37 (2) 22 (5) 13 (5) 12 (5) 7 (7) 3 (7) 0 (7) 0 (7) 0 (7) 30 (12) 16 (21) 8 (26) 5 (29) 3 (31) 2 (32) 1 (33) 0 (34) 0 (34) Progression free Survival (%) 100 80 60 40 20 N at risk (Events) Idelalisib + R 91 (0) Placebo + R 93 (0) Idelalisib + Rituximab Median PFS: NR Placebo + Rituximab Median PFS: 5.5 months 71 (3) 42 (6) 28 (7) 24 (8) 14 (11) 5 (11) 2 (11) 1 (11) 0 (11) 58 (17) 31 (31) 15 (38) 10 (43) 3 (48) 1 (50) 0 (51) 0 (51) 0 (51) CI, confidence interval; HR, hazard ratio; PFS, progression free survival; R, rituximab. 24 Coutre et al., J Clin Oncol 32:5s, 2014 (suppl; abstr 7012)

Response Rates Idelalisib + R Placebo + R Overall response rate a, %, (95% CI) (n=102; 101) b 77 (68-85) 15 (9-23) 50% reduction in lymph nodes c, %, (95% CI) (n=102; 101) b 92 (85-97) 6 (2-13) Organomegaly response, % Spleen (n=76; 64) b 72 22 Liver (n=52; 59) b 46 19 Hematologic response, % Hemoglobin (n=59; 57) b 73 40 Neutrophils (n=27; 25) b 74 68 Platelets (n=48; 49) b 88 55 a p<0.0001; b number of evaluable patients (idelalisib; placebo); c 50% reduction in sum of products of lymph node dimension. CI, confidence interval; ORR, overall response rate; R, rituximab. 25 Coutre et al., J Clin Oncol 32:5s, 2014 (suppl; abstr 7012)

Overall Survival 100 80 Idelalisib + Rituximab % Overall Survival 60 40 20 HR = 0.28 95% CI (0.11, 0.69) P = 0.003 Placebo + Rituximab 0 0 2 4 6 8 10 12 14 16 18 N at risk (Events) Idelalisib + R 110 (0) Placebo + R 110 (0) Time (Months) 102 (2) 68 (3) 47 (4) 33 (6) 25 (6) 11 (6) 6 (6) 2 (6) 0 (6) 93 (8) 61 (11) 39 (14) 31 (16) 20 (19) 13 (19) 5 (20) 1 (20) 0 (20) a Evaluable patients. mut, mutation; SPD, sum of products of lymph node dimension; R, rituximab. 26 Coutre et al., J Clin Oncol 32:5s, 2014 (suppl; abstr 7012)

Adverse Events 10% In Either Study Arm AE, n (%) Idelalisib + R (N=110) Placebo + R (N=108) Any Grade Grade 3 Any Grade Grade 3 Patients with any AE 106 (96) 70 (64) 106 (98) 56 (52) Pyrexia 38 (35) 3 (3) 18 (17) 1 (1) Fatigue 28 (26) 5(5) 30 (28) 3 (3) Nausea 28 (26) 0 23 (21) 0 Chills 23 (21) 2 (2) 17 (16) 0 Diarrhea a 21 (19) 4 (4) 16 (15) 0 Infusion related reaction 21 (19) 0 32 (30) 4 (4) Cough 19 (17) 1 (1) 30 (28) 2 (2) Bleeding b 15 (14) 1 (1) 20 (19) 1 (1) Dyspnea 14 (13) 3 (3) 21 (19) 3 (3) Constipation 14 (13) 0 12 (11) 0 Vomiting 14 (13) 0 9 (8) 0 Decreased appetite 13 (12) 0 11 (10) 2 (2) Night sweats 12 (11) 0 11 (10) 0 Pneumonia 11 (10) 9 (8) 14 (13) 10 (9) Rash 11 (10) 1 (1) 5 (5) 0 Headache 11 (10) 1 (1) 5 (5) 0 Edema peripheral 11 (10) 0 10 (9) 2 (2) Upper respiratory tract infection 8 (7) 2 (2) 12 (11) 2 (2) a 3/5 patients with colitis on idelalisib + R also reported diarrhea; b Includes 16 preferred terms. AE, adverse event; R, rituximab. 27 Coutre et al., J Clin Oncol 32:5s, 2014 (suppl; abstr 7012)

