Mantle Cell Lymphoma 2019: New Agents

Michael E. Williams, MD, ScMByrd S. Leavell Professor of MedicineChief, Hematology/Oncology DivisionPhysician Lead, Cancer Service LineUniversity of Virginia Cancer Center

Charlottesville, Virginia

Disclosures: Michael E. Williams, MD, ScM

• Clinical trial grant support to the University of Virginia: • Allos, Celgene, Gilead, Janssen, Novartis, Pharmacyclics, TG

Therapeutics

• Honoraria:• Xian Janssen

• Consultant: • Abbvie, Astra-Zeneca, Celgene, Janssen, Kite, Juno, TG Therapeutics,

Gilead Sciences, Verastem, Seattle Genetics, Sandoz

MCL Challenges

• Biologic and clinical heterogeneity• Better treatment endpoints• Improve duration of response• Optimize use of stem cell transplantation• Optimize use of targeted agents• Chemotherapy-free regimens• Cure

MCL: Typical Presentation• 74% male, average age 63 years

– Usually stage III-IV disease– MIPI scores may correlate with outcome

• Diffuse adenopathy, splenomegaly• Extranodal disease, especially GI tract• Clinically and biologically heterogeneous

– Blastoid variant is more aggressive– Complex karyotype or p53 mutation carry

poorer prognosis

Pathogenesis and Progression of Mantle Cell Lymphoma

M. Dreyling et al. Ann Oncol 2014

Indolent MCLClinical features:

– Splenomegaly– Minimal or no

adenopathy– Leukemic phase– May be confused

with CLL– Observe without

treatment if no symptoms

Molecular features:– Mutated IgVH genes– No p53 mutations– Few chromosomal

changes other than the t(11;14)

– SOX11 negative

Martin P, et al. J Clin Oncol.2009; 27:1209-1213.

Fernandez V, et al. Cancer Res. 2010;70:1408-1418.

MCL Initial Therapy: 2019• Watch/Wait patients

– indolent subtype, low tumor burden, asymptomatic (~20% of patients)

• Younger, fit patients, < 60-65 y– Rituximab plus a high-dose cytarabine -based

regimen (e.g.,R-DHAX) à Auto SCTà Maint. Rituximab (LeGouill et al, NEJM 2017)

– Is ASCT needed if MRD negative after induction therapy? (ECOG 5141)

– Non-HiDAC regimens also utilized pre-ASCT

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:ECOG 5141

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)

E5141 Study Schema: MCL

Initial therapy in older MCL patients: 2019

1. BR (Bendamustine-rituximab)

2. R-CHOP3. VR-CAP (Bortezomib plus R-CHP)4. R-BAC500 (BR plus cytarabine 500 mg/m2)

5. R2 (Lenalidomide-rituximab)

6. Clinical trial (e.g., BTKi, or BTKi combined with anti-CD20 or venetoclax)

Summary of non-intensive MCL induction regimens*

N Age ORR CR mPFS

R-CHOP 244 66 89% 42% (CT) 14.4 mo

VR-CAP 243 65 92% 53% (CT) 24.7 mo

BR** 188 70 ~90% ~45% (CT) 35-48 mo

RBAC500 57 71 91% 91% (PET) Not reached

*no maintenance therapy**pooled data from 3 trials

Sustained remission with Lenalidomide plus Rituximab as initial therapy of MCL

J Ruan et al, NEJM 2015; JCO 2018

• n=38, median f/u 64 mo. (21-78 mo.)• ORR 92%, CR 64% (by PET +/- BM; med. 11 mo. to reach CR)

• 3 yr PFS 80%, OS 90%• 5 yr estimated PFS 64%, OS 77%

– 8/10 patients in CR @ 3 yr are MRD negative– No difference in ORR for Low- vs High-risk MIPI– No correlation with Ki-67 score

• Toxicity: – Grade 3-4 neutropenia 50%, thrombocytopenia 13%– 1 pancreas cancer, 6 non-inv. skin cancer– Grade 3 infection in 3 pts

