PI3K inhibitors in CLL and lymphoma 11th European Congress on Hematologic Malignancies: From Clinical Science to Clinical Practice  13-15 March 2015 Barcelona, Spain PI3K inhibitors in CLL and lymphoma Gilles SALLES « Pathologie des Cellules Lymphoïdes » UMR 5239 CNRS – UCB – ENS – HCL Université de Lyon

Gilles SALLES DISCLOSURES OF COMMERCIAL SUPPORT Name of Company Research support Employee Consultant Stockholder Speaker’s Bureau Advisory Board Other Amgen YES Celgene Gilead Janssen Mundi-pharma Roche

PI3K Promotes Survival and Growth of Cancer Class I PI3K Isoform Cellular Expression Primary Physiological Role Alpha () Broad Insulin signaling and angiogenesis Beta () Platelet function Gamma () Leukocytes Neutrophil and T-cell function Delta () B-cell signaling, development and survival LYMPH NODE MALIGNANT B-CELL Reference: Okkenhaug Nat Rev Immunol 2003

Fruman D & Rommel C, Cancer Discovery 2011 Convergence of diverse stimuli on PI3K δ in B cells Fruman D & Rommel C, Cancer Discovery 2011

Idelalisib Class I PI3K Isoform a b g d 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 Class I PI3K Isoform a b g d Expression Ubiquitous Leukocytes EC50 (nM) >20,000 1,900 3,000 8 Reference: Lannutti, Blood, 2011 5

Initial clinical experience with PI3Kδ inhibitor: CAL101 / GS1101 / idelalisib

Flinn, Blood 2014 ; Kahl, Blood 2014 ; Brown, Blood 2014 Lymph node response in initial Phase I/II studies of GS-1101 in Previously Treated MCL, iNHL, and CLL Flinn, Blood 2014 ; Kahl, Blood 2014 ; Brown, Blood 2014

Changes in disease-related parameters. Idelalisib (GS1101) in CLL Changes in disease-related parameters. Jennifer R. Brown et al. Blood 2014;123:3390-3397

Fruman D & Rommel C, Cancer Discovery 2011 Inhibiting PI3Kδ targets both malignant B cells and the tumor microenvironment. Fruman D & Rommel C, Cancer Discovery 2011

Primary Study 116 Extension Study 117 Arm A N=110 Arm B N=110 Double-Blind Initial Therapy Double-Blind Continuous Therapy Blinded Dose Open-Label Arm A N=110 Rituximab (6 mo) Idelalisib (150 mg BID) Idelalisib (300 mg BID) Disease Progression Screen Placebo (BID) Idelalisib (150 mg BID) Arm B N=110 Rituximab (6 mo) Randomization/ Stratification Blinded, Independent Review Interim Analyses and Unblinding Independent Review

Idelasilib + rituximab Furman et al. NEJM 2014

Idelasilib + rituximab Furman et al. NEJM 2014

Idelasilib + rituximab Furman et al. NEJM 2014

Study GS-US-312-0116 (Phase 3) Overall Survival, Including Extension Study* Idelalisib + R vs Placebo + R → Idelalisib All Patients IGHV Unmutated Idelalisib + R (N=110) Placebo + R (N=110) Idelalisib + R (n=91) Placebo + R (n=93) N at risk IDELA + R 110 107 101 100 93 85 60 41 30 23 13 7 3 PBO + R 99 90 84 66 42 27 20 8 4 1 91 88 82 81 75 70 48 33 25 19 10 6 2 93 83 79 77 72 55 35 22 15 3 Median OS (95% CI) HR (95% CI) p-value IDELA + R NR ( ‒, ‒ ) 0.34 (0.19, 0.6) 0.0001 PBO + R 20.8 mo (14.8, ‒ ) Median OS (95% CI) HR (95% CI) p-value NR (19.0, ‒ ) 0.35 (0.19, 0.6) 0.0003 18.1 mo (14.8, ‒ ) *As randomized, including cross-over Sharman, ASH, 2014, Abstract 330

