Emerging Treatments and Evolving Pathways for the Management of - - PowerPoint PPT Presentation

Emerging Treatments and Evolving Pathways for the Management of Chronic Lymphocytic Leukemia

This educational activity is supported by an educational grant from AbbVie

Faculty

Jennifer R Brown, MD PhD Director, CLL Center Dana-Farber Cancer Institute Associate Professor Harvard Medical School Boston, Massachusetts

Disclosures

Dr Brown has served as a consultant for Janssen, Pharmacyclics, AstraZeneca, Sun, Redx, AbbVie, and Gilead. She has received grant/research support from Gilead.

Learning Objectives

· Discuss the importance of CLL biomarkers and staging in prognostic assessment and subsequent treatment decisions · Evaluate the efficacy, safety, and indications of new and emerging CLL treatments with respect to patient age, comorbidities, and overall health · Integrate the latest evidence-based guidelines, clinical trial results, and cost utility studies into the CLL clinical pathway development process · Implement strategies to improve guideline adherence and patient

• utcomes through the inclusion and sequencing of novel therapies in CLL

clinical pathways

Talk Outline and Key Topics

• Initial prognostic assessment
• Current first-line therapy options

– Selection of therapy

• Biologic criteria
• Fitness criteria
• Relapsed refractory CLL therapy

– Novel agents

CLL = chronic lymphocytic leukemia.

CLL: Chronic Lymphocytic Leukemia

• Most common adult “leukemia”
• 17,000 new cases per year
• Better thought of as a chronic, incurable low-grade

lymphoma

– Most patients present with asymptomatic increase in lymphocyte count – These asymptomatic patients do not require therapy initially – Therapy required once symptoms, low blood counts, or large lymph nodes intervene

IW-CLL Criteria for Initiating Therapy

AIHA = autoimmune hemolytic anemia; ALC = absolute lymphocyte count; ITP = immune thrombocytopenia; IW-CLL = International Workshop on Chronic Lymphocytic Leukemia meeting; LDT = lymphocyte doubling time.

• B symptoms, severe fatigue
• Progressive anemia/thrombocytopenia
• Massive or rapidly progressive splenomegaly or

lymphadenopathy

• LDT <6 months
• Refractory AIHA or ITP
• Note that ALC is not specifically a criterion

What Is High-risk CLL?

FISH = fluorescence in situ hybridization; IGHV = unique immunoglobulin gene rearrangement.

• Historically defined solely by clinical features:

– Stage, lymphocyte doubling time, b2m – Therapy resistance

• Biologic prognostic factors are increasingly important:

– FISH, TP53 mutation – IGHV – ? Novel somatic mutations: SF3B1, NOTCH1

Clonal Aberrations in CLL: Interphase FISH

Döhner H, et al. New Engl J Med. 2000;343:1910-1916.

83% Abnormal:

• No. patients (%)
• 13q deletion

178 (55)

• 11q deletion

58 (18)

• Trisomy 12

53 (16)

• 17p deletion

23 (7)

• 6q deletion

21 (6)

• Normal

57 (18)

Overall Survival by FISH

Döhner H, et al. New Engl J Med. 2000;343:1910-1916.

100 80 60 40 20 0 0 12 24 36 48 60 72 84 96 120 144 168

Patients surviving (%)

17p- 11q- 12q trisomy Normal 13q deletion as sole abnormality Del 17p: 32 m Del 11q: 79 m

Immunoglobulin VH Gene Mutation

Damle RN, et al. Blood. 1999;94(6):1840-1847.

Years from Diagnosis

Med Surv 9 yrs Med Surv >24 yrs

IGHV Mutation and Cytogenetics: Independent Predictors

Kröber A, et al. Blood. 2002;100(4):1410-1416.

TP53 Mutations in the DNA Binding Motifs Associate with Worse Survival

Trbusek M, et al. J Clin Oncol. 2011;29(19):2703-2708.

Regardless of 17p Del With 17p Del

TP53 Mutation Has a Dose-dependent Effect on OS

OS = overall survival. Yu L, et al. Blood. 2015;126(23):2907.

CLL-IPI: Final Model of Multivariate Analysis

B2M = beta 2 microglobulin; CLL-IPI = international prognostic index for CLL; HR = hazard ratio. Soumerai JD, et al. J Clin Oncol. 2016;34(suppl):abstr 7513.

Variable Adverse factor Coeff. HR TP53 (17p) deleted and/or mutated 1.442 4.2 Grading 4 Prognostic Score 0 – 10 IGHV status Unmutated 0.941 2.6 B2M, mg/L >3.5 0.665 2.0 Clinical stage Binet B/C or Rai I-IV 0.499 1.6 Age >65 years 0.555 1.7 2 1 2 1

Definition of Risk Groups

Soumerai JD, et al. J Clin Oncol. 2016;34(suppl):abstr 7513.

Score 1 2 3 4 5 6 7 8 9 10 Frequency 150 190 143 321 93 165 68 26 13 18 5

Risk group Score Patients, N (%) Survival after 5 years, % HR (95% CI) P value Very High 7 – 10 62 (5) 23.3 3.6 (2.6 - 4.8) <0.001

High 4 – 6 326 (27) 63.6 1.9 (1.5 - 2.3) <0.001

Intermediate 2 – 3 464 (39) 79.4 3.5 (2.5 - 4.8) <0.001 Low 0 – 1 340 (29) 93.2

CLL-IPI: Risk GroupsDa

Soumerai JD, et al. J Clin Oncol. 2016;34(suppl):abstr 7513.

Training dataset [N = 1192]

Time to Event [OS] (months)

156 144 132 120 108 96 84 72 60 48 36 24 12

Cum Survival

1,0 0,8 0,6 0,4 0,2 0,0

C- statistic = 0.724 [95% CI, 0.689 – 0.758]

Internal validation dataset [N = 575]

Time to Event [OS] (months)

156 144 132 120 108 96 84 72 60 48 36 24 12

Cum Survival

1,0 0,8 0,6 0,4 0,2 0,0

C- statistic = 0.777 [95% CI, 0.732 – 0.820]

What Is High-risk CLL?

• Comes down to:

– Patient factors: age, ECOG/comorbidities – Biologic factors: 17p, UM, 11q, B2M

ECOG = Eastern Cooperative Oncology Group scale

Recurrent Mutations Refine Prognosis

Balakas et al. Leukemia. 2014:1-8.

Previously Untreated CLL

1960s 1970s 1980s 1990s 2000s

Chemo-immunotherapy (CIT) 45% CR; better PFS & OS Alemtuzumab monotherapy 24% CR Bendamustine 30% CR Alkylating agents

• Chlorambucil
• Cyclophosphamide

5% CR Purine nucleosides

• Fludarabine
• Pentostatin
• Cladribine

5% - 20% CR Better PFS in younger pts Purine nucleosides and alkylators 30% CR Better PFS

2010s

BCR/BCL-2 inhibitors ???

BCL-2 = B-cell lymphoma-2; BCR = beta-cell receptor; CR = complete remission; PFS = progression-free survival.

CLL8 Study Design

CIRS = cumulative illness rating scale. Hallek M, et al. Lancet. 2010;376:1164-1174.

817 patients with untreated, active CLL and good physical fitness (CIRS ≤ 6, creatinine clearance ≥70 mL/min) R

FCR FC 6 courses

Follow up

C1 C2 C3 C4 C5 C6

Median observation time 5.9 years

Demographics similar between two treatment arms

CLL8: Addition of Rituximab to FC

REFERENCES Fischer K, et al. Presented at: American Society of Hematology 54th Annual Meeting; December 8-11, 2012; Atlanta, GA..

