MRD Negativity as an Outcome in CLL: Ongoing Challenges with Del 17p Patients

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1 MRD Negativity as an Outcome in CLL: Ongoing Challenges with Del 17p Patients Jennifer R Brown, MD PhD Director, CLL Center Dana-Farber Cancer Institute Associate Professor Harvard Medical School November 10, 2016

2 Disclosures Brown: Served as a consultant for Janssen, Pharmacyclics, Celgene, Roche/Genentech, Gilead, Infinity, Abbvie, Sun Biopharma This presentation will include off label discussion of venetoclax*, which is not approved for any indication in Brazil *Not approved for any indication in Brazil

3 Previously Untreated CLL 1960s 1970s 1980s 1990s 2000s 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 Chemo-immunotherapy (CIT) 45% CR; better PFS & OS Alemtuzumab monotherapy 24% CR Bendamustine 30% CR

4 CLL8: Addition of Rituximab to FC

5 CLL8: Survival after FCR by FISH 17p deletion +12q 13q-single 11q- Not 17p-/11q-/+12q/13q- 17p- Lancet 2010: 376: 1164

6 CLL8: Impact of TP53 Mutation on OS TP53: wild type mutated Therapy: FCR FC

7 CLL8 Multivariable Analysis: Predictive Factors Cox regression including: FC, FCR, TP53, NOTCH1, SF3B1, and treatment interaction PFS: HR p-value FCR <.001 TP53 mut <.001 SF3B1 mut NOTCH1 mut Interaction OS: HR p-value FCR TP53 mut <.001 NOTCH1 mut Interaction

8 PFS by MRD Levels in CLL8 Measured in PB at Final Restage PR pts CR pts p <.0001 p =.0004 Boettcher et al., JCO, 2012

9 CLL10 Study: FCR vs BR in Front-line Consort Diagram 688 CLL patients screened centrally for: immunophenotype genomic aberrations (FISH) IGHV sequencing CIRS GFR 564 underwent 1:1 randomization FCR n = 284 BR n = treatment before randomization 1 patient decision 1 misdiagnosis (MCL) ITT: FCR n = 282 ITT: BR n = 279 Median observation time: 37.1 (0-59.9) months

10 CLL10 Study: FCR VS BR in Front-Line ITT Progression-free survival = Primary endpoint Median PFS FCR 55.2 months BR 41.7 months P < HR = = > 1.388

11 CLL10 Study: FCR vs BR in Frontline Response FCR n=274 BR n=273 p value CR (CR + CRi) 47.4% 38.1% CR 40.1% 36.3% CRi 7.3% 1.8% PR 50.4% 59.7% ORR 97.8% 97.8% 1.0

12 CLL10 Study: FCR vs BR in MRD Negativity MRD Minimal negativityresidual disease FCR (MRD) %(N) in ITT n=282 BR %(N) n=279 BM at FR 26.6% (75/282) PB at FR PB 12 months after FR 48.6% (137/282) 19.7% (47/238) 11.1% (31/279) 38.4% (107/279) 9.0% (20/222) PB 18 months after FR 18.0% (37/206) 8.5% (16/187) BM=bone marrow; FR=final restaging; PB=peripheral blood

13 Patient Flow Chart Patients randomized within CLL8 and CLL10 trial (n = 1378) Pts without MRD from PB at EOT (n = 733) Non-responders at EOT (n = 18) Unconfirmed CRs at EOT (n = 46) PR pts with not sufficiently evaluated response (missing lymph node, spleen measurement or lymphocyte count) at EOT (n = 26) Target population (pts with definitive CR(i) or PR and MRD measurement from PB at EOT) (n = 555)

14 Results: Patient Characteristics Baseline characteristics and prognostic factors Treatment FC FCR BR Non-target population (n = 823) 35.0% 48.1% 16.9% Target population (n = 555) 21.8% 53.0% 25.2% Median age (y) 61 (30-81) 61 (33-81) Male 71.3% 77.1% Binet stage A B C 10.8% 54.8% 34.3% 13.7% 51.3% 35.0% Genetic aberrations by FISH: del (17p) del (11q) 6.9% 21.7% 1.5% 25.0% IGHV Unmutated 62.5% 62.1% s- TK (U/L) > % 74.1% s- β2m (mg/l) > % 33.9%

