Therapeutic Approaches for Mantle Cell Lymphoma and Upfront Treatment of Hodgkin Lymphoma

Mitchell R Smith, MD, PhDProfessor of MedicineAssociate Center Director for Clinical InvestigationsDirector, Division of Hematology and OncologyGW Cancer CenterWashington, DC

Disclosures

Data and Safety Monitoring Board/Committee Eastern Cooperative Oncology Group

Speakers Bureau AstraZeneca Pharmaceuticals LP, EUSA Pharma

MCL: Prognostic Features

MIPI:Age, PS, LDH, WBC+ Ki67 > 30%

Young patients on Nordic 2&3 trials HDAC-R does not overcome p53mut status

Overall Survival

NCCN GUIDELINES: MCL Frontline therapy 2020AGGRESSIVE:

• Nordic regimen (R-Maxi-CHOP alt R-HiDAC → autoSCT)• R-CHOP/R-DHAP • R-DHA+PLATINUM• R-HyperCVAD/R-HDMtx+Ara-C• BR (category 2B)

Consolidation HDC/autoSCT + post-SCT rituximab q8wk x 3 years

LESS AGGRESSIVE:Preferred:• BR• VR-CAP• R-CHOP [+ Rituximab maintenance]• Lenalidomide-Rituximab (R2)Others:• Modified R-HyperCVAD (part A) + rituximab maintenance• ?RB-cytarabine (RBAC) (category 2B)

Rituximab maintenance?

MCL Frontline therapy: AGGRESSIVE• U.S. Intergroup S1106 (completed): BR x 6 vs R-HCVAD-MA x 4, then HDC/autoSCT• EA4151 / BMT-CTN1601: Investigator Choice of Initial Regimen

• Post-induction MRD negative, randomize to SCT or No SCT, + rituximab x 3 years• Post-induction MRD+, SCT and eligible for other SCT/maintenance trials

• European MCL Network TRIANGLE:

• Ibr-R “window” until CR or up to 12 cycles followed by R-HCVAD-MA x 4 (age ≤ 65), no SCT • 80% low risk sMIPI, Ki67 < 50%, median age 56• RR to Ibr-R 88% CR + 12% PR• 3 year estimated PFS 85% (median f/u 22 months, range 2-24 mos)

Wang et al ASH2019 A3987

ObservationR-CHOP/ R-DHAP x 6 ASCT

2 yrs I-maintenance

2 yrs I-maintenance

R R-CHOP/ R-DHAP x 6 + I

R-CHOP/R-DHAP x 6 + I

ASCT Observation

Observation

Arm A + Ibrutinib

Ibr but NO ASCT

MCL Frontline therapy: LESS AGGRESSIVE

R-CHOP x4 → RIT: 10 year f/uSmith MR et al Leukemia 2017N = 56

Overall Survival

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

Prob

abilit

y

Months since registration

PFS: BR only

N = 106Median age 70Rummel ASCO 2016

E1411: BR(±V) + R(±Len)

Mean age 67 years (range 42-90)Smith MR et al ASH 2019

PFS by MRD STATUS, POST-CYCLE 3

N=169

N=21

Median PFS ~ 5 yearsMedian PFS 43 months (3.5 yrs)

0 2 4 6 8 10years

MCL Frontline therapy: LESS AGGRESSIVER2 regimen: 5-year follow-upN = 38

Ibrutinib-Rituximab, age > 65Jain P et al ASH 2019 A3988N = 50

Median f/u 22 months60% CR + 28% PR60% still on study, 38% off study, 4 PD, rest toxicityExcluded blastoid or Ki67> 50%,

but 3 pts have transformed

Ruan J et al Blood 2018

NCCN GUIDELINES: MCL 2nd-Line therapy 2020Shorter response to initial chemoimmunotherapy:Preferred:

BTKiacalabrutinibibrutinibzanubrutinib

Lenalidomide-Rituximab (R2)Venetoclax (off label)

Category 2B: R2+ibrutinib; ibrutinib + venetoclax

Longer response to initial CIT:Preferred:

BR (if not previously given)Bortezomib ± rituximabBTKiLenalidomide-Rituximab (R2)

Other recommended: Venetoclax (off label)

Category 2B: BR + bortezomibPEPCR-CHOP or VRCAP (if not previously given)