• Relapsing pts respond to second line Rx

ECOG Trial: E1411 - Phase 2 Intergroup Trial: Initial Therapy of Mantle Cell Lymphoma

REGISTRATION

BR x 6

BVR x 6

Lenalidomide + Rituximab

BR = Bendamustine, Rituximab V= Bortezomib

Randomized phase II, N ~ 328; 82 eligible per arm

BR x 6

BVR x 6

Lenalidomide + Rituximab

Rituximab

Rituximab

M. Smith, Study PI; accrual completed September 2016

E1411 - Phase 2 Intergroup Trial: Initial Therapy of Mantle Cell Lymphoma

REGISTRATION

BR x 6

BVR x 6

Lenalidomide + Rituximab

BR = Bendamustine, Rituximab V= Bortezomib

Randomized phase II, N ~ 328; 82 eligible per arm

BR x 6

BVR x 6

Lenalidomide + Rituximab

Rituximab

Rituximab

M. Smith, Study PI; accrual completed September 2016

As of Oct. 2019, at 89% for events, anticipated data analysis Spring 2019

Treatment options in relapsed MCL

• Younger, fit patient, including post-ASCT– Consider allo SCT, with curative intent

• Older or less fit patients– Depends on initial therapy and prior response– Clinical trial preferred– Ibrutinib, Acalabrutinib, Lenalidomide/Ritux,

Venetoclax +/- anti-CD20, Bortezomib/Ritux

• Elderly, serious coexisting illness– BTKi or rituximab, palliate symptoms

P. Perez-Galan et al. Blood. 2011

The B-cell receptor pathway is activated in most B-cell malignancies

OverexpressedDown-regulated

Modified from P. Perez-Galan et al. Blood. 2011

The B-cell receptor pathway : Selected Inhibitors

Fostamatinib,Entospletinib

Ibrutinib,Acalabrutinib,Zanabrutinib

Idelalisib,Duvelisib, Copanlisib

Everolimus,Temsirolimus

Venetoclax

Bortezomib,Carfilzomib,Ixazomib

Targeted, non-Chemotherapy Approaches for Relapsed/Refractory MCL

Agent N Response Rate mDOR

Bortezomib 155 33% 9.2 months

Temsirolimus 54 22% 7.1 months

Lenalidomide 134 28% 16.6 months

Lenalidomide-rituximab

52 57% 18.9 months

Idelalisib 40 40% 4 months

Ibrutinib 111 68% 17.5 months

Acalabrutinib 124 81% 72% at 12 m

Venetoclax 28 75% 12 months

Ibrutinib-Venetoclax 24 71% (all CR) 80% at 12 m

PFS and OS by Prior Line of TherapyPooled analysis of 3 studies in Relapsed/Refractory MCL (n=370)

§ Median PFS was nearly 3 years in patients with 1 prior line of therapy

PFS

Median 33.6 mo(19.4-42.1)

Median 8.4 mo (7.1-12.8)

Median PFS overall (95% CI): 13.0 (8.4-16.8) months

Median OS overall (95% CI): 26.7 (22.5-38.4) months

Patients censored from OS analysis upon study discontinuation. CI, confidence interval; NE, not estimable.

OS

Median NR (36.0-NE)

Median 22.5 mo(16.2-26.7)

S. Rule, et al. Brit J Haematol 2017

Acalabrutinib

• Second generation BTK inhibitor– FDA Approved in Mantle cell lymphoma with at least one prior

therapy– Dose: 100 mg twice daily until unacceptable toxicity or

progression• More specific for BTK, fewer off target effects than ibrutinib

– Less TEK kinase inhibition

Herman S, CCR 2017

Acalabrutinib in relapsed or refractory mantle cell lymphoma (ACE-LY-004): a single-arm, phase 2 trial

Wang M, et al. Lancet 2018

Acalabrutinib in R/R MCL

Compared to ibrutinib (n=370, pooled data, 3 trials) more favorable patient population in the acalabrutinib trial (n=124)