15 Patient Flow Chart Patients randomized within CLL8 and CLL10 trial (n = 1378) Pts without MRD from PB at EOT (n = 733) Non-responders at EOT (n = 18) Unconfirmed CRs at EOT (n = 46) PR pts with not sufficiently evaluated response (missing lymph node, spleen measurement or lymphocyte count) at EOT (n = 26) Target population (pts with definitive CR(i) or PR and MRD measurement from PB at EOT) (n = 555) MRD- CRs (n = 186) MRD+ CRs (n = 39) MRD- PRs (n = 161) MRD+ PRs (n = 169) Median observation time: 45.4 months

16 Results: PFS grouped by MRD and clinical response at EOT Median PFS p value (compared to MRD- CRs) MRD- CRs 68.9 mo - MRD+ CRs 44.4 mo p = MRD- PRs 61.7 mo p = MRD+ PRs 28.1 mo p < MRD- PRs vs. MRD+ CRs p = 0.047

17 MVA Analysis: Impact of MRD and Clinical Response COX regression PFS Univariate comparison HR Lower 95 % CI Upper p value MRD status Positive vs. negative < Clinical response PR vs. CR = Deletion 17p Yes vs. no < IgHV analysis Unmutated vs. mutated < 0.001

18 Target Patient Population Target population (pts with definitive CR(i) or PR and MRD measurement from PB at EOT) (n = 555) MRD- CRs (n = 186) MRD+ CRs (n = 39) MRD- PRs (n = 161) MRD+ PRs (n = 169) Only lymphadenopathy (n = 25) Only bone marrow involvement (n = 18) Only splenomegaly (n = 78) > 1 involvement (n = 40)

19 Results: PFS grouped by MRD and clinical response (including MRD- PR subgroups) at EOT Median PFS p value (compared to MRD-CRs) MRD- CRs 68.9 mo - MRD- PRs: - with splenom. - with ly. node - with BM - > 1 above 72.0 mo 38.7 mo 56.8 mo 51.8 mo p = p < p = p = MRD+ CRs 44.4 mo p = MRD+ PRs 28.1 mo p < 0.001

20 Conclusions Summary MRD and clinical response are both strong predictors of PFS MRD in combination with clinical response predicts PFS more accurately than clinical response alone Single splenomegaly as sole abnormality at EOT has no impact on PFS in MRD- PR patients Del17p patients still at very high risk, less likely to be MRD neg

21 FCR300: PFS and OS Proportion Surviving PFS OS Events Total Median yrs Median Follow-up Time All: 9.8 yrs Alive: 11.5 yrs yrs Mos Wierda WG, et al. iwcll 2013 Abstracts

22 FCR300: PFS by IGHV Mutation Status Proportion Progression Free Group Events Total IGHV-M IGHV-UM Unknown P < Mos Wierda WG, et al. iwcll 2013 Abstracts

23 First-line FCR300: PFS and OS Outcomes by MRD Status Overall Survival Months Months Strati, et al. Blood. 2014;123(24):

24 First-Line FCR: Rossi Data Overall Survival Mut IGHV, no 11 or 17 17p UM IGHV or 11q Rossi et al. Blood. 2015;126: 1921.

25 MRD Negativity Predicts Best PFS & OS Kwok et al; Blood 2016 e

26 Better PFS and OS if MRD Neg After First Line Therapy Kwok et al; Blood 2016 e

27 MRD Neg Does Not Overcome Poor Prognosis of Del(17p/11q) Kwok et al; Blood 2016 e

28 Ibrutinib (PCI-32765): BTK Inhibitor O Forms a specific and irreversible bond with cysteine-481 in Btk NH 2 Potent Btk inhibition N N N N IC 50 = 0.5 nm Orally available N O Once daily dosing results in 24-hr sustained target inhibition