CLL8: Addition of Rituximab to Fludarabine and Cyclophosphamide

REFERENCES Fischer K, et al. Presented at: American Society of Hematology 54th Annual Meeting; December 8-11, 2012; Atlanta, GA..

CLL8: Survival After FCR by FISH

Hallek M, et al. Lancet. 2010;376:1164-1174. Stilgenbauer et al.

• Blood. 2014 May

22;123(21):3247-54.

17p deletion

+12q 13q-single 11q- Not 17p-/11q-/+12q/13q- 17p-

CLL8: Impact of TP53 Mutation on OS

Eichhorst et al. Lancet Oncol. 2016 Jul;17(7):928-942. Stilgenbauer et al. Blood. 2014 May 22;123(21):3247-54.

FCR FC TP53: wild type mutated Therapy:

CLL8 Multivariable Analysis: Predictive Factors

Eichhorst et al. Lancet Oncol. 2016 Jul;17(7):928-942. Stilgenbauer et al. Blood. 2014 May 22;123(21):3247-54.

Cox regression including: FC, FCR, TP53, NOTCH1, SF3B1, and treatment interaction PFS: HR P value FCR 0.544 <0.001 TP53mut 3.607 <0.001 SF3B1mut 1.355 0.012 NOTCH1mut 1.652 0.022 Interaction OS: HR P value FCR 0.654 0.002 TP53mut 4.470 <0.001 NOTCH1mut 1.331 0.344 Interaction

MDACC: TTF After FCR Based on FISH (2004-2010)

Courtesy of M Keating.

12 24 36 48 60 72

Months

0.0 0.2 0.4 0.6 0.8 1.0

• Pts. Failed FISH

36 23 17p- 75 30 11q- 67 18 Trisomy 12 100 18 13q- 70 19 Negative

CLL10 Study: FCR vs BR in Frontline

GFR = glomerular filtration rate; MCL = mantle cell lymphoma. REFERENCE

Consort Diagram

immunophenotype genomic aberrations (FISH) IGHV sequencing CIRS GFR 688 CLL patients screened centrally for: 564 underwent 1:1 randomization FCR n = 284 BR n = 280 ITT: FCR n = 282 ITT: BR n = 279

• 1 treatment before

randomization

• 1 patient decision
• 1 misdiagnosis (MCL)

Median observation time: 37.1 (0-59.9) months

Eichhorst et al. Lancet Oncol. 2016 Jul;17(7):928-942.

CLL10 Study: FCR vs BR in Frontline (Cont’d)

• = P

P <0.001 HR = 1.626 = >1.388 P <0.001 HR = 1.626 = >1.388 Median PFS FCR 55.2 months BR 41.7 months Median PFS FCR 55.2 months BR 41.7 months

= Primary

Eichhorst et al. Lancet Oncol. 2016 Jul;17(7):928-942.

CLL10 Study: FCR vs BR in Frontline (Cont’d)

ORR = objective response rate; PR = partial remission. Eichhorst et al. Lancet Oncol. 2016 Jul;17(7):928-942.

Response FCR n=274 BR n=273 P value CR (CR + CRi) 47.4% 38.1% 0.031 CR 40.1% 36.3% CRi 7.3% 1.8% PR 50.4% 59.7% ORR 97.8% 97.8% 1.0

CLL10 Study: FCR vs BR in MRD Negativity

BM=bone marrow; FR=final restaging; MRD = minimal residual disease; PB=peripheral blood. Eichhorst et al. Lancet Oncol. 2016 Jul;17(7):928-942.

• Minimal residual disease (MRD) in ITT

MRD negativity FCR %(N) n=282 BR %(N) n=279 BM at FR 26.6% (75/282) 11.1% (31/279) PB at FR 48.6% (137/282) 38.4% (107/279) PB 12 months after FR 19.7% (47/238) 9.0% (20/222) PB 18 months after FR 18.0% (37/206) 8.5% (16/187)

Adverse event FCR (%) N= 279 BR (%) N=278 P value Neutropenia 84.2 59.0 <0.001 Anemia 13.6 10.4 0.20 Thrombocytopenia 21.5 14.4 0.03 Infection 39.1 26.8 <0.001 Sec Neoplasm* 6.1 3.6 0.244 TRM 4.6 2.1 0.107 Infections 2.5 2.1

• Sec Neoplasm

1.1

• Other

1.0

CLL10 Study: FCR vs BR in Frontline

Eichhorst et al. Lancet Oncol. 2016 Jul;17(7):928-942.

Adverse Events CTC °3-4 (1st cycle until end of study)

*sAML/MDS: FCR=6, BR=1

CLL10 Study: FCR vs BR in Front-line

Eichhorst et al. Lancet Oncol. 2016 Jul;17(7):928-942.

Infections CTC 3-4 in detail

Adverse event FCR (% of pt) BR (% of pt) P value

All Infections 39.1 26.8 <0.001 Infections during therapy

• nly

22.6 17.3 0.1 Infections during first 5 months after therapy 11.8 3.6 <0.001 All infections in patients ≤65years 35.2 27.5 0.1 All infections in patients >65years 47.7 20.6 <0.001

Predictors of PFS in Multivariable Analysis

Eichhorst et al. Lancet Oncol. 2016 Jul;17(7):928-942.

COX regression PFS Univariate comparison Hazard ratio 95% Confidence Interval P value Lower Upper

Treatment arm BR

• vs. FCR

1.680 1.270 2.222 <0.001 S-TK (U/L) >10

• vs. ≤ 10

1.581 1.104 2.265 0.012 Cytogenetic subgroup del (11q) vs no del(11q) 1.878 1.391 2.536 <0.001 IGHV MS Unmutated vs mutated 1.937 1.357 2.763 <0.001

Predictors of OS in Multivariable Analysis

Eichhorst et al. Lancet Oncol. 2016 Jul;17(7):928-942.

COX regression OS Univariate comparison Hazard ratio 95% Confidence Interval P value Lower Upper Age at study entry >65 years vs ≤65 years 1.880 1.118 3.162 0.017 IGHV MS Unmutated vs mutated 3.739 1.832 7.630 <0.001

CLL10: FCR vs BR

• FCR more effective in CR, MRD, PFS

– Most noticeable in patients <65 yo

• FCR toxicity higher especially in those >65 yo

– No growth factors or antibiotic prophylaxis

• Young fit

– FCR

• Older fit or intermediate fitness

– Role for BR

FCR300: PFS and OS

Wierda WG, et al. iWCLL 2013 Abstracts.

Mos Proportion Surviving Events Total Median 186 300 6.5 yrs 113 300 11+ yrs Median Follow-up Time All: 9.8 yrs Alive: 11.5 yrs 1.0 0.8 0.6 0.4 0.2 24 48 72 96 120 144 168 PFS OS

FCR300: PFS by IGHV Mutation Status

Wierda WG, et al. iWCLL 2013 Abstracts.

Mos Proportion Progression Free IGHV-M 33 82 IGHV-UM 114 131 Group Events Total

P < .0001

Unknown 39 87 1.0 0.8 0.6 0.4 0.2 24 48 72 96 120 144 168

First-line FCR300: PFS and OS Outcomes by MRD Status

Strati P, et al. Blood. 2014;123(24):3727-3732.