Rule S, et al. Brit J Haematol 2017;Wang M, et al. Lancet 2018

Ibrutinib560 mg/day

Acalabrutinib100 mg 2x/day

Med age 67.5 68 (61-75)

Median prior lines of therapy

2 (1-9) 2 (1-2)

sMIPI high 32% 17%

sMIPI int 45% 44%

sMIPI low 24% 39%

Blastoid 12% NR

Prior SCT 34% 18%

Refractory NR 24%

Acalabrutinib vs. Ibrutinib in MCL

• Acalabrutinib appears to have better safety profile– Very infrequent atrial fibrillation and bleeding events– More headache with acalabrutinib

• Acalabrutinib was used in less heavily pre-treated patients– Can’t say that it is more effective in MCL as yet– Head-to-head trial of ibrutinib vs acalabrutinib (ACE-CL-006)

enrolled high-risk, relapsed CLL; results pending• In MCL, both agents have efficacy, choose based on patient

factors• If a patient fails a BTK inhibitor, consider switch to venetoclax • If a BTK inhibitor is stopped for toxicity, use the alternative BTK

agent• Acala plus BR, and other combinations, in current clinical trials

Zanabrutinib in patients with relapsed/refractory mantle cell lymphoma

Y Song, et al, Abstract 015ICML Lugano 2019

• Single-agent phase 2 study, 160 mg bid• Given until intolerance or progression• n=86 enrolled in 13 centers in China• Median f/u 13.9 mo (0.3-18 mo)• Zana d/c in 19 (22%) due to progression and

in 9.3% due to toxicity• ORR 84.7%, CR 76.5%, median PFS 16.7 m• AE: neutropenia, thrombocytopenia,

infections; no Afib, grade 3 bleed in 2.3%

COMBINATION OF IBRUTINIB WITH RITUXIMAB (IR) IS HIGHLY EFFECTIVE IN PREVIOUSLY UNTREATED

ELDERLY (>65 YEARS) PATIENTS (PTS) WITH MANTLE CELL LYMPHOMA (MCL) – PHASE II TRIAL

Jain P, et al. MD Anderson Cancer CenterAbstract 011

ICML 2019, Lugano

Front-line ibrutinib plus rituximab in MCL

Response CR PR Stable disease

ORR

IR combo 69% 26% 5% 95%

MRD neg. 65%

• n= 42 (blastoid and Ki67> 50% excluded)• Median age 71y (range 65-84), ECOG PS 0-1=98%• Ibrut 560mg/d x 28 d, then start Rituximab x 2y

• Treatment continued until intolerance or progression• 23/42 (55%) required dose reduction of ibrutinib• Median duration on study = 19 mo; 4 PD, 2 deaths

Venetoclax

BH3-only family member proteins include BIM, BAD, PUMA, and NOXA

Venetoclax Binds to and Inhibits Overexpressed

BCL-2

Venetoclax

BH3-only

BAK BCL-2 BCL-2

An Increase in BCL-2 Expression Allows the Cancer Cell to Survive

Mitochondria

Pro-apoptotic Proteins

(BAX, BAK)

Anti-apoptotic Proteins(BCL-2)

21Apoptosis is Initiated

Apoptosome

APAF-1

Cytochrome c

Active Caspase

Procaspase

3

BAX

Courtesy of Dr. Sven deVos, UCLA

• FDA-approved for CLL/SLL, with or without del 17p, with at least 1 prior therapy;

• Approved Nov. 2018 for AML pts > 75y in combination with aza, decitabine or AraC

Venetoclax Monotherapy in NHLDavids M, JCO 2017

Venetoclax Monotherapy in NHLDavids M, JCO 2017

Revised Dose Ramp-Up to Mitigate the Risk of Tumor Lysis Syndrome When Initiating Venetoclax in Patients With Mantle Cell Lymphoma

MS Davids, G von Keudell, CA Portell, JB Cohen, et alJ Clin Oncol 2018; 36: 3525-7