29 Blood Lymphocytes vs. Lymph Nodes Mean Percent Change from Baseline ALC SPD Month SPD = sum of products of lymph node dimension Month O Brien et al. J Clin Oncol 32:5s, 2014 (suppl; abstr 7014). 11

30 1102: Response Over Time Patients With Response* (%) 100% 80% 60% 40% 20% 0% CR/P R Median time to first 1.9 months (range, 1.4 response: 23.2) Median time to best 7.4 months (range, 1.7 response: 31.8) 94% of patients who achieved a PR-L converted to better response Months From Initiation of Study Treatment Best response to ibrutinib improves over time *Cumulative response as assessed by investigator O Brien et al. J Clin Oncol 32:5s, 2014 (suppl; abstr 7014).

31 100% 80% 60% 40% 1102 Best Response (Investigator-Assessed) 90% 84% 89% 7% 11% 23% 1% 3% 80% 74% 55% CR npr PR PR+L SD PD 20% 0% Median DOR in months (range)3 Month 30 (95% CI) 6% 10% 0% 3% 4% 2% 4% 5% 2% TN (n = 31) R/R (n = 101) Total (N = 132) NR (0 to 35.0+) NR (0 to 35.2+) NR (0 to 35.2+) 100.0% (NE) 79.1% (64.2 to 88.4) 85.3 (74.4 to 91.8) 5/6 patients who received prior idelalisib responded to ibrutinib (4PR, 1 PR+L) 2/5 responders continue treatment with one additional patient moving on to SCT O Brien et al. J Clin Oncol 32:5s, 2014 (suppl; abstr 7014).

32 1102 PFS by Cytogenetics (FISH) in 1.0 Relapsed/Refractory CLL Progression-Free Survival (Proportion) month PFS Del17p Del11q No del17p/ 11q 45.9% 74.2% 89.0% (95% CI) ( ) ( ) ( ) Median PFS 28.1 mos NR NR del17p del11q No del17p or del11q + Censored Months From Initiation of Study Treatment O Brien et al. J Clin Oncol 32:5s, 2014 (suppl; abstr 7014).

33 Overall Survival by Cytogenetics (FISH) in Relapsed/Refractory Population 1.0 Overall Survival (Proportion) del17p del11q No del17p or del11q + Censored Del17p Del11q No del17p/11q 30-month OS 65.9% 84.9% 93.9% (95% CI) ( ) ( ) ( ) Median OS NR NR NR Months From Initiation of Study Treatment O Brien et al. J Clin Oncol 32:5s, 2014 (suppl; abstr 7014).

34 HELIOS: BR +/- Ibrutinib PFS Chanan-Khan A, et al. ASCO Annual Meeting Abstract

35 HELIOS: MRD Negativity MRD Negativity Presented By Asher Alban Chanan-Khan at 2015 ASCO Annual Meeting

36 HELIOS: MRD Negativity

37 Phase II Ibrutinib FCR in Previously Untreated, Younger Patients with CLL PI: Matthew Davids, MD Primary endpoint: MRD negative CR Goal: Cure One week lead-in ibrutinib, then continuous during FCR x 6 and ongoing until progression Required pegfilgrastim, infectious prophy Fully accrued at 35 patients but awaiting amendment to expand

38 Patient Characteristics (n=27 evaluable) Median age at enrollment: 55 yrs (range 43-65) 7/25 (28%) had del(11q) and 1/25 (4%) had del(17p) with TP53 mutation. Unmutated IGHV was present in 11/17 (65%) ZAP-70 was positive in 17/23 (74%) 1/16 (6%) pt had NOTCH1 mutation

39 Preliminary Toxicity Summary (n=27 evaluable) -10 patient safety lead-in: No unexpected toxicities -Hematologic toxicity: Neutropenia (26%; 15% gr 3-4) Thrombocytopenia (56%; 19% gr 3-4) Anemia (19%, 4% gr 3-4) -Non-hematologic toxicity (in 15% of pts) gr 1/2 nausea (63%), fatigue (33%), bruising (33%), rash (19%), and gr 1 diarrhea (15%)