Del17p/TP53 Mutation (Either) ‡ Study GS-US-312-0116 (Phase 3) Overall Survival, Including Extension Study* Idelalisib + R vs Placebo + R → Idelalisib Del17p/TP53 Mutation (Either) Del11q Positive Idelalisib + R (n=46) Placebo + R (n=49) Idelalisib + R (n=25) Placebo + R (n=23) N at risk IDELA + R 46 45 41 40 39 30 23 16 12 5 2 PBO + R 49 37 33 25 17 11 8 4 1 N at risk 25 24 23 22 20 17 12 8 7 6 5 3 1 21 16 11 2 Median OS (95% CI) HR (95% CI) p-value IDELA + R NR (18.8, ‒ ) 0.31 (0.15, 0.65) 0.001 PBO + R 14.8 mo (8.4, ‒ ) Median OS (95% CI) HR (95% CI) p-value NR ( ‒, ‒ ) NA 0.21 18.1 (11.1, ‒ ) *As randomized, including cross-over Sharman, ASH, 2014, Abstract 330

‡ Study GS-US-312-0116 (Phase 3) Adverse Events in ≥15% of Patients Idelalisib + R vs Placebo + R → Idelalisib IDELA + R (N=110) PBO + R → IDELA (N=108) Any Grade, % Grade ≥3, % AE by Preferred Term 2nd IA Update Any AE 96 98 64 80 100 52 78 Pyrexia 35 44 3 6 17 32 1 Diarrhea/colitis 21 42 16 ̶ 13 Fatigue 26 36 5 28 43 Cough 34 2 Nausea 31 Chills 22 Infusion reaction 19 20 30 4 Constipation 11 Decreased appetite 12 10 Pneumonia 18 8 9 Dyspnea 25 Rash Vomiting Upper respiratory infection 7 15 24 Edema, peripheral Night sweats 14 Asthenia Abdominal pain Sharman, ASH, 2014, Abstract 330

Select Lab Abnormalities Idelalisib + R vs Placebo + R → Idelalisib ‡ Study GS-US-312-0116 (Phase 3) Select Lab Abnormalities Idelalisib + R vs Placebo + R → Idelalisib Idelalisib + R (N=110) Placebo + R → Idelalisib (N=108) Any Grade, % Grade ≥3, % 2nd IA Update ALT/AST elevation 40 49 8 10 20 53 1 6 Neutropenia 60 66 37 41 51 68 27 43 Anemia 29 33 7 32 50 17 24 Thrombocytopenia 19 11 14 18 Conclusions Phase 3 subgroup analysis demonstrates comparable efficacy of idelalisib + rituximab in the presence or absence of high-risk genomic alterations OS is higher for patients on idelalisib + rituximab despite cross-over in extension design Idelalisib + rituximab has an acceptable safety profile in patients with relapsed/refractory CLL Sharman, ASH, 2014, Abstract 330

Update on a Phase 2 Study of Idelalisib in Combination With Rituximab in Treatment-Naïve Patients ≥65 Years With Chronic Lymphocytic Leukemia or Small Lymphocytic Lymphoma Susan M. O'Brien, Nicole Lamanna, Thomas J. Kipps, Ian W. Flinn, Andrew D. Zelenetz, Jan A. Burger, Leanne M. Holes, Yoonjin Cho, Ronald L. Dubowy, Steven E. Coutre

Idelalisib + rituximab in first line CLL Study 101-08 results

Idelalisib + rituximab in first line CLL Study 101-08 results

Treatment-emergent AE in ≥20% patients Laboratory Abnormalities Idelalisib + rituximab in first line CLL Study 101-08 results Treatment-emergent AE in ≥20% patients Laboratory Abnormalities AE, n(%) All Patients Any Grade AE Grade ≥3 AE Any AE 64 (100) 57 (89) Diarrhea/colitis 49 (77) 27 (42) Rash 37 (58) 8 (13) Pyrexia 2 (3) Nausea 24 (38) 1 (2) Chills 23 (36) Cough 21 (33) Fatigue 20 (31) Pneumonia 18 (28) 12 (19) Dyspnea 16 (25) 4 (6) Headache 15 (23) Vomiting 14 (22) Insomnia 13 (20) Patients, n (%) All Patients Grade ≥3 Transaminase elevation 15 (23) Neutropenia 18 (28) Anemia 2 (3) Thrombocytopenia 1 (2)

