Key issues in mantle cell lymphoma

John P. Leonard MDRichard T. Silver Distinguished Professor of Hematology and Medical Oncology

Associate Dean for Clinical Research

Vice Chairman, Joan and Sanford I. Weill Department of Medicine

Disclosures

Consulting advice:

Teva Oncology, Oncotracker, Gilead Sciences Inc, Juno, Celgene Corporation, Nanostring Technologies, Genmab, Biotest, Regeneron Pharmaceuticals, AbbVie Inc, Sutro

Key questions in approaching MCL

§ How do we approach maintenance therapy in older and younger patients with MCL?

-What is the status of clinical trials?

§ What is the approach for relapsed MCL patients with relative contraindications to ibrutinib?

- ? Role of venetoclax

§ What is the likely toxicity of ibrutinib use over time?

§ What about CDK 4/6 inhibitors in MCL?

MCL “standard” initial treatment options

Observation

R-­CHOP

Modified R-­HyperCVAD

Bortezomib-­R-­CAP

R-­Bendamustine

vs

R-­CHOP/DHAP/ASCT

R-­HyperCVAD/MTX/Ara-­C

R-­HyperCVAD/MTX/Ara-­C/ASCT

Nordic

Less intensive

More intensive

What would one look for in maintenance therapy for MCL?

§ Cure (no current evidence of such)

§ Overall survival benefit (maybe)

§ Progression-­free survival benefit (probably)

- Is this the best endpoint?

§ Quality of life benefit (maybe)

- If staying in remission improves QOL

- If maintenance toxicity doesn’t hurt QOL

- If allowing a less toxic regimen overall helps QOL

R maintenance after R-­CHOP improves OSin older MCL patients

Kluin-­Nelemans H et al. N Engl J Med 2012;;367:520-­531

0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1

0 12 24 36 48 60 72 84 96

Probability

Months since registration

PFS (all registered pts)

Median: 64.2 months

Pts at risk 168 133 110 94 70 38 11

N = 168

Current data with Bendamustine + Rituximab (+/-­ maint R) Up-­front MCL

Median age 71, 84% MIPI int/high risk

Rummel et al, ASCO 2016

0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1

0 12 24 36 48 60 72 84 96

Probability

Months since registration

PFS (randomized pts)

MR vs. observation after BR therapy in MCL

months events(median) (n)

Observation 54.7 29R maint. 72.3 21

R maintenancen = 60

Patients: n = 168

Observationn = 62

Patients randomized: n = 122

Patients analyzed (n = 122)

Rummel et al, ASCO 2016;;Abstract 7503.

HR = 0.71p = 0.2267

0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1

0 12 24 36 48 60 72 84 96

Probability

Months since registration

Hazard ratio, 1.51 (95% CI 0.70 – 3.25)p = 0.2974

months events(median) (n)

Observation n.y.r. 11R maint. n.y.r. 15

N = 122

Pts at riskObserv 62 58 57 52 43 21 8R maint 60 59 53 44 38 23 5

Overall Survival after Bendamustine + RituximabObservation vs Maintenance (Randomized pts only)

Rummel et al, ASCO 2016

1

Rituximab 375 mg/m2

Lenalidomide 20 mgDays 1-­21 q28

Time (months)2 3 4 5 6 7 8 9 10 11 12

Lenalidomide + Rituximab as initial therapy for MCL

Ruan J et al. N Engl J Med 2015;;373:1835-­1844.

POD

N=38

Age 65 years 42-­86 yMIPI Low 13

Int 13High 12

Ki67 <30% 26>30% 8

RR CR 61%PR 26%SD 3%PD 5%

E1411: Randomized Phase 2 Intergroup Trial: Initial Therapy for Mantle Cell Lymphoma

REGISTRATION

BR x 6

BVR x 6

Lenalidomide+ Rituximab

BR x 6

Rituximab

Rituximab

Lenalidomide+ Rituximab

BVR x 6

Rituximab maintenance after SCT prolongs survival in younger MCL patients

Le Gouill et al (Lysa/Goelams group), Abst 145 (Saturday)

§ Previously untreated MCL < 66 yrs, 53% MIPI low risk

§ R-­DHAP x 4 (+ R-­CHOP-­14 in NR), then R-­BEAM auto SCT

§ 299 enrolled, 240 randomized post SCT to observation vs maintenance R once every 3 mo x 2 years, 50+ mo F/U

§ 4 year PFS 68%, OS 78% for entire group

§ 4 year PFS 82% MR vs 65% Obs (p=0.0005)

§ 4 year OS 89% MR vs 81% Obs (p=0.04)

§ Toxicity data not yet reported

ECOG 4151: A Randomized Phase III Trial of Consolidation with Autologous Hematopoietic Cell Transplantation Followed by Maintenance Rituximab vs. Maintenance

Rituximab Alone for Patients with Mantle Cell Lymphoma In Minimal Residual Disease-­Negative First Complete

Remission

An Intergroup Study in Mantle Cell Lymphoma

Timothy Fenske, MD;; Medical College of Wisconsin (ECOG)Brian Till, MD;; University of Washington (SWOG)

Kristie Blum, MD;; The Ohio State University (Alliance)Brad Kahl, MD;; Washington University (ECOG)

Study Schema

PREREGISTRATION*

ARM AAuto-­HCT + Rituximab

Clonal Marker Present?