Overall Survival

50 40 30 20 10 0.0 0.2 0.4 0.6

Proportion Not Progressed

0.8 1.0

MRD- MRD+ p<0.001 n events MRD- 70 1 MRD+ 91 23 MRD- MRD+

50 40 30 20 10 0.0 0.2 0.4 0.6

Proportion Alive

0.8 1.0

p<0.006 n events MRD- 70 MRD+ 91 11

Months Months

MRD-negative Status at EOT Strongly Associated with PFS but Modified by IGHV

EOT = end of treatment. Thompson P, et al. MRD analysis after FCR.

First-line FCR: Rossi Data

Rossi D, et al. Blood. 2015;126:1921-1924.

Overall Survival

17p UM IGHV or 11q Mut IGHV, no 11 or 17

Second Malignancy Risks

Rossi D, et al. Blood. 2015;126:1921-1924. Thompson PA, et al. Blood. 2016 Jan 21;127(3):303-9.

MDACC Italian Data

Low-risk Intermediate-risk High-risk 0% 10% 20% 40% 30% 50% Prevalence of second tumors

3.9% (3/77) 12.1% (21/173) 19.0% (4/21)

p=0.0500 Probability Time (years)

MRD Negativity Predicts Best PFS and OS

Kwok M, et al. Blood. 2016;128(24):2770-2773.

MRD Negativity Does Not Overcome Poor Prognosis of Del(17p/11q)

Kwok M, et al. Blood. 2016;128(24):2770-2773.

Better PFS and OS If MRD Negativity After First-line Therapy

Kwok M, et al. Blood. 2016;128(24):2770-2773.

Summary: Fit Patients

• FCR remains most effective upfront therapy
• A subset of patients remain progression free

more than 10 yrs:

– Mutated IGHV, low risk FISH

• Key predictors of outcome after therapy:

– 17p / TP53 mutn – 11q deletion and IGHV mutation status – Response (CR) and MRD status

First-line Treatment of CLL

CALGB = Cancer and Leukemia Group B Eichhorst BF, et al. Blood. 2011 Feb 10;117(6):1817-21.

• For physically fit patients, FCR prolongs survival
• Until recently, no “standard” treatment in elderly population

– Phase 3 CLL elderly trial: fludarabine vs chlorambucil

Fludarabine NOT superior to chlorambucil in PFS or OS

– Chlor

– Retrospective analysis of CALGB first-line CLL trials

• No benefit of fludarabine over chlorambucil in patients age ≥70 yrs
• Rituximab added benefit regardless of age

Chlorambucil Fludarabine Fludarabine Chlorambucil

PFS OS

Association of Age and Comorbidity in CLL: Meta-analysis of GCLLSG CLL4 and CLL5 Trials

Cramer P, et al. Blood. 2006;108:Abstract 2840.

• Incidence of comorbidities increases with age

– <20% of youngest patients had comorbidities – >60% of oldest patients had comorbidities

• Number of comorbidities increases with age

– ~5% of youngest patients had ≥2 comorbidities – >30% of oldest patients had ≥2 comorbidities

CLL11: Study Design

Goede V, et al. N Engl J Med. 2014 Mar 20;370(12):1101-10.

Previously untreated CLL

Total CIRS score >6 and/or creatinine clearance <70 mL/min N=780 (planned)

R A N D O M I Z E 2:1:2

590 patients

G-Clb vs. Clb

Primary analysis data cut-off: 07/2012

GA101 + chlorambucil x 6 cycles R-Clb vs. Clb

Primary analysis data cut-off: 08/2012

Rituximab + chlorambucil x 6 cycles Chlorambucil x 6 cycles (control arm)

CLL11: Study Design (Cont’d)

Previously untreated CLL

Total CIRS score >6 and/or creatinine clearance <70 mL/min N=780 (planned)

R A N D O M I Z E 2:1:2

590 patients

Chlorambucil x 6 cycles (control arm) G-Clb vs. R-Clb

Primary analysis data cut-off: 05/2013

Additional 190 patients

GA101 + chlorambucil x 6 cycles Rituximab + chlorambucil x 6 cycles

Goede V, et al. N Engl J Med. 2014 Mar 20;370(12):1101-10.

Lymphocyte Counts After Obinutuzumab and CLB

Goede V, et al., Leukemia. 2013;27:1172-1174. Goede V, et al. N Engl J Med. 2014 Mar 20;370(12):1101-10.

G-Clb (n=333) % R-Clb (n=330) % Male 61 62 Median age, years (range) 74 (39-89) 73 (40-90) Aged ≥65 years 81 78 Aged ≥75 years 46 42 Median ECOG PS (range) 1 (0-3) 1 (0-3) Median CIRS score 8.0 8.0 CIRS score >6 78 75 Median CrCl 62.5 62.6 CrCl <70 mL/min 65 64 CrCl <50 mL/min 27 25

Baseline Patient Characteristics

Goede V, et al. N Engl J Med. 2014 Mar 20;370(12):1101-10.

Adverse Events of Interest

a Safety population for G-Clb includes 5 patients randomized to R-Clb who received 1 infusion of

GA101 in error

b Incidence rate of 3% in any treatment arm

AE = adverse event.

Goede V, et al. N Engl J Med. 2014 Mar 20;370(12):1101-10.

G-Clb (n=336)a % R-Clb (n=321)a % Any AE grade ≥3b 70 55 Infusion-related reaction 20 4 Neutropenia 33 28 Anemia 4 4 Thrombocytopenia 10 3 Infection 12 14 Pneumonia 4 5

Minimal Residual Disease

As measured by central laboratory assessment (ASO-RQ-PCR) at 3 months after end of treatment; bone marrow samples were usually only taken from patients thought to be in CR. Goede V, et al. N Engl J Med. 2014 Mar 20;370(12):1101-10.

Progression-free Survival (Head-to-Head)

Median observation time: G-Clb, 18.8 months; R-Clb, 18.6 months. Type 1 error controlled through closed test procedure; P value of the global test was <0.0001. Independent Review Committee- assessed progression-free survival (PFS) was consistent with investigator-assessed PFS. Goede V, et al. N Engl J Med. 2014 Mar 20;370(12):1101-10.

3 6 9 12 15 18 21 24 27 30 33 36 39 330 317 309 259 163 114 72 49 31 14 5 2 330 307 302 278 213 156 122 93 60 34 12 4 1 1.0 0.9 0.8 0.7 0.6 0.5 0.4 0.3 0.2 0.1 0.0 Progression-free survival Time (months) G-Clb: R-Clb:

• No. at risk

Overall Survival (GA101)

Median observation time: G-Clb, 23.2 months; Clb, 20.4 months. No multiplicity adjustment was done for secondary endpoints. Goede V, et al. N Engl J Med. 2014 Mar 20;370(12):1101-10.

Total number of deaths: G-Clb, 22 (9%); Clb, 24 (20%)

3 6 9 12 15 18 21 24 27 30 33 36 39 118 109 105 103 102 94 70 56 44 29 15 5 238 226 223 221 215 211 170 144 115 71 34 14 2 1.0 0.9 0.8 0.7 0.6 0.5 0.4 0.3 0.2 0.1 0.0 Overall survival Time (months) G-Clb: Clb:

• No. at risk

Overall Survival (Head-to-Head)

Median observation time: G-Clb, 18.8 months; R-Clb, 18.6 months. No multiplicity adjustment was done for secondary endpoints. Goede V, et al. N Engl J Med. 2014 Mar 20;370(12):1101-10.

