1. Should Novel BCR Antagonists Be Part of Frontline Therapy for CLL?
Richard R. Furman
Weill Cornell Medical College

2. Yes

3. The Evolution of Treatment Options in CLL
Alkylators
CR: 5%
ORR: 30-50%
1970s
Purine Analogs
CR: %
ORR: %
1980s
Purine + alkylators
CR: 35%
ORR: %
1990s
Chemo-immunotherapy
CR: %
ORR: %
2000s
TKIs / SMIs
CR: ???
ORR: %
2010s

4. Survival of CLL Patients by Decade2 4 6 8 10 12 14 16 18 20
0.0
0.2
0.4
0.6
0.8
1.0
Pts. Died Year Rx
<1980
Proportion Surviving
Years
Courtesy of Michael J. Keating, MDACC

5. Change in Natural History: Summary
Increase in overall survival for patients as a group
By stage, no benefit for Binet A and B, but benefit seen for Binet stage C
Better supportive therapies?
Novel agents?
Shift to earlier stage disease at diagnosis:
Cohort % Stage A Survival
I ( ): 26.3% 38 months
II ( ): 50.3% 54 months
III ( ): 72.0% 93 months

6. Survival of CLL Patients By Treatment
Total Died Subgroup
Initial Dx
st Rx
st fludarabine salvage
fludarabine refractory
100 80 60
Overall survival (%) 40
Alkylating agents failed 20
Fludarabine failed 24 48 72 96
120
144
Time (Months)
MDACC data, M Keating.

7. So we need better treatments!

8. More Reasons To Avoid Chemotherapy
40% of deaths of CLL patients are associated with second solid tumors, acute leukemia/MDS or Richter’s transformation.
This includes 71% of deaths in first remission!

9. Risk of t-MN with F vs. FC Initial Therapy of CLL
TOTAL
N enrolled
141
137
278
t-MN 9 4 13
Additional Therapy:
yes no 2 7 3 1
Crude Incidence
6.4%
2.9%
4.7%
Cumulative Incidence
(at 7 yrs)
8.2%
4.6%
Smith, M Blood; 118: 3525

10. Patients Age >65: Survival by Treatment > 2004
Proportion

11. BCR-associated Kinases: Proven Effective Therapeutic Targets
Syk (spleen tyrosine kinase):
fostamatinib
PRT062070
GS-9973
Btk (Bruton’s tyrosine kinase):
ibrutinib
CC-292
ACP-196
PI3K (phosphatidyl 3-kinase:
Idelalisib (GS-1101)
IPI-145
AMG319
Nat Rev Immunol 2:945

12. Targeting the “BCR++” Antigen Pathway:

13. PI3 Kinase Signaling: At the Crossroads

14. Idelalisib: Specific Inhibitor of p110d
Tyrosine Phosphorylation
PI3K Isoforms
Expression
Broad
Leukocytes
Gene KO effect
Lethal
Benign
Physiological role
Insulin signaling
Angiogenesis
unknown
Signaling, development & survival
Neutrophil,
T-cell development
IC50 (nM)
2154
427 8
182

15. CLL Patients Treated with Idelalisib 150 mg BID
81%
Response Rate
72%
Decrease by 50% of nodal SPD
PR with lymphocytosis (Cheson 2012)
PR by IWCLL criteria (Hallek 2008)
33%
39%
Nodal
Response
Overall
Response
Brown J. ASCO 2013

16. Idelalisib + +R +B +BR Response Rate 95% CI LNR = Nodal ResponseOR
LNR OR
LNR OR
LNR = Nodal Response
OR = Response by IWCLL criteria (Hallek 2008)
Coutre S. ASH 2012, Abs 191

17. Idelalisib in Relapse / Refractory CLL Progression Free Survival
Overall Survival
Median PFS = 17.1 months
Median OS not reached
Brown J. ASCO 2013