YES

NO

Post-­inductionRestaging (CR, PR, SD/PD) Submit blood to Adaptive for MRD assessment (MRD pos or MRD neg)

MRD neg CR**

RANDOMIZATION

Submit tumor tissue to Adaptive Biotechnologies forclonal marker testing

ARM BRituximab

Arm CAuto-­HCT + Rituximab

MRD neg PRMRD indeterminateMRD pos CR or PR

* Pre-­registration can occur any time during induction or within 2 months after** These patients will be stratified by MIPI-­c and type of induction (containing high dose Ara-­C and no Ara-­C)

What about relapsed pts? MCL treatment summary

Dreyling M et al. Ann Oncol 2014;;25:iii83-­iii92

à

What are potential ibrutinib toxicities or contraindications?

§ Bleeding: Ibrutinib inhibits collagen-­mediated platelet aggregation

- Any grade bleeding or bruising event: 50%

§ Grade 3/4 thrombocytopenia 13%

§ Contusion 18%;; epistaxis 11%;; petechiae 10%

§ Grade ≥3 bleeding: 6%

§ Atrial fibrillation

- 11% overall, Grade 3: 6%;; Grade 4: 0%

- Median time to onset 140 days (41-­520)

Kemel et al, 2015;; Wang et al, 2015.

Table 3. Prevalence of select AEs by 6-­month intervals

Select AEsn (%)

1-­6 mo(n = 111)

7-­12 mo(n = 72)

13-­18 mo(n = 51)

19-­24 mo(n = 41)

>24 mo(n = 22)

Any diarrhea

49 (44%) 21 (29%) 15 (29%) 8 (20%) 6 (27%)

Grade 3 5 (5%) 0 0 1 (2%) 0

SAE 1 (1%) 0 0 0 0

Any infection

76 (69%) 43 (60%) 30 (59%) 22 (54%) 9 (41%)

Grade ≥3 20 (18%) 11 (15%) 6 (12%) 5 (12%) 1 (5%)

SAE 16 (14%) 9 (13%) 4 (8%) 5 (12%) 1 (5%)

Any bleeding

46 (41%) 17 (24%) 17 (33%) 14 (34%) 5 (23%)

Major bleeding

6 (5%) 1 (1%) 3 (6%) 2 (5%) 2 (9%)

PINNACLE Study: Bortezomib in Relapsed/Refractory MCL

§ Bortezomib 1.3 mg/m2

on D1, 4, 8, and 11 of a 21-­day cycle for up to 17 cycles

§ Relapsed/MCL (n=144)

- 96% ≤2 prior therapies

- 37% prior intensive chemotherapy

Goy et al, 2009;; Fisher et al, 2006.

Table 2. Best Response to Treatment (n=141) by Algorithm and by Investigator Assessment

Response

By Algorithm By Investigator

No. % 95% CI No. % 95% CI

CR+CRu+PR 47 33 26 to 42 57 40 32 to 49

CR+CRu 11 8 4 to 14 11 8 4 to 14

CR 9 6 3 to 12 8 6 2 to 11

PR 36 26 19 to 34 46 33 25 to 41

SD 47 33 26 to 42 46 33 25 to 41

PD 35 25 18 to 33 37 26 19 to 34

No Post-­baseline Assessment

12 9 4 to 14 1 <1 0 to 4

Abbreviations: CR, complete response;; CRu, unconfirmed CR;; PD, progressive disease;; PR, partial response;; SD, stable disease

Lenalidomide in Relapsed/Refractory MCL§ Phase II EMERGE trial (n=134)

-Median of four prior therapies including bortezomib

- Prior SCT in 29%;; dose intense therapy in 33%

§ Lenalidomide 25 mg/day on D1-­21 of a 28 day cycle until PD or intolerable adverse events (AEs)

ORR (CR/CRu) 28% (7.5%)

Med DOR (95% CI) 16.6 months (7.7-­26.7)

Med OS (95% CI) 19.0 months (12.5-­23.9)

Med Time to Response 2.2 months

Grade 3/4 AEs in >15% Neutropenia 43%Thrombocytopenia 28%

Goy et al, 2013.