Total number of deaths: G-Clb, 28 (8%); R-Clb, 41 (12%)

3 6 9 12 15 18 21 24 27 30 33 36 39 330 320 314 305 255 203 169 138 105 61 27 8 333 316 310 303 261 214 170 144 115 71 34 14 2 1.0 0.9 0.8 0.7 0.6 0.5 0.4 0.3 0.2 0.1 0.0 Overall survival Time (months) G-Clb: R-Clb:

• No. at risk

CLL11: TTNT G-Clb vs R-Clb

Goede V, et al. Leukemia. 2015 Jul;29(7):1602-4.

• No. at risk

GClb 333 291 282 274 267 253 238 232 218 209 189 173 139 102 72 54 26 17 5 2 RClb 330 313 303 276 243 225 208 177 160 142 126 112 87 62 42 33 18 10

Time to new anti-leukemic treatment

Time (months)

0.0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1.0

Stratified HR 0.57 95% CI 0.44–0.74 P <0.0001

3 6 9 12 15 18 24 36 30 42 48 54 60 21 33 27 39 45 51 57

51.1 38.2 G‐Clb R‐Clb

Summary: Unfit Patients

• Randomized phase 3 trials establish PFS benefit of adding

anti-CD20 antibody to chlorambucil

• Only obinutuzumab has been compared head-to-head with

rituximab, with improved MRD negativity and PFS—but not improved OS

• Time to next therapy quite good for 6 months of well-

tolerated treatment VS

• Kinase inhibitors likely to move into this space where

resources permit

– How should therapy be selected?

PCYC-1102/1103 Phase 2 Study Design

O’Brien SM, et al. American Society of Hematology 59th Annual Meeting and Exposition. Atlanta, GA; December 9-12, 2016. Abstract 233.

Patients with CLL/SLL treated with

• ral, once-daily

ibrutinib (420 or 840 mg/day) Long-Term Follow-Up ≥SD

*R/R includes patients with high-risk CLL/SLL, defined as

progression of disease <24 months after initiation of a chemoimmunotherapy regimen or failure to respond

Relapsed/Refractory* (R/R) n=101 Treatment Naïve (TN) ≥65 years n=31

Phase 2 (PCYC-1102) N=132 Extension Study (PCYC-1103)

After ~5 years

• f

follow- up

Ibrutinib Treatment Continued in 65% TN and 30% R/R Patients

O’Brien SM, et al. American Society of Hematology 59th Annual Meeting and Exposition. Atlanta, GA; December 9-12, 2016. Abstract 233.

Disposition TN (n=31) R/R (n=101) Median time on study, months (range) 62 (1–67) 49 (1–67) Duration of study treatment, n (%) ≤1 year >1–2 years >2–3 years >3–4 years ≥4 years 5 (16%) 1 (3%) 1 (3%) 24 (77%) 24 (24%) 14 (14%) 9 (9%) 19 (19%) 35 (35%) Patients remaining on ibrutinib therapy, n (%) 20 (65%) 30 (30%) Primary reason for discontinuation, n (%) Progressive disease Adverse event Consent withdrawal Investigator decision Lost to follow‐up 1 (3%) 6 (19%) 3 (10%) 1 (3%) 33 (33%) 21 (21%) 5 (5%) 11 (11%) 1 (1%)

Survival Outcomes by Chromosomal Abnormalities Detected by FISH in R/R Patients

O’Brien SM, et al. American Society of Hematology 59th Annual Meeting and Exposition. Atlanta, GA; December 9-12, 2016. Abstract 233.

Progression-Free Survival Overall Survival

Median OS 5-year OS Del17p (n=34) 57 mo 32% Del11q (n=28) NR 61% Trisomy 12 (n=5) NR 80% Del13q (n=13) NR 91% No abnormality** (n=16) NR 83% Median PFS 5-year PFS Del17p (n=34) 26 mo 19% Del11q (n=28) 55 mo 33% Trisomy 12 (n=5) NR 80% Del13q (n=13) NR 91% No abnormality** (n=16) NR 66%

The majority (90%) of patients with complex karyotype had R/R disease (median 4 prior therapies).

Survival by Complex Karyotype

NR = not reached. O’Brien SM, et al. American Society of Hematology 59th Annual Meeting and

• Exposition. Atlanta, GA; December 9-12, 2016. Abstract 233.

Progression-Free Survival Overall Survival

Media n PFS 5-year PFS Complex karyotype (n=41) 33 mo 36% No complex karyotype (n=71) NR 69% Media n OS 5-year OS Complex karyotype (n=41) 57 mo 46% No complex karyotype (n=71) NR 84%

PFS for Patients with Del17p CLL

• n Ibrutinib (n=243)

Jones J, et al. EHA Annual Meeting 2016. Copenhagen, Denmark; June 9-16, 2016. Abstract S429.

Estimated 12- mo PFS, % (95% CI) Estimated 24- mo PFS, % (95% CI) Estimated 30- mo PFS, % (95% CI) 80% (74, 84) 63% (57, 69) 55% (48, 62) Median time on study = 28 months (range: 0.3-61)

PFS of Del17p Patients +/- Complex Karyotype in the PCYC-1102/1103 Study

Median PFS, mo Del17p + CK (n=22) 25 Del17p no CK (n=10) 52 Median OS, mo Del17p + CK (n=22) 32 Del17p no CK (n=10) NR

• 69% of del17p patients had CK vs 31% of del17p patients without CK

– Median age (range): 65 y (49-79) vs 60 y (44-82) – Median prior therapies (range): 4 (1-9) vs 2.5 (0-12) – Median platelets (range): 72×109/L (20-151) vs 110×109/L (17-310) – Rai stage III-IV: 64% vs 40%

CK = complex karyotype; NR = not reached. Jones J, et al. EHA Annual Meeting 2016. Copenhagen, Denmark; June 9-16, 2016. Abstract S429.

PCYC 1112 RESONATE: PFS by Del17p

Progression-Free Survival (%) Months

100 90 80 70 60 50 40 30 20 10 3 6 9 12 15 18 21 24

Ibrutinib with del17p (n=63) Ibrutinib without del17p (n=132) Ofatumumab with del17p (n=64) Ofatumumab without del17p (n=132)

Brown, et al. Leukemia. 2017.

PCYC 1112 RESONATE: PFS by TP53 / Del17p

Brown, et al. Leukemia. 2017.

Front-line Ibrutinib in del(17p)

Farooqui MZ, et al. Lancet Oncol. 2015;16(2):169-176.

100 80 60 40 20

Overall Survival (%) 6 12 18 24 30 Months

Relapsed/Refractory Previously Untreated P = 0.42

Overall Survival

Previously Untreated Relapsed Refractory N 35 16 Median Follow-up 15 months 26 months Rai Stage III/IV 63% 75% Bulky adenopathy 23% 50% IGHV unmutated 63% 75%

PFS 82%, OS 80% at 24 mos

Ibrutinib for Upfront Therapy of 17p Deleted CLL:

• Clearly the drug of choice given current data

– But unsatisfying as a single agent given the continuous relapse and Richter’s seen in any trial with reasonably long follow-up….

• BUT still no combination data in an upfront

setting

• 17p remains an unmet need not yet adequately

addressed…

• SCT still needs to be considered

RESONATE-2 (PCYC-1115/1116) Study Design

Barr, et al. Blood. 2016.

Patients (N=269)

• Treatment-naïve

CLL/SLL with active disease

• Age ≥65 years
• For patients 65-69

years, comorbidity that may preclude FCR

• del17p excluded

ibrutinib 420 mg

• nce daily until

progression chlorambucil 0.5 mg/kg (to maximum 0.8 mg/kg) days 1, 15 of 28- day cycle up to 12 cycles

CLL PD

• r 1115

study closure PCYC- 1116 Extension Study* In clb arm, n=55 crossed

• ver to

ibrutinib following PD Stratification factors

• ECOG status (0-1 vs. 2)
• Rai stage (III-IV vs. ≤II)

R A N D O M I Z E 1:1 Efficacy (PFS, OS, ORR) determined by investigator-assessment.

