NEW DRUGS IN LYMPHOMA

Mats Jerkeman

Lund University

Sweden

DISCLOSURE OF INTERESTMats Jerkeman

Research grants: Abbvie, Gilead, Janssen, Celgene

Honoraria: Acerta, Gilead, Janssen, Celgene, Roche

WHAT’S NEW AND INTERESTING?

”External agents”

� Immunoconjugates

� Bispecific antibodies

� Immunosensitizing antibodies

� CARs

”Internal agents”

� BCR inhibitors

� BCL2 inhibitors

� EZH2 inhibitors

� Brentuximab vedotin

� Inotuzumab ozogamicin

� Polatuzumab vedotin

IMMUNOCONJUGATES IN LYMPHOMA

CALICHEAMICIN - ALEXANDER THE GREAT

Micromonospora echinospora

Lime stone – Mavroneri River, Greece

Styx

INOTUZUMAB OZOGAMICIN

• Anti CD22

• Toxin: calicheamicin

• Randomized phase III in 338 R/R DLBCL not ASCT eligible

• Randomized R+InO or Investigator’s choice (BR or Gem-R)

• Overall survival was not significantly different for R‐InO versus IC (P = 0·708)

• Specific toxicity – hepatic veno-occlusive disease

(Dang et al, Br J Haem 2017)

Approved for ALL

POLATUZUMAB VEDOTIN

• Anti CD79b

• Toxin: MMAE

• Randomized phase 2 in R/R FL and DLBCL (Sehn, ASCO 2018)

• 80 FL and 80 DLBCL pts were randomized to pola 1.8 mg/kg + BR or BR for 6 cycles

• The most common grade 3–5 AEs higher in pola+BR v BR were cytopenias, febrile neutropenia, and infections.

•

PET-CR and PFS were similar between FL arms.

In DLBCL:

� pola+BR showed significantly higher PET-CR rates (p = 0.012)

� longer median (m) PFS (p < 0.0001) and mOS (p = 0.0008).

Ongoing phase 3 – R-CHOP+ /- pola (POLARIX)

MONOMETHYL AURISTATIN E (MMAE)

Anti-mitotic agent

Derived from dolastatins

Dolabella auricularia – Eared Sea Hare

BISPECIFIC ANTIBODIES

Bring lymphoma cells + T-cells together

• Blinatumumab CD19/CD3

• Long term infusion (8 weeks)• IgG like – short infusion

• CD20/CD3

• Regeneron – REGN1979

• Genentech - Mosunetuzumab

• Genmab

BLINATUMOMAB – PHASE 2 R/R DLBCL

21 patients, ORR 43%, CR 19%.

The most common adverse events with

stepwise dosing were tremor (48%),

pyrexia (44%), fatigue (26%), and edema

(26%).

Grade 3 neurologic events 22%

Viardot , Blood 2016

Approved for ALL

REGN1979 – PHASE 1 (ASH 2018 - ABSTRACT 1690)

• 54 pts

• ORR 56% (Mixed B-cell

lymphomas)

• Cytokine release syndrome

(CRS) (48%), Grade 3 6%

• Neurotoxicity grade 1-2 (31%)

Bannerji, Abstract 1690

MOSUNETUZUMAB – PHASE 1 – ASH 2018 (ABSTRACT 399)

98 pts –DLBCL, FL, MCL

CRS grade 1-2 in 31%

1 grade 3 neurotoxicity

ORR 33% in DLBCL, 50% in FL

CR 27% - durable

CD20-TCB – ASH 2018 –ABSTRACT 226

Roche - 2:1 format - 2 x CD20 , 1x CD3

Phase 1 - 64 pts –mixed B-cell lymphomas

CRS grade 1-2 – 22%

No neurotoxicity

At dose >300microg

ORR 38%, CR 24%

Hutchings – Abstract 226

IMPROVE ANTIBODY EFFICACY

ANTIBODIES ENHANCING MACROPHAGE MEDIATED ADCC

Anti-CD47 – blocking ’Don’t eat me’ signal Anti-CD32b –blocking the inhibitory Fc receptor

Advani R, NEJM 2018

5F9 + rituximab – in rituximab refractory diseaseDLBCL: ORR and CRR - 40% and 33%

FL: ORR and CRR - 71% and 43%

Mild toxicity

Other anti-CD47: AO-176, SRF-231

B-CELL RECEPTOR INHIBITION - TARGETS

SYK PKCβ

BTK PI3K

RAC

CARD11

BCR inhibitors - Mantle cell lymphoma

Agent(s) Population Phase Number of

patients

ORR Median PFS

(months)