MCL: NOT SO NOVEL AGENTS

MODE OF ACTION AGENT

B CELL SIGNALINGBTKiPI3Ki (idelalisib short DoR, dual PI3K α+δ?)mTORCi (temsirolimus) EU approved

ANTIBODIES

BISPECIFIC ANTIBODIESANTIBODY DRUG CONJUGATE

OFATUMUMAB OBINUTUZUMAB (not that exciting)UBLITUXIMAB

BLINATUMOMAB (αCD3/αCD19 bispecific Ab)POLATUZUMAB VEDOTIN

PRO-APOPTOTIC VENETOCLAX (ABT-199)

IMMUNE THERAPY

CHECKPOINT BLOCKADE

LENALIDOMIDE (R2)CAR-T CELL THERAPYNIVOLUMAB/PEMBROLIZUMAB

Relapsed/Refractory MCL

THERAPY STATUS N Median Age PRIOR Rx ORR CR DOR (mos)

BORTEZOMIB APPROVED 155 65 1 (1-3) 33% 8% 9

LENALIDOMIDE+ rituximab

APPROVED(not filed)

13452

6772

4 (2-10) 2 (1-4)

28%57%

8%36%

1719

IBRUTINIB APPROVED 111 68 3 (1-5) 67% 23% 18

ACALABRUTINIB APPROVED 124 68 2 (1-5) 81% 40% 20

ZANUBRUTINIB APPROVED 118 61 2 (1-4) 84% 59% 20

VENETOCLAX Off-label 28 72 3 (1-7) 75% 21% 14

IBR-VEN Phase 2 24 68 2 (1-6) 71% TETE

R2-IBRUTINIB Phase 2 50 69 2 (1-7) 76% 56% 16

CART (modified axi-cel) Phase 2 60 65 93% 67%

Hodgkin Lymphoma (cHL):1st Line Therapeutic Approaches

Mitchell R Smith, MD, PhDProfessor of MedicineAssociate Center Director for Clinical InvestigationsDirector, Division of Hematology and OncologyGW Cancer CenterWashington, DC

Advanced Stage Hodgkin Lymphoma (cHL):NCCN Guidelines v1.2020

ABVD x 2 PET/CT Deauville 1-3 A-VD x 4 Observe vs ISRT to initial bulky sites or PET+ sites(80% of patients)

Deauville 4 ABVD or escBEACOPP x 2 PET/CT if Neg, 2 more cycles sameif +, biopsy, Rx as refractory

Deauville 5 escBEACOPP x 2

RATHL. Johnson PW et al NEJM 2016GHSG HD15. Engert, A et al Lancet 2012ECHELON-1. Connors JM et al NEJM 2018S0816 Press OW, et al. J Clin Oncol. 2016

Useful in certain circumstances:BV-AVD (with growth factor) category 2B

Category 2A in select patients, e.g. no neuropathy, IPS 4-7 or bleomycin contraindicated

S0816 n=331 2-yr PFS

PET2 - 271 (82%) 82%PET2 +escBEACOPP

60 (18%) 64%

33

Advanced Stage Hodgkin Lymphoma (HL)

Moccia AA. J Clin Oncol. 2012;30(27):3383-8

Time (years)0

01234> 4

1.0

0.8

0.6

0.4

0.2

2 4 6 8 10

IPS 4-7Age ≥ 45 yr

Albumin < 4.0 g/dL

WBC ≥ 15 x 109/L

Hemoglobin < 10.5 g/dL

Lymphocytes < 0.6x109/L or < 8%

Male sex

Stage IV

IPS 0-3

RATHL

Johnson P, et al. New Engl J Med. 2016;374(25):2419-29

IPSS: PFS for ABVD patientsABVDx2 -> A-VD x 4

PFS for PET2+ (Deauville 4-5)

PFS for PET2- (Deauville 1-3)

ASH 2019, Abstract 4026. Bartlett N et al

82%

75%

ECHELON-1

ECHELON-1: TOXICITYINITIAL REPORT1 A-AVD ABVD

Any grade ≥ 3 83% 66%

Hospitalizations 37% 28%

grade ≥ 3 ANC 54% 39%

Febrile Neutropenia (+/- G-CSF prophylaxis) 21% 11% 8% 7%

Peripheral sensory neuropathy grade ≥ 3 5%

Does ECHELON-1 change approach to advanced HL?