*Patients could enroll in separate extension study PCYC-1116 after independent review committee- confirmed PD or at study PCYC-1115 closure for continuing treatment and follow-up.

ibrutinib 420 mg

• nce daily until

progression

Characteristic Ibrutinib (n=136) Chlorambucil (n=133) Median age, years (range) ≥70 years, % 73 (65–89) 71 72 (65–90) 70 ECOG performance status, % 1 2 48 8 50 9 Rai stage III or IV, % 44 47 CIRS score >6, % 31 33 Creatinine clearance <60 mL/min, % 44 50 Bulky disease ≥5 cm, % 40 30 β2-microglobulin >3.5 mg/L, % 63 67 Hemoglobin ≤11 g/dL, % 38 41 Platelet count ≤100 x 109/L, % 26 21 Del11q, % 21 19 Unmutated IGHV, % 43 45

Patient Characteristics

Barr et al, Blood. 2016.

RESONATE 2: PFS and OS by Investigator Assessment

Burger JA, et al. N Engl J Med. 2015 Dec 17;373(25):2425-37

• 18-month PFS rate: 90% with

ibrutinib vs. 52% with chlorambucil

• AEs: 14% hypertension, 6%

atrial fibrillation, 4% major hemorrhage, 2 sudden deaths

• 24-month OS rate: 98% with

ibrutinib and 85% with chlorambucil

• 3 deaths on ibrutinib arm vs 17

deaths on chlorambucil arm

Ibrutinib Significantly Improved PFS in Patients Regardless of IGHV Status

Barr, et al. Blood. 2016.

79% of patients continue on ibrutinib treatment on study with 83% of patients receiving at least 2 years of treatment

(n=40) (n=58) (n=42) (n=60)

ORR in the Ibrutinib Arm

• 1. Barr, et al. Blood. 2016; 2. Burger, et al. NEJM. 2015.

71% 86% 67% 74% 65% 18% 14% 20% 21% 20% 0% 10% 20% 30% 40% 50% 60% 70% 80% 90% 100%

All Patients (N=136) With Del11q (n=29) Without Del11q (n=101) Unmutated IGHV (n=58) Mutated IGHV (n=40)

PR-L PR nPR CR/CRi

1% 1% 1% 2% 3% 95% 88% 100% 92% 90% Best Response (%)

*Response rates with chlorambucil are the same as in the original report 2

Ibrutinib CR rates continue to improve over time: increasing from 7% at 12 months to 15% at 24 months to 18% with median follow-up of 29 months1

Treatment-emergent AEs (≥Grade 3) Over Time in First-line Ibrutinib Patients (≥4% Over 29 Months Median Follow-Up)

Barr et al. Blood. 2016.

• Grade ≥3 AEs in ≥4% of patients over the 29 mo follow-up: neutropenia (12%),

pneumonia (7%), anemia (7%), hypertension (5%), hyponatremia (4%), and atrial fibrillation (4%)

• Major hemorrhage occurred in 7% of ibrutinib-treated patients (1 Grade 2, 7 Grade 3, 1

Grade 4; 5 in first 12 months and 4 between 1-2 years)

• Atrial fibrillation occurred in 10% of ibrutinib-treated patients

(1 Grade 1, 7 Grade 2, 6 Grade 3)

Ibrutinib Arm 0-≤12 months (n=135), % >12-24 months (n=123), % >24-36 months (n=112), % Neutropenia 8 4 Pneumonia* 5 2 1 Anemia 6 1 1 Hypertension 4 2 Hyponatremia 2 2 Atrial fibrillation 1 4

Barr et al, Blood 2016.

Ibrutinib for Upfront Therapy: What Are the Issues?

• Only data in a non-representative population of

very healthy older patients with low disease burden and disease risk, short follow-up, and a very poor comparator arm

• Patients all 65 or over—but low comorbidity
• Toxicity is not negligible even in this population (afib,

hemorrhage, arthralgia)

OSU Experience: Long-term Ibrutinib

Woyach JA, et al. J Clin Oncol. 2017 May 1;35(13):1437-1443.

Cumulative Incidence Estimates At 2 Years At 3 Years At 4 Years CLL progression 5.0% 10.8% 19.1% Transformation 7.3% 9.1% 9.6% Other event 18.7% 23.9% 25.0%

Predictors of Ibrutinib Discontinuation: OSU Experience

Transformation Progressive CLL Other Event

Variable HR P HR P HR P Complex karyotype (yes v no) 5.00 .008 2.81 .006

• MYC abnormality (yes v no)

2.15 .051

• Del17p (yes v no)
• 2.14

.016

• Age ( v <65 years)
• 0.49

.023 2.02 .004 Prior therapies > 3 (yes v no)

• 1.99

.005

Woyach JA, et al. J Clin Oncol. 2017 May 1;35(13):1437-1443.

OSU: Discontinuation for Non-PD by Age

Maddocks et al. JAMA Oncology. 2015

Real World KI Use: Reasons for Discontinuation

KI = ____. Mato et al, Blood. 2016.

Most Common Reasons for Ibrutinib Discontinuation

Ibrutinib Toxicity

51%

CLL progression

28%

Richter’s transformation

8%

SCT / CAR-T

2%

Unrelated death or other

11%

Others:

• Arthralgia
• Edema
• Diarrhea/GI

5 Most Common Toxicities as a Reason for Discontinuation Atrial fibrillation 20% Infection 12% Hematologic 9% Bleeding 9% Pneumonitis 8%

PFS for Alternate KI by Discontinuation Reason

Mato et al, Blood. 2016.

RT excluded from analysis

Retrospective Analysis of Toxicities and Outcomes for Ibrutinib-treated Patients: Design and Patient Characteristics

Mato et al, Blood. 2016.

Retrospective analysis: 621 ibrutinib-treated patients at 9 US cancer centers or ConnectⓇ CLL Registry

Characteristics, n Ibrutinib in Frontline (n=80) Ibrutinib in Relapse (n= 536)

Median age at diagnosis, years (range) 62 (37-88) (N=78) 60 (22-95) (n=532) Prior therapies, median (range) 2 (1-10) del(17p), % 37% (n=76) 26% (n=368) del(11q), % 19% (n=75) 35% (n=367) TP53 mutation, % 12% (n=42) 13% (n=142) Complex karyotype (≥ 3 abnormalities), % 40% (n=60) 34% (n=214) Median time from diagnosis to Ibrutinib, months (range) 26 (1-232) 78 (1-660) Median ibrutinib starting dose, mg 420 420 Ibrutinib as monotherapy, % 68% (n=80) 89% (n=536) Ibrutinib hold required, % 30% (n=79) 37% (n=310) Ibrutinib dose adjustment required, % 15% (n=79) 20% (n=309)

546 patients (88%) were treated with commercial drug; Clinical trial patients were younger (median age 57 vs 61 years), had longer time from diagnosis to ibrutinib (median 85 vs 72 months), and were more consistently initiated at 420 mg (100% vs 89%).

Retrospective Analysis of Toxicities and Outcomes for Ibrutinib-Treated Patients: Discontinuations

Mato et al, Blood. 2016.