Original Article

Ibrutinib plus Venetoclax for the Treatment of Mantle-Cell Lymphoma

Constantine S. Tam, M.B., B.S., M.D., Mary Ann Anderson, M.B., B.S., Ph.D., Christiane Pott, M.D., Ph.D., Rishu Agarwal, M.B., B.S., Sasanka Handunnetti, M.B.,

B.S., Rodney J. Hicks, M.B., B.S., Kate Burbury, M.B., B.S., Gillian Turner, B.N., M.I.P.H., Juliana Di Iulio, Ph.D., Mathias Bressel, M.Sc., David Westerman, M.B., B.S., Stephen Lade, M.B., B.S., Martin Dreyling, M.D., Sarah-Jane Dawson, M.B.,

B.S., Ph.D., Mark A. Dawson, M.B., B.S., Ph.D., John F. Seymour, M.B., B.S., Ph.D., and Andrew W. Roberts, M.B., B.S., Ph.D.

N Engl J MedVolume 378(13):1211-1223

March 29, 2018

Ibrutinib plus venetoclax in MCL: Study Schema

Tam CS et al. N Engl J Med 2018;378:1211-1223

24 patients; 23 relapsed or refractory; most high-risk including MIPI score and TP53 mutations

Kinetics of Response and Clearance of Minimal Residual Disease (MRD)

Tam CS et al. N Engl J Med 2018;378:1211-1223

Tam CS et al. N Engl J Med 2018;378:1211-1223

Progression-free survivalMedian follow-up 16 mo

Duration of Response

Overall survival

Tan et al, NEJM 2018

MCL: Ibrutinib plus venetoclaxn = 24

Complete response by PET/CT scan = 71%

3 non-responders

Toxicity mostly grade 1-2 diarrhea, fatigue

Grade 3-4:33% neutropenia12% diarrhea4% bleeding8% atrial fibrillation8% tumor lysis

Phase I/Ib study of Ven and Ibr

Major inclusion/exclusion • Ibrutinib naïve • Not high risk for TLS• Relapsed to >/=1 prior

chemotherapy regimen

Week 2 Week 1 Week 2 Week 3+

Ibrutinibdosing per allocation

Venetoclax 100mg

200mg200mg Arms

A, B, & D100mg

400mg Arms

C, E, & F

20mg 50mg

Week 1

Cycle 1Cycle 0

Ibrutinib 560 mg/d after 6 mo of combination therapy

Schema: 2 week ramp-up of venetoclax before ibrutinib

Phase I/Ib study of Ven and Ibr

Major inclusion/exclusion • Ibrutinib naïve • Not high risk for TLS• Relapsed to 1 prior

chemotherapy containing regimen

Week 2 Week 1 Week 2 Week 3+

Ibrutinib dosing per allocation

Venetoclax 100mg

200mg200mg Arms

A, B, & D100mg

400mg Arms

C, E, & F

20mg 50mg

Week 1

Cycle 1Cycle 0

Ibrutinib 560 mg/d after 6 months of combination therapy

Schema: 2 week ramp up venetoclax before ibrutinib

Multi-institution phase I/Ib study of ibrutinib with venetoclax in relapsed or refractory MCL. Portell et al, ASH 2019

Ibrutinib Combined With Venetoclax in R/R Mantle Cell Lymphoma (SYMPATICO)

• Initiated May 2017• Sponsor: Pharmacyclics• Phase 3 multinational, randomized, double-

blind study to compare the efficacy and safety of the combination of ibrutinib/venetoclax vs. ibrutinib/placebo in subjects with MCL

• R/R MCL, 1-5 prior treatments

Improving Outcomes in MCL: The Next 3-5 Years

• Increasing molecular and pathogenic insights

• Risk-adapted therapy, e.g. p53 mutated

• Maintenance therapies, à MRD-driven?

• Combine targeted agents, minimize standard chemotherapy and ASCT

• Rational therapeutic sequencing• Limited therapy duration