40 Preliminary Toxicity Summary (n=27 evaluable) -Bleeding events: gr1 epistaxis in 1 patient -No grade 3/4 infections -SAEs: gr 4 febrile neutropenia, gr 3 atrial fibrillation, and gr 3 transaminitis in 1 pt each

41 Preliminary Efficacy Summary (n=22 evaluable) ORR: (22/22) = 100% CR/CRi: (10/22) = 45% MRD negative CR = 45% Bone marrow MRD: (19/22) = 86% negative PR: (12/22) = 55% 11/12 pts with PR had residual nodes < 2.5 cm Median duration of therapy 7.7 mo (range ) 25/27 patients remain on ibrutinib maintenance

42 Comparison of ClonoSEQ with Four Color Flow Cytometry ClonoSEQ Identifies disease in 30% of patients neg by FC Brown et al, ASH 2014; Aw et al, manuscript in p

43 Efficacy Against Persistent Lymphs in Ibrutinib Treated Patients Cervantes-Gomez et al. Clin Cancer Res; [Epub ahead of print]

44 Venetoclax* (ABT-199) Response in Relapsed/Refractory CLL/SLL Response Overall response All (n = 116) del(17p) (n = 31) F- Refractory (n = 70) IGHV Unmutated (n = 46) 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 (24, 53) 83 (70, 93) *Not approved for any indication in Brazil Roberts AW, et al. N Engl J Med Online ahead of print.

45 Venetoclax* (ABT-199) in Relapsed/Refractory CLL/SLL *Not approved for any indication in Brazil Roberts AW, et al. N Engl J Med Online ahead of print.

46 Detailed Risk Stratification of Patients for Tumor Lysis 2014 EHA Annual Meeting, Poster

47 Venetoclax* in High-Risk R/R CLL with del17p: Baseline Characteristics Characteristic, n (%) N=107 a (%) Age, years Median, range 67, 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) Low 19 (18) TLS risk category Medium 43 (40) High 45 (42) Rai stage III or IV 51(48) IGHV Unmutated 30 (81) *Not approved for any indication in Stilgenbauer et al., ASH 2015 (abstract LBA-6, oral presentation)

48 Venetoclax* in high-risk R/R CLL iwcll Response (74%) with 17p del MRD-negativity Median time-to-first response: 0.8 months ( ) Median time to CR/Cri (16%): 8.2 months ( ) *Not approved for any indication in Of 45 patients tested, 18 achieved MRD-negativity in peripheral blood Stilgenbauer S et al, Blood 2015; 126(23): LBA-6.

49 Del 17p CLL: Durability of Venetoclax* Activity Duration of Response (N=85) PFS and OS (N=107) 12-month estimates: All responders: 84.7% CR/CRi/nPR: 100% MRD-negative: 94.4% *Not approved for any indication in Brazil 12-month estimates (95% CI): PFS: 72.0% (61.8, 79.8) OS: 86.7% (78.6, 91.9) Stilgenbauer et al, ASH 2015

50 Dosing Schedule of Venetoclax* and Final Escalation Strategy: Rituximab Week 1 20 D1 mg a Week 1 D2 50 mg 7 b Week 2100 mg Week mg Week 4 Cohor t Dose Month 1 Cohort Dose Months 2 6 Cohort Dose Month 7 Venetoclax* monotherapy Rituximab: D1 c 375 mg/m 2 D1 of Months mg/m 2 Dose escalation phase: 200, 300, 400, 500, 600mg/day cohorts (n = 41) Safety expansion phase: 400mg/day cohort (n = 8) Data pooled for these safety and efficacy analyses *Not approved for any indication in Brazil

51 Rapid Reduction in Absolute Lymphocyte Counts During Early Venetoclax* Dosing 200 Absolute Lymphocyte Count a Weeks on Venetoclax* b ALC (x10 9 /L) Weeks on 4 5 venetoclax* *Not As approved of January for 21, any 2015 indication in Brazil Median ALC % ALC >4 x 10 9 /L 100 a a 17 patients did not have lymphocytosis at baseline b Rituximab started at week 3 5 depending on time of enrollment and escalation schedule 32/32 (100%) patients with baseline lymphocytosis achieved ALC < 4 x 10 9 /L Median time to reduction to ALC < 4 x 10 9 /L 3 weeks (range: 1 9)

