1. 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

2. 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

3. 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

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

5. 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

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

7. 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

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

9. 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

10. 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

11. Idelasilib + rituximab Furman et al. NEJM 2014

12. Idelasilib + rituximab Furman et al. NEJM 2014

13. Idelasilib + rituximab Furman et al. NEJM 2014

14. Study GS-US (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

15. Del17p/TP53 Mutation (Either)‡
Study GS-US (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

16. ‡
Study GS-US (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

17. Select Lab Abnormalities Idelalisib + R vs Placebo + R → Idelalisib‡
Study GS-US (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

18. 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

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

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

21. Treatment-emergent AE in ≥20% patients Laboratory Abnormalities
Idelalisib + rituximab in first line CLL Study 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)

22. 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

23. 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

24. 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

25. 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

26. Study 101-09: Overall Response Rate (ORR)
Characteristic
June-2013
June-2014
ORR, n (%)
71 (57%)
72 (58%)
95% CI
( )
(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

27. Study 101-09: Lymph Node Response by Disease Group‡
Study : 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:

28. 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

29. Study 101-09: Adverse Events‡
Study : 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)

30. Study 101-09: Adverse events (cont’d)‡
Study : 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

31. 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

32. Other PI3K inhibitors

33. 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

34. 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

35. 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

36. 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)

38. 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]

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

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

42. 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….