18. Adverse Events (> 15%) and Selected Lab Abnormalities (N=54)
AE, n (%)
Any Grade (%)
Grade  3 (%)
Fatigue
17 (32)
1 (2)
Diarrhea
16 (30)
3 (6)
Pyrexia
2 (4)
Cough
13 (24)
Back pain
12 (22)
Rash
URI
Pneumonia
11 (20)
10 (19)
Night sweats
Chills
9 (17)
Laboratory abnormality, n (%)
AST, increased*
ALT, increased*
*15 subjects total with transaminase elevations
Brown J. ASCO 2013

19. Ibrutinib: “Specific” Inhibitor of BTK
B-cell antigen receptor (BCR) signaling required for B cell survival
Bruton’s Tyrosine Kinase (Btk) is an essential element of the BCR signaling pathway
Inhibitors of Btk block BCR signaling and induces apoptosis

20. PCYC-1102: Overall Response
Among those patients whose initial response was PR-L, the majority achieved classic response by IWCLL criteria:
TN: 9/13 (69%)
R/R: 38/49 (78%)
Combined ORR + (PR-L):
TN = (84%)
R/R = (88%)
Furman RR. IWCLL 2013.

21. PCYC-1102: Progression Free Survival at 26 months
TN: 96.3%
R/R: 73.6%
No del17p/11q: 92.2%
del11q: 72.9%
del17p: 53.1%
Furman RR. IWCLL 2013.

22. PCYC-1102: Patient Disposition
TN ≥ 65 Years
n = 31
R/R
n = 85
Median time on treatment, months
 21.3 (0.3, 26.6)
16.3 (0.3, 28.7)
Patients still on treatment, n (%)
26 (84)
53 (62)
Patients discontinuing treatment, n (%)
5 (16)
32 (38)
Reasons for treatment discontinuation, n (%) AE
Treatment-related AE
Death due to AE
2 (6)
1 (3)
10 (12)
1 (1)
1 (1)a
Disease progression*
SCT (while in response)
Investigator decision (not SCT)
Patient decision
Lost to Follow-up
4 (5)
3 (4)
*7 patients (1 TN, 6 R/R) had disease progression with Richter’s transformation
Furman RR. IWCLL 2013.
Furman RR. iWCLL 2013

23. PCYC-1102: AEs All Grades in >15% of Patients
Diarrhea (TN 68%, R/R 53%), fatigue, and URI were the most common adverse events
Furman RR. IWCLL 2013.

24. Rate of > Grade 3 Infections / 100 patient months
Rate of Severe Infections with Ibrutinib (PCYC-1102 Study – Rel/Ref Population)
Rate of > Grade 3 Infections / 100 patient months
First 6 months
>7 months
All Patients (N=85)
7.1
2.6
By duration of exposure:
<12 months (N=22)
17.7
4.1
>12 months (N=63
4.8
Byrd J. NEJM 2013.

25. PCYC-1102: Changes in Median Serum Immunoglobulin Levels – TN + R/R
Furman RR. IWCLL 2013.

26. Incidence of Acquired Resistance Following Ibrutinib Treatment in CLL Patients
*5 patients with mutations came from 10 evaluable patients (i.e. 3 were not available to sequence)
Stilgenbauer, S. IWCLL 2013.

27. Patient Characteristics with Acquired SNVs
Study
Age
Gender
# of
Prior Treatments
Cytogenetics
Ibrutinib Treatment
Duration on Ibrutinib
Best Response
Mutation
PCYC-04753 59
Female 5
17p-, +12
560 mg qd
621 days PR
C481S BTK
PCYC-1102 75
Male 2
17p-, complex karyotype
420 mg qd
673 days
R665W PLCg2
PCYC-1108 3
11q-
BR x 6 cycles 420 mg qd
388 days CR
PCYC-1109 51
complex karyotype
Ofatumumab x 24 weeks 420 mg qd
674 days 69 9
840 mg qd
868 days
Stilgenbauer, S. IWCLL 2013.