Reasons for Discontinuation, % Ibrutinib in Front Line Ibrutinib in Relapse Commercial use (n=10) Clinical Trial (n=9) Commercial Use (n=200) Clinical Trial (n=31) Toxicity 50 78 53 39 CLL progression 10 22 19 36 Other/unrelated death 10 12 13 Physician or patient preference 20 6 10 RT DLBCL 5 SCT/CAR-T cells 4 3 Financial concerns 1 Secondary malignancy 10 1 RT Hodgkin lymphoma 1

With a median follow-up of 14.5 months, estimated discontinuation rate was 42%; median time to discontinuation was 7 months

Retrospective Analysis of Toxicities and Outcomes for Ibrutinib-treated Patients

Mato et al. American Society of Hematology 58th Annual Meeting. San Diego, CA; December 3-6, 2016. Abstract #3222.

• Median PFS and OS for entire cohort were 36 months and NR, respectively

(median follow-up 17 months)

• PFS was not significantly different based on use in front-line vs relapsed

(P=0.27) or commercial use vs clinical trial (P=0.14)

• In multivariable model, complex karyotype validated as independent predictor
• f PFS (HR 1.6, CI 1.1-2.5, P=0.04) but not OS (HR 1.6, CI 0.9-3.1, P=0.1)

Bleeding Events by Time to New Event Onset in PCYC-1102

• In PCYC-1102, major bleeding occurred in 5% of patients

– Most bleeding events occurred early, during the first 3-6 months of therapy

Jones JA et al. Br J Haematol. 2017 Jul;178(2):286-291.

AF Incidence Over Time on Ibrutinib

Ibrutinib (n=49) Patients with Event (%) Months from Study Initiation 20 40 60 80 100 0‐4 4‐8 8‐12 12‐18 0‐4 4‐8 8‐12 12‐18 Comparator (n = 12)

• De novo
• Prior history
• De novo

Prior history

5 10 15 20 25 30 35 40 45 0‐4 4‐8 8‐12 12‐18 18‐24 24‐30 30‐36 >36 Prior History De Novo

Patients with Event (%) Months from Study Initiation Brown JR et al, Haematologica.

Risk Factors for AF in Ibrutinib RCTs

Brown JR et al, Haematologica 2017.

Conclusions: Ibrutinib in R/R CLL

• Ibrutinib in R/R CLL has excellent results, mostly PRs (not a cure)

– Median PFS 52 mos on clinical trial

• Worse for 17p, complex karyotype, 11q
• BUT: outside trials, 40% stop in 14 mos, mostly due to adverse events,

and median PFS is 36 mos

– Real-world outcomes are not aligning with trials – Better management strategies for toxicity, and/or less toxic BTK inhibitors, may be needed

• Those patients who progress on drug have been difficult to salvage

– RT about 30-50% of the time in the relapsed setting, although randomized trials are balanced so far – Frequent BTK Cys481 mutations

• Next-generation drugs: more specific; target BTK

Cys mutation

Ibrutinib for Upfront Therapy: What Are the Issues?

• NO data in young fit patients to whom RESONATE-2

data are being generalized

– Who often do not want indefinite therapy – Who do not achieve CR much less MRD negativity – Who if maintained on ibrutinib may be hard to salvage on relapse

• No data that CIT can be used later

– Cost and compliance are huge issues

PCYC 1112 RESONATE: PFS by Line of Therapy

Brown et al. American Society of Hematology 56th Annual Meeting. San Francisco, CA; December 6-9, 2014.

PFS by Prior Lines of Therapy: RESONATE and RESONATE-2

O’Brien et al. American Society of Clinical Oncology Annual Meeting. Chicago, IL; June 3-7, 2016.

OSU Experience: Long-Term Ibrutinib

Cumulative Incidence Estimates (95 % Cl) At 2 Years At 3 Years At 4 Years CLL progression 5.0% 10.8% 19.1% Transformation 7.3% 9.1% 9.6% Other event 18.7% 23.9% 25.0% Woyach JA, et al. J Clin Oncol. 2017 May 1;35(13):1437-1443.

Venetoclax (ABT-199) Response in Relapsed/Refractory CLL/SLL

Roberts AW, et al. N Engl J Med. 2015. 374(4):311-322.

Response All (n = 116) del(17p) (n = 31) F- Refractory (n = 70) IGHV Unmutated (n = 46) Overall response 79% 71% 79% 76% CR 20% 16% 16% 17% PR 59% 55% 63% 59% Bulky nodes (>5 cm) N CR/CRi % (95% CI) ORR % (95% CI) Yes 67 6 (2, 15) 78 (66, 87) No 48 38 (24, 53) 83 (70, 93)

Venetoclax (ABT-199) in Relapsed/Refractory CLL/SLL

Roberts AW, et al. N Engl J Med. 2015. 374(4):311-322.

Adverse Events

All Grades ≥20% of pts N=105 n (%) Diarrhea 42 (40) Neutropenia 38 (36) Nausea 37 (35) Upper respiratory tract infection 35 (33) Fatigue 27 (27) Cough 21 (20) Grades 3/4 ≥ 5% pts n (%) Neutropenia 35 (33) Anemia 10 (10) Febrile neutropenia 7 (7) Thrombocytopenia 7 (7) Hyperglycemia 7 (7) Tumor lysis syndrome (TLS) 7 (7) Hypokalemia 5 (5)

Roberts AW, et al. N Engl J Med. 2015. 374(4):311-322.

Detailed Risk Stratification of Patients for Tumor Lysis

19th Congress of the European Hematology

• Association. Milan, Italy; June 12-15, 2014.

Poster 868.

Venetoclax Dosing Schedule

Stilgenbauer S et al, Lancet Oncol. 2016 Jun;17(6):768-778.

High tumor burden: any lymph node ≥10 cm; or both lymph node ≥5 cm and ALC ≥25x109/L

• To mitigate TLS risk, patients received prophylaxis with uric acid lowering

agents and hydration starting at least 72 hours before first venetoclax dose

• Patients with high tumor burden were hospitalized for first dose at 20 and 50

mg and received IV hydration and rasburicase

• Laboratory values were monitored at first dose and each subsequent dose

increase

Venetoclax in High-risk R/R CLL with del17p: Baseline Characteristics

Stilgenbauer S et al, Lancet Oncol. 2016 Jun;17(6):768-778.

Characteristic, n (%) N=107a (%) Age, years Median, range 67, 37–85 Sex Male 70 (65) Prior therapies Median, range 2, 1–10 Prior bendamustine / refractory 54 (50) / 38 (70) Prior fludarabine / refractory 78 (73) / 34 (44) Bulky nodes One or more nodes ≥ 5 cm 57 (53) TLS risk category Low 19 (18) Medium 43 (40) High 45 (42) Rai stage III or IV 51(48) IGHV Unmutated 30 (81)

Venetoclax in High-risk R/R CLL with 17p del

Stilgenbauer S, et al. Blood. 2015; 126(23):LBA-6. Stilgenbauer S et al, Lancet Oncol. 2016 Jun;17(6):768-778.

 Of 45 patients tested, 18

achieved MRD-negativity in peripheral blood

 Median time-to-first response:

0.8 months (0.1–8.1)

 Median time to CR/Cri (16%):

8.2 months (3.0–16.3)

iwCLL Response (74%) MRD-negativity

Del 17p CLL: Durability of Venetoclax Activity

Stilgenbauer S, et al. 57th American Society of Hematology Meeting and Exposition. Atlanta, GA; December 5-8, 2015. Abstract LBA-6, oral presentation.