• Does the PFS benefit/fewer patients requiring “salvage” therapy justify the neurotoxicity/need for G-CSF/added hospitalizations?

• Should we abandon the PET-response adapted approach that gives us 80% of patients who will do well with ABVD x 2 → A-VD x 4?

• Should we consider cost?

• Should we think of overall strategy rather than simply PFS?• When is best time to use brentuximab vedotin? For all patients or just for relapse therapy?

Abutalib & Armitage ASCO Post Jan 2018

Moskowitz et al. Blood 2018; 132:2639-42

• In ECHELON-1 with 4 yr f/u, mPFS is 82% (BV-AVD) vs 75% (ABVD)

• If we treat 100 patients, • 75 will do well with either regimen• 18 will relapse regardless of regimen• 7 avoid 2nd line therapy

• Using data from AETHERA trial:• Of 25 post-ABVD relapses, 15 do well post ASCT + BV (AETHERA), so 10 “fail”,

and overall success rate 90%• Of 18 post-BV-AVD failures, what if BV resistant and their “salvage” rate is 40%,

then 7 do well, and 11 “fail”, and overall success rate is 89%

Strategic Thinking

cHL in Patients ≥ 60 years• A(B)VD x 2: if PET2-, then A-VD x 4

PET2+ “individualized therapy”GHSG reported bleo for 2 cycles tolerable in older patients [I do not give B in this age group]

• BV • single agent ORR 92%, CR 73%, but med PFS 11 months• BV + Dacarbazine (N = 22, age ≥ 60) ORR 100%, CR 62%, med PFS 18 months • BV-bendamustine toxic Friedberg, JW et al Blood 2017; ASCO 2018

• BV-AVD • Age ≥ 60• BV x 2, A-VD x 4, BV x 4 [NOT CONCURRENT]• EFS @ 2 yr 80% (95% CI 65-89%)• OS @ 2 yr 93%

Evens, AM et al JCO 2018

FDA Approval of Brentixumab Vedotin (BV) in Combination with Chemotherapy for Adults with Previously Untreated Systemic Anaplastic Large Cell Lymphoma (sALCL) and CD30-Expressing Peripheral T-Cell LymphomasPress Release – November 16, 2018

https://www.fda.gov/drugs/fda-approves-brentuximab-vedotin-previously-untreated-salcl-and-cd30-expressing-ptcl

The FDA has approved BV in combination with CHP chemotherapy (cyclophosphamide/doxorubicin/prednisone) for previously untreated sALCL or other CD30-expressing peripheral T-cell lymphomas (PTCL), including angioimmunoblastic T-cell lymphoma and PTCL not otherwise specified. This is the first FDA approval for previously untreated PTCL including sALCL.

Approval was based on ECHELON-2 (NCT01777152), a double-blind, multicenter trial that randomized 226 patients to BV plus CHP and 226 patients to cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP).

Horwitz S et al. Lancet 2019;393(10168):229-40

ECHELON-2: Brentuximab Vedotin (BV) with Chemotherapy for CD30-Positive Peripheral T-Cell Lymphoma

HR 0.71p = 0.0110

Median in BV + CHP48.2 months

Median in CHOP20.8 months

Time from randomization (months)

Prog

ress

ion-

free

surv

ival

(%)

Horwitz S et al. Lancet 2019;393(10168):229-40

ECHELON-2: Overall Survival

• Median OS was not reached in either subgroup, though it was numerically in favor of BV + CHP for key patient subgroups analyzed.

Immune Checkpoint Inhibitors in cHL• cHL depends on tumor microenvironment signals and T cell interactions• Often amplify 9p24.1 and express PD-L1• Very active in relapsed cHL:

• Nivolumab ORR 69%, DOR 17 months. Approved for R/R cHL after ASCT and BV• Pembrolizumab ORR 65%. Approved for R/R cHL after 3 lines of therapy• Combinations with ipilimumab, BV and all 3 studied

• 1st Line Combinations:• CheckMate 205 Arm D in advanced stage HL: Nivo x 4 → N-AVD

• N = 51• PET2- 71%, EOT PET- 75%• mPFS at 2 years 80%

• Phase II NIVAHL trial: GHSG [ASH 2019] concurrent vs sequential Nivo-AVD in early unfavorable, all + RT = feasible

• Current Intergroup Trial for advanced stage cHL: Randomized Phase 3 of BV-AVD vs N-AVD