Idelalisib With Ofatumumab for Relapsed or Refractory CLL Phase 1b Combination Study Extension Study Ofatumumab 300 mg, Week 1 then 1000 mg weekly x 8 then 1000 mg monthly x 3 Idelalisib, 100 or 150 mg BID, continuously Idelalisib, 150 mg BID 48 weeks Until end of benefit Designs Endpoints Eligibility Extension Study Phase 1b trial, 48 weeks duration Safety (primary) Efficacy (secondary): ORR, DOR, and PFS Age 18 years Relapsed/refractory CLL requiring treatment (IWCLL 2008) Idelalisib single-agent therapy after 48 weeks for patients who continue to benefit Coutre et al. EHA 2013

Lymph Node Response (LNR), Overall Response Rate (ORR) 100 Response Rate ±95% CI 75 50 25 81% n=17 76% CR 14% n=3 71% n=5 PR 62% n=13 0 LNR* N=21 ORR** N=21 ORR Del17p/TP53mut N=7 * Decrease by 50% of nodal SPD ** IWCLL (Hallek 2008) Coutre et al. EHA 2013

Progression Free Survival (PFS), Overall Survival (OS) Idelalisib + O (N=21) Med. PFS = 17.4 mos Med. OS not yet reached Coutre et al. EHA 2013

Idelalisib with Rituximab and/or Bendamustine for Relapsed or Refractory CLL Phase 1b Combination Study R, 375 mg/m 2 weekly x 8 Idelalisib, 100 or 150 mg BID, 48 weeks continuously B, 70 or 90 mg/m 2 D1 + D2, C1 6 Idelalisib, 100 or 150 mg BID, 48 weeks continuously Extension Study Idelalisib, 150 mg BID, continuously B, 70 mg/m 2 D1 + D2, C1 6 R, 375 mg/m 2 C1 6 Idelalisib, 150 mg BID, 48 weeks continuously Designs Endpoints Eligibility Extension Study Phase 1b trial, 48 weeks duration Safety (primary) Efficacy (secondary): ORR, DOR, and PFS Age 18 years Relapsed/refractory CLL requiring treatment (IWCLL 2008) Idelalisib single-agent therapy after 48 weeks for patients who continue to benefit Barrientos et al. ASCO 2013

Overall Response Rate* a Response Rate ±95% CI +R (n=19) +B (n=18) +BR (n=15) Overall (N=52) Del17p/TP53mut (n=11) Idelalisib * ITT analysis a Response by IWCLL criteria (Hallek 2008) Barrientos et al. ASCO 2013

Idelalisib + Bendamustine Idelalisib + Bendamustine + Rituximab Slide #33 Baseline IGHV unmutated CD 38 +, ZAP 70 + 17p del, trisomy 12 4 prior tx After 4 cycles Baseline IGHV unmutated CD 38 +, ZAP 70 11q del 7 prior tx After 4 cycles

Progression Free Survival* Idelalisib +R/+B/+BR % Progression-free Survival 100 80 60 40 20 All, N=52 Median PFS = 28 months 0 0 BL 4 8 12 16 20 24 28 32 BL 4 8 12 16 20 24 28 32 Months 100 80 60 40 20 del17p/tp53, n=11 Median PFS = 20 months No del17p/tp53mut, n=41 Median PFS not yet reached Months * ITT analysis of primary + extension study Extension study assessments based on standard of care Barrientos et al. ASCO 2013

Side Effects Fatigue Diarrhea Colitis/intestinal perforation Pyrexia/pneumonia Pneumonitis Transaminitis

Conclusions The use of targeted agents in CLL could redefine treatment goals Enhanced cytotoxicity Low intensity approach Combination chemoimmunotherapy Chemo sensitization Durable remissions Single agent Chronic disease suppression Foundation for nonchemotherapy based regimens Recognize possible drug related side effects early

Thank you! Questions? jbarrientos@nshs.edu