Study 101-09: Phase 2 Monotherapy in Refractory iNHL Single-Arm Study (N=125) Idelalisib 150 mg BID continuously Accrual Completed October 2012 Therapy maintained until progression Long Term follow-up Tumor assessments: Weeks 0, 8, 16, 24, 36, 48 Every 12 weeks thereafter Evaluated by Independent Review Committee 2 radiologists with adjudication if needed clinical review Primary endpoint: Overall Response Rate (ORR) Secondary endpoints: Duration of Response (DOR) Progression Free Survival (PFS) Safety Quality of life 22

Study 101-09: Baseline Characteristics Male/Female, n (%) 80/45 (64%/36%) 64 [33 – 87] 72 (58%) 28 (22%) 10 (8%) 15 (12%) Age, (years) median, [range] Disease type, n (%) FL SLL LPL/WM MZL LDH (>ULN), n (%) Bulky Disease (> 7 cm ) 38 (30%) 33 (26%) Neutropenia (ANC< 1.5K/ul) Anemia (Hb < 10 gm/dL) Thrombocytopenia (Pl < 75K) 17 (14%) 19 (15%) 23

Study 101-09: Prior Therapy Exposure Characteristic N=125 Number of prior regimens Median, [Range] 4 [2 – 12] Prior Therapy Rituximab Alkylating Agent Bendamustine Anthracycline Purine Analog Stem Cell Transplantation 125 (100%) 81 (65%) 80 (64%) 42 (33%) 14 (11%) Median time from last regimen to study entry, mo 3.9 24

Study 101-09: Prior Therapy Refractoriness Characteristic Rituximab Alkylating agent B-R R-CHOP R-CVP 125/125 (100%) 124/125 (99%) 47/60 (78%) 40/56 (71%) 29/36 (81%) Bendamustine 61/81 (75%) Refractory to ≥ 2 regimens Refractory to last regimen 99 (79%) 112 (90%) 25

Study 101-09: Overall Response Rate (ORR) Characteristic June-2013 June-2014 ORR, n (%) 71 (57%) 72 (58%) 95% CI (47.6 - 65.6) (48.4 – 66.4) Complete Response 7 (6%) 12 (10%) Partial Response 63 (50%) 59 (47%) Minor Response (LPL/WM patient) 1 (1%) Stable Disease 42 (34%) 41 (33%) Progressive Disease 10 (8%) Not Evaluable 2 (2%) 26

Study 101-09: Lymph Node Response by Disease Group ‡ Study 101-09: Lymph Node Response by Disease Group 3 patients had no postbaseline computed tomographic scan evaluation; *2 of these patients were not evaluable; †1 had progressive disease by lymph node biopsy. ‡Criterion for lymphadenopathy response.1 *Criterion for lymphadenopathy response.1 †Response in LPL/WM group predominantly determined by IgM response. 1. Cheson BD, et al. J Clin Oncol 2007;25:579-86.

Study 101-09: Duration Of Response (DOR) All Subjects 2014 Median DOR = 12.5 months Analysis includes subjects who achieved a CR or PR (or MR for WM subjects) according to IRC assessments

Study 101-09: Adverse Events ‡ Study 101-09: Adverse Events AE Occurring in >15%, n (%) Any Grade Grade ≥3 Diarrhea/colitis 63 (50) 24 (19) Cough 40 (32) Nausea 39 (31) 2 (2) Fatigue 38 (30) Pyrexia 4 (3) Dyspnea 23 (18) 6 (5) Decreased appetite 1 (1) Abdominal pain 21 (17) 3 (2) Upper respiratory infection Vomiting 20 (16) Decreased weight 19 (15)