Retrospective analysis: Outcomes of post-­ibrutinib progression

31 2 073 38 18 10 6 4 3 1 0

0 10 20 30 40

Overall Survival (month)

0.0

0.2

0.4

0.6

0.8

1.0

Surv

ival

Pro

babi

lity

12

2: Received subsequent treatment1: Did not receive subsequent treatmentGroup

Logrank p <.0001+ Censored

31 2 073 38 18 10 6 4 3 1 0

0 10 20 30 40

Overall Survival (month)

0.0

0.2

0.4

0.6

0.8

1.0

Surv

ival

Pro

babi

lity

12

2: Received subsequent treatment1: Did not receive subsequent treatmentGroup

Logrank p <.0001+ CensoredCharacteristic N %

All 114 100%CR 13 11%PR 45 39%Duration 4.7

mo95% CI 3.8-­

5.7Post-­ibrutinib All 104 100%

Received treatment post-­ibrutinib

73 70%

Time from ibrutinibto next therapy

0.3 mo

95% CI 0.2-­0.5 mo

MIPI

• High risk 35 48%• Intermediate risk 18 25%• Low risk 9 12%• Unknown 11 15%

Subsequent treatment

• Rituximab 39 53%• Lenalidomide 19 26%• Cytarabine 13 18%• Bendamustine 12 16%• Bortezomib 7 10%• Anthracycline 5 7%• PI3K inhibitor 4 5%

Whole group median OS: 2.9 mo (95% CI 1.6-­4.9)No treatment OS: 0.8 mo (95% CI 0.3-­1.4) Treated median OS: 5.8 mo (95% CI 3.7-­10.4)TTNT with first subsequent therapy

N=67;; 2.4 mo (95% CI 1.4-­3.3)Univariate Cox regression analysis for OS:

MIPI prior to ibrutinib (HR 1.81)duration of ibrutinib (HR 0.96)Martin et al Blood 2016;;127(12):1559-­63.

Reductions in Lymph Node Size Phase I Study of Venetoclax (ABT-­199) in Lymphoma

Davids MS, et al. J Clin Oncol. 2014;;32(5S): Abstract 8522.

• 27/50 (54%) of patients had 50% reduction in nodal size

WMMCL

FLDLBCL

MZLPMBCL

100

50

0

-­50

-­100

Best Percent Change

• 27/50 (54%) of patients had 50% reduction in nodal size

Phase I Study of Venetoclax in Lymphoma

Davids MS, et al. J Clin Oncol. 2014;;32(5S): Abstract 8522.

Histology

Overall response (CR + PR)

Complete response n (%)

Partial response n (%)

Stable disease n (%)

Progressivedisease n (%)

D/C prior to response n (%)

Total evaluable(n = 59) 48% 3 (5) 25 (42) 15 (26) 12 (20) 4 (7)

DLBCL (n = 18) 28% 1 (6) 4 (22) 1 (6) 9 (50) 3 (5)

FL (n = 13) 31% 1 (8) 3 (23) 9 (69) -­ -­

MCL (n = 19) 68% 1 (5) 12 (63) 4 (21) 1 (5) 1 (5)

WM (n = 4) 75% -­ 3 (75) 1 (25) -­ -­

MZL (n = 3) 67% -­ 2 (67) 1 (33) -­

MM (n = 1) -­ -­ -­ -­ 1 (100) -­

PMBCL (n = 1) 100% -­ 1 (100) -­ -­ -­

Leonard J P et al. Blood 2012;;119:4597-­4607

Palbociclib (CDK4/6 inhibitor) induced changes in Rb phosphorylation and Ki-­67 expression in pre-­ and on-­treatment lymph node biopsies

Cell death

pG1

Palbociclib

CDK4/6

Metabolism

PI3KBTK

PI3K inhibitorBTK inhibitor

PIK3IP1NFkBPIK3IP1

NFkB

Di Liberto, et al, unpublishedChiron et al, Cancer Discovery, 2014

PIK3IP1 Inhibition of PI3K in G1 Arrest Induced by CDK4 Inhibition Reprograms MCL for IbrutinibTherapy (abst 610)Di Liberto (Monday)

Prolonged inhibition of CDK4 reprograms MCL cells for killing by BTK or PI3K inhibition

Phase I trial of palbociclib plus ibrutinib

Enrollment:

N=20 at 5 dose levels

Median prior therapies = 1 (1-­5)

6 refractory to last therapy

§ 3 DLT

-Platelets DL3

-Rash x 2 DL5

§ Dose level 4 RP2D

Best response• ORR – 67%• CR – 44%

• 1 year PFS 68%• 1 year response duration 100%• No responder progressed to date

Abstract 150 (Sunday), Martin et al

Key issues in choosing therapy for chronic/incurable disease

§ Goals of therapy (survival benefit, cure)

- PFS less relevant than true quality of life

§ Better characterization of multiple and chronic toxicities

§ How much is compliance an issue in affecting efficacy and toxicity?

§ Chronic/ongoing therapy vs intermittent/retreatment – need to characterize pros/cons

§ Are quality of life metrics sufficiently robust to serve as primary endpoints?

- Measured continuously over time vs specific time points

§ Measuring true costs for individuals and society