52 Responses by Subgroup Best Response, n (%) All n=49 del17p n=9 Fludarabinerefractory n=9 IGVH unmutated n=19 Overall Response 41 (84) 7 (78) 5 (56) 16 (84) CR/CRi 20 (41) 3 (33) 4 (44) 7 (37) PR/nodular PR 21 (43) 4 (44) 1 (11) 9 (47) SD 5 (10) 1 (11) 2 (22) 1 (5) Disease progression 2 (4) 0 1 (11) 1 (5) Death (TLS) a 1 (2) 1 (11) 1 (11) 1 (5) 38 patients remain on study 11 discontinued (6 due to PD; 3 withdrew consent; 2 due to AE) As of a January Fatal TLS 21, 2015 event previously reported; no other fatal TLS events occurred after May 2013 protocol amendment

53 Time to Response Rituximab Venetoclax* Percent of all Patients Achieving Response PR CR Median time to response Response Level Months Median (range) PR (n = 40) a 2.8 ( ) CR (n = 20) 7.8 ( ) Time on venetoclax Bone marrow biopsy (Months) Time on Venetoclax* (Months) a 1 patient went from SD to CR at 15.7 months *Not approved for any indication in As of January 21, 2015 Brazil

54 Preliminary Duration of Response Percent not progressed Months CR patients at risk: PR patients at risk: CR PR Duration of response is calculated from earliest response to last visit a Post data cut-off, 1 patient who achieved a CR (at 6.5 months) and stopped therapy shortly thereafter had asymptomatic progression after 23.7 months off therapy Graph shows data as of January 21, 2015

55 Bone Marrow Minimal Residual Disease (MRD) MRD was assessed using local institutional methods and sensitivity 10-4 Response Classification MRD-negative MRD-positive Not evaluable CR/CRi (n=20) PR (n=21) Other (n=8) 1 a 1 b 6 c Total, n/n (%) 24/49 (49) 16/49 (33) 9/49 (18) a PR unconfirmed; b SD; c No sample As of January 21, 2015

56 Durability of Complete Responses Following Cessation of Venetoclax* 6 patients discontinued venetoclax* after CR/CRi Patients remain on study, a median time of 12 months (0 21) a off venetoclax* 4/6 were MRD-negative 6/6 had not progressed at data cut-off Post data cut-off, 1 MRDpositive patient has asymptomatic progression 23.7 months after stopping therapy b Time on venetoclax Time off venetoclax Months ** * * MRD-positive patient with asymptomatic progression after data cut-off ** A subsequent CT scan showed lymph node size (previously 1.5 cm) now 1.7 cm, thus now PR a At the time of the data cutoff, 1 patient had just stopped venetoclax* monotherapy and did not have measurable time off of venetoclax b Progression occurred after the data cut-off Graph *Not shows approved data as for of January any indication 21, 2015 in Brazil

57 Summary MRD negativity as measured by four color flow cytometry is a very strong predictor of PFS and OS after CIT Kinase inhibitors as single agents very rarely result in MRD negativity Higher with chemoimmunotherapy Venetoclax* as a single agent does induce MRD negativity; correlation with PFS and OS requires longer follow-up but is likely Combinations of venetoclax* with other targeted therapies have the potential to induce MRD negativity *Not approved for any indication in Brazil

58 Ongoing Clinical Trials in CLL 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 IPI-145 IPI vs Ofa Ph 3 IPI-145-Obin after BCRi I=Ibrutinib; Co=with comorbidities

59 Fourth Generation of GCLLSG Trials Risk, Stage and Fitness Adapted, Using Targeted Agents Active disease CLL13 CLL14 Go go Slow go FCR/BR AR AG AIG CLB-G AG Disease (MRD) eradication and longer survival Long-term disease-control with minimal side effects