Study 101-09: Adverse events (cont’d) ‡ Study 101-09: Adverse events (cont’d) Hematologic Lab Abnormalities Hematologic Lab Abnormalities Patients, n (%) Any Grade Baseline On Study Neutrophils decreased 29 (23) 71 (57) 7 (6) 35 (28) Hb decreased 64 (51) 41 (33) 1 (1) 3 (2) Platelets decreased 43 (34) 36 (29) 4 (3) 10 (8) ALT/AST Elevations Patients, n (%) Grades 1-2 Grade 3 Grade 4 ALT/AST elevation 45 (36) 15 (10) 3 (2) Patients with Grades 1-2 ALT/AST elevations could continue idelalisib treatment (resolve/accommodation) Grade ≥3 was reversible with drug interruption 15 of 18 patients with Grade ≥3 were rechallenged 11 (73%) did not have recurrence of Grade ≥3 4 (27% had recurrence

Study 101-09: Summary and Conclusions Idelalisib, selective oral PI3K-δ inhibitor, demonstrates high response rates (ORR 57%) in double refractory iNHL Response durations were prolonged (median 12.5 months) Safety profile in these patients on continuous therapy was manageable Phase 3 clinical trials in combination with Rituximab, or Bendamustine/Rituximab are ongoing

Other PI3K inhibitors

PI3K-δ and PI3K-γ Support the Growth and Survival of B-cell and T-cell Malignancies Phase 1 evaluation of IPI-145, an oral PI3K-δ,γ inhibitor Early evidence of therapeutic potential across a broad range of hematologic malignancies

IPI-145 Activity in R/R iNHL Supports Development at 25 mg BID Early Evidence of Durable Responses 53% (8 of 15 patients) dosed with ≤ 25 mg BID IPI-145 progression free at one year 73% ORR (11 of 15 patients) Includes 3 CRs, and 1 MR in a patient with Waldenström's Updated data from Kahl et al, ICML 2013

Nodal Responses in CLL with IPI-145 Therapy R/R CLL 98% (42/43) of patients had a reduction in adenopathy by CT assessment 89% (24/27) dosed ≤ 25 mg BID had a nodal response (≥ 50% reduction in adenopathy) Treatment Naïve CLL Nodal responses in 3/6 patients, including 2 patients with p53 mutation Flinn et al, ASH 2014

IPI-145 Early Evidence of Activity in T-cell Lymphomas (TCL) Population Patients (n) Best Response n (%) Evaluable ORR CR PR SD PD TCL 26 10 (38) 1 (4) 9 (35) 7 (27) C-TCL 14 4 (29) 7 (50) 3 (21) P-TCL 12 6 (50) 1 (8) 5 (42) ORR = objective response rate; CR = complete response; PR = partial response; SD = stable disease; PD = progressive disease; C-TCL = cutaneous TCL; P-TCL = peripheral TCL Early evidence of activity in C-TCL and P-TCL with IPI-145 up to 75 mg BID Safety profile in line with comorbidities seen in patients with advanced hematologic malignancies (Horwitz et al, ICML 2013; Douglas et al, ASH 2013)

  DLBCL N=26 FL N=24 Best overall response, n (%) Complete response (CR) 1 (3.8) Partial response (PR) 2 (7.7) 6 (25.0) Stable disease (SD) 5 (19.2) 15 (62.5) Progressive disease (PD) 12 (46.2) 1 (4.2) Unknown (UNK) 6 (23.1) 2 (8.3) Overall response rate (ORR: CR+PR) [95% CI] 3 (11.5) [2.5–30.2] 6 (25.0) [9.8–46.7] Disease control rate (DCR: CR+PD+SD) [95% CI] 8 (30.8) [14.3–51.8] 21 (87.5) [67.6–97.3]

COPANLISIB : Phase I/II study - Dreyling et al., ASH 2013

COPANLISIB : Phase I/II study - Dreyling et al., ASH 2013

PI3K inhibition in CLL & Lymphoma Several drugs have demonstrated clinical activity in NHL and CLL, with different spectrum of activity / toxicity according to the specificity against different PI3K isoforms The PI3Kδ inhibitor idelalisib was approved in US and EU based on a marked activity: In double refractory iNHL In R/R CLL in combination with rituximab (phase III study) and in the first line ttt of 17p/P53- patients Its toxicity profile imposes a careful management of patients Multiple trials evaluating combination of these different drugs are currently being performed With rituximab / other anti-CD20, with chemotherapy, with other kinase inhibitors or other targeted agents….