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

Yes

The Evolution of Treatment Options in CLL Alkylators CR: 5% ORR: 30-50% 1970s Purine Analogs CR: 20 - 30% ORR: 50 - 80% 1980s Purine + alkylators CR: 35% ORR: 75 - 90% 1990s Chemo-immunotherapy CR: 41 - 70% ORR: 90 - 95% 2000s TKIs / SMIs CR: ??? ORR: 70-100% 2010s

Survival of CLL Patients by Decade 2 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 45 44 <1980 88 83 1980-1989 319 225 1990-1999 933 195 2000-2010 Proportion Surviving Years Courtesy of Michael J. Keating, MDACC

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 (1970-1979): 26.3% 38 months II (1980-1989): 50.3% 54 months III (1990-1998): 72.0% 93 months

Survival of CLL Patients By Treatment Total Died Subgroup 609 129 Initial Dx 327 167 1st Rx 794 548 1st fludarabine salvage 233 158 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.

So we need better treatments!

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!

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. 2011. Blood; 118: 3525

Patients Age >65: Survival by Treatment > 2004 Proportion

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

Targeting the “BCR++” Antigen Pathway:

PI3 Kinase Signaling: At the Crossroads

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

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

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

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

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

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

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.

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.

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

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.

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.

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

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.

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.