• 12-month estimates (95% CI):

– PFS: 72.0% (61.8, 79.8) – OS: 86.7% (78.6, 91.9)

• 12-month estimates:

– All responders: 84.7% – CR/CRi/nPR: 100% – MRD-negative: 94.4%

Pooled Multi-Trial Analysis of Venetoclax Efficacy in R/R CLL

Stilgenbauer S et al, Lancet Oncol. 2016 Jun;17(6):768-778; Roberts AW et al, Blood 2016 128:3230

• ORR 76% for all patients and in patients receiving the

400 mg RP2D of venetoclax

• CR/CRi rate was 22%; median time to CR/CRi was 8.3

months

• MRD-negativity in the marrow achieved in 57/387

patients (15%) including 21/211 patients (10%) with del(17p)

• Estimated 12 month and 24 month PFS in all 387

patients was 76.8% (95% CI 72.1-80.8) and 57.8 (95% CI 51.8-63.4) respectively

Patient Disposition N=387 Venetoclax 400 mg/day*, n 305 Median duration of venetoclax, months (range) 16.3 (0.03-54) Discontinuation, % Due to PD Due to AEs Due to stem cell transplant Withdrew consent 50 34 10 3 3

DOR and PFS in All Patients

Pooled Analysis of Venetoclax Efficacy

PFS by Best Response PFS by Marrow MRD Status

DOR (24-month estimate) DOR n % (95% CI) All patients 296 65.7 (58.4-72.0) Marrow MRD negative 57 94.2 (78.2-98.6) Marrow MRD non-negative* 239 58.3 (50.0-65.8) CR + CRi 85 92.7 (81.3-97.2) No CR/CRi 211 53.5 (44.4-61.8) Neither del(17p) nor TP53 mutation 63 77.9 (62.2-87.7) Either del(17p) or TP53 mutation 178 60.9 (51.6-69.0)

PFS by TP53 Status

Roberts AW et al, Blood 2016 128:3230

M14-032: Venetoclax After Failure of Ibrutinib

• Phase 2, open-label study evaluating venetoclax for patients with CLL who relapsed

after or are refractory to ibrutinib (Arm A) or idelalisib (Arm B)

• Primary study objectives: ORR and safety
• Secondary and exploratory objectives: DoR, PFS, OS, MRD

Inclusion criteria: – Indication for treatment by iwCLL criteria1 – ECOG 0, 1, or 2 – Adequate bone marrow function – ANC ≥1000/μL – Hg ≥8 g/dL – Platelets ≥30,000/mm3 – CrCl ≥50 mL/min Exclusion criteria: – Richter’s transformation confirmed by PET scan and biopsy – Active and uncontrolled autoimmune cytopenias – Allogeneic stem cell transplant within 1 year of study entry

Jones J, et al. EHA Annual Meeting 2016. Copenhagen, Denmark; June 9-16, 2016. Abstract 637.

Patient Characteristics

Arm A n=43 Arm B n=21 Age, median (range), years 66 (48 – 80) 68 (56 – 85) Unmutated IGVH,* n/N (%) 25/29 (86) 11/13 (85) del(17)(p13.1),* n/N (%) 21/43 (49) 2/21 (10) Baseline laboratory values, median (range) Hemoglobin, g/dL Platelet count, x109/L Lymphocyte count, x109/L 11.2 (5.8 – 14.6) 117 (20 – 446) 19 (.2 – 263) 12.2 (7.1 – 14.4) 115 (30 – 439) 14 (.3 – 407) Bulky nodal disease, n (%) ≥5 cm ≥10 cm 15 (35) 7 (16) 11 (52) 5 (24) Prior therapies, median (range) 4 (1 – 12) 3 (1 – 11) Prior ibrutinib, n (%) Months on ibrutinib, median (range) Refractory, n (%) 43 (100) 17 (1 – 56) 39 (91) 5 (24) 6 (2 – 11) 2 (10) Prior idelalisib, n (%) Months on idelalisib, median (range) Refractory, n (%) 4 (9) 10 (2 – 31) 2 (5) 21 (100) 8 (1 – 27) 14 (67)

Jones J, et al. EHA Annual Meeting 2016. Copenhagen, Denmark; June 9-16, 2016. Abstract 637.

Safety

Jones J, et al. EHA Annual Meeting 2016. Copenhagen, Denmark; June 9-16, 2016. Abstract 637.

Event, n (%) All Patients N=64 Any grade AE 64 (100) Common all-grade AEs (≥20% patients) Neutropenia Thrombocytopenia Diarrhea Nausea Anemia Fatigue Decreased WBC Hyperphosphatemia 37 (58) 28 (44) 27 (42) 26 (41) 23 (36) 20 (31) 14 (22) 14 (22) Event, n (%) All Patients N=64 Grade 3/4 AEs 53 (83) Common grade 3/4 AEs (≥10% patients) Neutropenia Thrombocytopenia Anemia Decreased WBC Febrile neutropenia Pneumonia 29 (45) 18 (28) 14 (22) 8 (13) 7 (11) 7 (11) Serious AEs 34 (53) Febrile neutropenia Pneumonia Multi-organ failure Septic shock Increased potassium 6 (9) 5 (8) 2 (3) 2 (3) 2 (3)

No clinical TLS was observed; 1 patient with high tumor burden met Howard criteria for laboratory TLS

Data as of June 10, 2016

Efficacy

Jones J, et al. EHA Annual Meeting 2016. Copenhagen, Denmark; June 9-16, 2016. Abstract 637.

Data as of June 10, 2016

Arm A n=43 Arm B n=21 Best response, n (%) Assessed by Assessed by IRC Investigator IRC Investigator ORR 30 (70) 29 (67) 13 (62) 12 (57) CR/CRi 1 (2) 3 (7) 0/0 3 (15) nPR 2 (5) PR 29 (67) 24 (56) 13 (62) 9 (43) Non-responder* SD PD D/C‡ 13 (30) – – – 14 (23) 9 (21) 1† (2) 4 (9) 8 (38) – – – 9 (43) 8 (38) 1† (5)

Current Status

Jones J, et al. EHA Annual Meeting 2016. Copenhagen, Denmark; June 9-16, 2016. Abstract 637.

Data as of June 10, 2016

Median time on study (range): Arm A, 13 months (0.1–18); Arm B, 9 months (1.3–16)

Efficacy Per Independent Review

Jones J, et al. EHA Annual Meeting 2016. Copenhagen, Denmark; June 9-16, 2016. Abstract 637.

Data as of June 10, 2016

• Median DoR, PFS, and OS had not been reached after 11.8 months of follow-up
• Estimated 12 month PFS for all patients: 80% (95% CI: 67%, 89%)

Venetoclax

• Venetoclax as a single agent has an ORR 76%, CR 22%

and 15% BM MRD negativity in heavily pretreated relapsed refractory patients

– DOR is much higher if CR or MRD negativity

• Activity is preserved in del17p patients and those who

have progressed on ibrutinib or idelalisib

• Clinical care required due to TLS
• No data yet in the upfront setting
• Resistance likely to emerge

– ? Early signal of excess Richter’s transformation

PI3K Signaling Pathway as a Target in B Cells

Where Does Idelalisib Stand?