Ibrutinib R/R MCL 3 139 72% 15

Tirabrutinib R/R MCL 1 12 92% N/A

Zanobrutinib R/R MCL 1 32 88% N/A

Acalabrutinib R/R MCL 2 124 75% N/A

Idelalisib R/R MCL 1 40 40% 3.7

Copanlisib R/R MCL 2 11 64% 3.7

Fostamatinib R/R MCL 1-2 9 11% N/A

DLBCL

Agent(s) Population Phase Number of

patients

ORR

Ibrutinib R/R ABC-DLBCL 2 29 40

Ibrutinib R/R GCB-DLBCL 2 20 5

Tirabrutinib R/R Non-GCB DLBCL 1 13 75

Zanobrutinib R/R DLBCL 1 4 25

Fostamatinib R/R DLBCL 1-2 23 22

Enzastaurin R/R DLBCL 2 55 5

BCR inhibitors - Follicular lymphoma

Agent(s) Population Phase Number

of patients

ORR Median

PFS(mo

nths)

Idelalisib R/R FL 2 72 54% 11

Copanlisib R/R FL 2 104 59% 11

Duvelisib R/R FL 2 83 41% N/A

Ibrutinib R/R FL 2 40 30% N/A

Entospletinib R/R FL 1 41 20% 5.7

Mb Waldenström

Agent(s) Population Phase Number of

patients

ORR Median

PFS

Ibrutinib R/R WM 2 63 90% N/A

Zanobrutinib R/R WM 1 33 94% N/A

Idelalisib R/R WM 2 10 80% 22

Agent(s) Population Phase Number of

patients

ORR Median

PFS

Ibrutinib R/R MZL 2 63 51% 18

Idelalisib R/R MZL 2 15 47% N/A

Duvelisib R/R MZL 2 18 33% N/A

Marginal zone lymphoma

BCL2 inhibitors

� BCL2 – inhibits apoptosis

� Over expressed in FL, DLBCL, MCL, CLL

� Romidepsin (HDACi) – down regulates BCL2, BCL-XL and MCL1

� Oblimersen – BCL2-antisense, long term infusion

� Navitoclax (ABT-263) – inhibits BCL2 + BCL-XL

� Dose limiting toxicity – thrombocytopenia

� Venetoclax (ABT-199) – pure BCL2 inhibitor

� Neutropenia

� Tumor lysis syndrome

� 13% if rapid ramp up (2-3 weeks), 3% (subclinical) with 5 weeks ramp up – 20, 50, 100, 200, 400 mg/day

Venetoclax in lymphoma – phase 1 (n=109)

Davids M, JCO 2017

VENETOCLAX

• Possible dose response relationship

• MCL?

• FL?

MCL

FLDLBCL

Resistance to venetoclax

� MCL1 –up regulation

� CyklinE/CDK2 stabilizes MCL1

� CDK-inhibitors – dinaciclib

� MCL1-specific BH3 mimetics

� Rituximab down regulates MCL1

� Phosphorylation of BCL2

Epigenetic therapy - EZH2 inhibition

� EZH2 - Histone methyltransferase

� cause repression of transcription

� Opposed by MLL

� promotes an open chromatin state

� Loss-of-function mutations in MLL are seen in

89% of FL and 32% of DLBCL

� Gain-of –function mutations in EZH2 are found in

27% of FL, and 22% of GC-DLBCL

Arrests B-lymphocytes in a state of immaturity and perpetual proliferation

Tazemetostat - EZH2 inhibitor

� Most common AE: asthenia (21 [33%]), anaemia (nine [14%]), anorexia (four [6%]), muscle spasms (nine [14%]),

nausea (13 [20%]), and vomiting (six [9%]), usually grade 1-2.

Preliminary data phase 2 (ASH 2018 + Lugano 2017)

The ORR (CR + PR) was:

� 17% in pts with DLBCL with EZH2 mutations (N = 36) – median DoR 44w +

� 17% in pts with DLBCL with wt EZH2 (N = 121) –median doR 28 w

� 63% in FL pts with EZH2 mutations (N = 8)

� 28% in FL pts with wt EZH2 (N = 46)

Ribrag Abstract 4196, ASH 2018

PROPHECIES

• DLBCL

• Polatuzumab combinations with R-chemo?

• MCL

• BTK inhibitors in 1st line therapy

• Venetoclax

• FL

• Immunosensitizing agents + rituximab?

• Bispecifics?

• EZH2i-combos (in case of EZH2-mutation)?