• Highly active in R/R (and untreated) CLL
• Several categories of toxicity:

– Autoimmune: transaminitis, diarrhea/colitis, and pneumonitis – Neutropenia and sepsis (primary cause of infectious deaths on halted upfront trials): less common without BR, monitor and use growth factor – Opportunistic infections: PJP, CMV

• With current information, idelalisib use in CLL is limited to

the relapsed refractory setting and after ibrutinib

– Yet very limited data on response after ibrutinib, where we clearly need it

Comparison of Safety Profiles of PI3K Inhibitors

1Jones et al. 51st

ASCO Annual Meeting. Chicago, IL; May 29- June 2, 2015;

2Aggregated from

Idelalisib Prescribing Information; 3Patel et

• al. 51st ASCO Annual
• Meeting. Chicago, IL;

May 29-June 2, 2015;

4Aggregated from

Burris et al, Lunning et al, Fowler et al, 51st ASCO Annual Meeting. Chicago, IL; May 29- June 2, 2015.

Idela + Ofa (ASCO ’15)1 (n=173) Idelalisib Label (CLL & NHL)2 (n=256) Duvelisib (ASCO ‘15)3 (n=18) TGR-1202 All Studies (ASCO 2015)4 (n=137) Grade 3/4 Grade 3/4 Grade 3/4 Grade 3/4

Diarrhea/ Colitis

20% 10% 22% 1%**

Pneumonia 13% 16% N/A 4% ALT Elevations N/A 11% N/A 2% AST Elevations N/A 7% N/A 2%

ALT/AST Elevations

13% N/A 17% 2%

Discontinua- tions due to AE

31% 12% 33% 4%

Where Are We?

• Highly effective risk stratification
• Highly effective chemoimmunotherapy
• 3 classes of oral targeted inhibitors, mostly approved

as single agents given continuously

• Very limited data on whether sequential therapy will

work and in what order

– Including whether CIT will work after novel agent therapy upfront

• Very limited data on combinations or time limited

therapy, or outcomes after discontinuation for progression or adverse events

• Short follow-up

Relapsed Therapy for CLL

• If ibrutinib naïve: then ibrutinib

– Could change with expected expanded venetoclax label – For patients with very long response to prior chemoimmunotherapy and no adverse prognostic markers, can consider repeat CIT

• If progressed on ibrutinib: then venetoclax
• If off ibrutinib for adverse event: idelalisib, venetoclax

Front-line Therapy for CLL

Asymptomatic (incl. high risk pts) Observe (W&W) Symptomatic (active disease by IWCLL) 17p‐/TP53mut1 Ibrutinib Clinical Trial Venetoclax R‐HDMP Idelalisib ± R4 Alemtuzumab5 No 17p‐/TP53mut Fit2 Less Fit3 Unfit Ibrutinib <65‐70, no 11q mutated IGHV Obinutuzumab + Clb >65‐70 FCR (Ibrutinib) BR / PCR Ibrutinib Obinutuzumab + Clb Ibrutinib BR / PCR Ofatumumab + Clb Rituximab + Clb FIT UNFIT ECOG 1912 (FCR v IBR‐R) (NAIG) Alliance A041202 (BR v IBR‐R v IBR) (NAIG) UK FLAIR trial (FCR vs IBR‐R) PCYC‐1130 (Obin‐Clb v Obin‐IBR) GCLLSG CLL13 (CIT vs 3 VEN based arms) CLL14 (Obin‐Clb v Obin‐Ven)

1 17p‐ and/or TP53 mutation 2 CIRS <= 6, CrCl >=70 ml/min 3 CIRS > 6 or CrCl < 70 ml/min 4 Approved frontline in EU but

not recommended due to toxicity

5 Only available compassionate use

from the manufacturer

<65‐70, unmutated IGHV FCR Ibrutinib Ofatumumab + Clb Rituximab + Clb

Should Biologic Agents Replace Chemo?

• PROs:
• Oral
• Well tolerated (mostly!)
• Highly effective even in

high-risk disease

– Efficacy difference from chemo is most marked in relapsed setting – Randomized trials are assessing the upfront setting

• CONs:
• Given continuously indefinitely –

patients don’t like it vs 6 mos chemo and done!

• Do not want to abandon CURE

with FCR in IGHV mut CLL

• Many low-grade nagging side

effects

– Unknown long-term effects

• Tolerability worsens with

increasing age

• Unknown ability to salvage after

relapse

• Cost

Recent Cost Analysis for CLL Therapy

JCO 35: 166, 2017

Increase in Lifetime Costs to Payers and Patients

JCO 35: 166, 2017

Projected Costs of CLL Management

JCO 35: 166, 2017

How Can We Address These Cons?

• Risk-adapted front-line therapy
• Find effective, well-tolerated combinations that induce

deep remissions

• Stop therapy after a fixed, relatively short period of time

(6-24 mos)

• Advantages:

– Patient preference – Reduce long-term side effects – Reduce cost – Reasonable chance that subsequent relapse will still be sensitive to prior agents

What Is the Future?

• In fit or higher-risk patients: combination therapy to achieve deep, ideally

MRD-negative remissions (?cure) and give treatment breaks: saves money and toxicity and avoids resistance

• Sequential single agents lead to resistance but may be adequate for older

more frail pts or those with lower disease risk: can we stop?

• 17p - BTK / BCL2 / aCD20 combination
• Older higher disease risk (11q, maybe IGHV unmutated)

– BTK- or BCL-2 or combo

• Older lower disease risk – aCD20-clb
• Younger IGHV mutated/low-risk FISH: FCR-based therapy may be curative

– Need better understanding of which patients achieve these outcomes

• Younger IGHV unmutated patients have continuous relapse with FCR but
• ften achieve MRD negativity that leads to 5+ years remission

– Good candidates for combination trials, with goal of MRD negativity and therapy discontinuation

Ongoing Clinical Trials in CLL

Co = with comorbidities; I = ibrutinib.

Agent Initial Therapy Relapsed Therapy Ibrutinib FCR vs IR – two Ph 3 Ibrutinib – FCR – Ph 2 BR vs IR vs I – Ph 3 I-Obin vs Clb-Obin – Ph 3, >65/Co I in Del 17p CLL – Ph 2 BR +/- I – Ph 3 I vs IR ABT-199 Next slide ABT199-R vs BR – Ph 3 ABT199 after BCRi

Fourth-generation GCLLSG Trials Risk, Stage, and Fitness Adapted, Using Targeted Agents

Active disease CLL13 CLL14 Go go Slow go Ven-G Disease (MRD) eradication and longer survival Long-term disease-control with minimal side effects CLB-G Ven IG FCR/ BR VenR VenG

G = obinutuzumab; Ven = venetoclax.

Acknowledgments

DFCI Biostatistics Donna Neuberg Lillian Werner Haesook Kim Kristen Stevenson Research Nurses Karen Francoeur Victoria Patterson Kathleen McDermott Kim Coleman

• NIH, NHGRI
• CLL Research

Consortium

• ACS

MO Pilot Grant Okonow-Lipton Fund Melton Fund Rosenbach Fund Lymphoma Program, DFCI Arnold S Freedman David C Fisher Ann S Lacasce Eric Jacobsen Philippe Armand Matthew Davids Caron Jacobson Brown Lab, DFCI Ben Lampson Siddha Kasar Bethany Tesar Stacey Fernandes Lijian Yu Reina Improgo Josephine Klitgaard Weijie Poh Clinical Research Staff Sara Schlegel John Hanna Krystle Benedict Karen Campbell Shannon Milillo Hazel Reynolds Wu Lab, DFCI Catherine Wu Lili Wang Youzhong Wan Center for Cancer Genome Discovery Megan Hanna Laura Macconaill Broad Institute Eric Lander Gaddy Getz Carrie Sougnez Nir Hacohen Stacey Gabriel Mike Lawrence Petar Stojanov Andrey Sivachenko Kristian Cibulskis David Deluca Ritz Lab, DFCI Tiago Matos

Questions?