6 frederick

FREDERICK HAGEMEISTER, MDHouston, USA

• Professor of Medicine, Dept of Lymphoma/

Myeloma at the University of Texas MD Anderson

Cancer Center

• Dr Hagemeister is a leading authority in the field of

Lymphoma. He has performed pioneering work in

Hodgkin’s lymphoma and has published oevr 200

peer-reviewed papers in leading medical journals. Dr

Hagemeister is also a great supporter of fellows in

training and junior faculty. He serves as a mentor to

large number of rottating students and faculty.

Anti-PD-1 and Anti-CD30 Antibodies for Hodgkin Lymphoma:

An ASH Update

F B Hagemeister, MD

Department of Lymphoma/Myeloma

M. D. Anderson Cancer Center

Beijing, China, February 1, 2015

Anti-PD-1 and Anti-CD30 Antibodies for HL: An ASH Update

• Phase I Nivolumab for Relapsed/Refractory HL

The Immune System’s Role in Fighting Malignancy

2 major components play

important roles in control

of malignancy

1. Innate response

Consists of proteins

and cells (NKs) the

first line of defense

2. Adaptive response

Capable of responding

to new antigens (T- and

B- Cells)

Antibody

Made

Migration

of T-Cells

Periphery

Antigen

Release

NK Killing

APC

Activation

T –Cell

Activation

PD-1 is Inactivated by PD-L1 and PD-L2 on Tumor Cells

• PD-1 is a protein on T-Cells that dampens the

normal immune response

•Tumor cells can evade normal T-cell attack

• Inactivate T-cell function by activation of PD-1 via

PD-L1 and PD-L2

• T-Cells are “exhausted”

• Cannot attack tumor cells

• Inactivation is reversible

PD-L1 is Upregulated in Tumor cells

• Chromosome 9p24.1 amplification upregulates

PD-L1 in tumor cells, as can EBV infection

• Multiple tumor types utilize the PD-L1 and PD-L2

interaction with PD-1 to escape immune

surveillance

– Breast, NSCLC, Kidney, Colon, Melanoma,

Hematologic Malignancies overexpress PD Ligands

– Two anti-PD-1 antibodies, Nivolumab and

Pembrolizumab, have been recently approved for

therapy of Metastatic Melanoma

– Ongoing studies in many other tumors

Phase I Nivolumab in Rel/Ref HL: Preliminary Safety, Efficacy and Biomarker Results

• 23 Hodgkin lymphoma patients from larger study in

hematologic malignancies

– Dosing: 1-3 mg/kg with no MTD reached in Phase I

– Expansion cohort 3 mg/kg chosen, week 1, 4 and q 2

wk for maximum 2 years

• Drug-related adverse events (> 10%, all reversible)

Armand et al. ASH 2014 # 289

Event Any Gr, # (%) Gr 3, # (%)

Any 18 (78) 5 (22)

Rash 5 (22) 0

Platelets 4 (17) 0

Fatigue, fever, diarrhea,

nausea, pruritis

3 each (13) 0


• Population: Med 35 years old (20-54)

• RS cells from 10 pts studied by FISH for PD-L

– All had 3-15 copies of PD-L1 or PD-L2

– Patterns characterized by amplification, relative copy gain, or polysomy of 9P24.1


Feature Number %

ECOG 1 17 74

Path NS 22 96

# Prior TXs 2-3 8 35

4-5 7 30

> 5 8 35

Prior TXs BV 18 78

SCT 18 78



Response Pts,

N =24

(%)

SCT Fail,

BV Fail

N=15, %

SCT Naïve,

BV Fail

N=3, %

BV

Naïve

N=5,%

Overall 20 (87) 87 100 80

Best Resp CR 4 (17) 7 0 60

PR 16 (70) 80 100 20

SD 3 (13) 13 0 20

6 MO PFS % 86 85 n/c 80

1st evaluation at 8 weeks of therapy

Median follow-up – 40 weeks



• Phase Ib Pembrolizumab for Relapsed/Refractory

HL After Brentuximab Failure

Phase Ib Pembrolizumab (MK-3475) for HL after Brentuximab Failure: KEYNOTE-013

• 31 with Rel/Ref HL: Path NS or MC

– All relapsed from or failed BV therapy

– 3 or more prior therapies in 28 (97%)

– Prior ASCT = 20 (69%)

• Pembrolizumab given 10mg/kg every 2 weeks

– Evaluation based on response at 12 weeks (6 doses)

• Tolerability: 16 (55%) of pts experienced one or more treatment-related AEs, but no Gr 4-5 events.

• Results at med follow-up at 38 weeks

– 29 Cases evaluable

– ORR 66%, CR 21%, PR 45%, SD 21%

Moskowitz, ASH 2014 # 290



Response

Rate

SCT ineligible

or refused* N=9

SCT failed

N=29

Total N=9

Overall 44 75 66

CR 22 20 21

PR 22 55 45

SD 33 15 21

“Clinical

Benefit”

78 90 86

PD 22 10 14

*1 refused SCT





• Phase I Nivolumab for Relapsed/Refractory

Lymphoid Malignancies

Phase I Nivolumab (BMS-936558) for Relapsed/Refractory Lymphoid Malignancies

Lesokhin et al. ASH 2014 # 291

Features

N=83

FL

N=10

DLBCL

N-11

Other

B N=8

MF

N=13

PTCL

N=5

Other

T N=3

MM

N=27

Prior SCT

(%)

20 18 0 0 40 0 54

Prior TX 2

(%)

10 18 15 0 40 0 30

3 30 27 38 15 20 0 15

4 10 27 0 31 20 33 22

> 4 20 18 38 46 20 33 30

1 had CML, 2 had PMBCL, 2 had non-

cut T-cell NHL, (data not shown)

Phase I Nivolumab (BMS-936558) for Relapsed/Refractory Lymphoid Malignancies

Lesokhin et al. ASH 2014 # 291

Resp

All B

29

FL

10

DLCL

11

All T

23

MF

13

PTCL

5

MM

27

PMBL

2

%OR 28 40 36 17 15 40 0 0

%CR 7 10 9 0 0 0 0 0

%PR 21 30 27 17 15 40 0 0

%SD 48 60 27 43 69 0 67 100

Ongoing studies in DLBCL

and FL

Phase II Trial of Pidilizumab (CT-011) Plus

Rituximab for Relapsed FL: Schema

CT-011 – IV at 3.0 mg/kg/cycle q 4 wks, max 12

Rituximab – IV at 375 mg/m2 weekly for 4 doses

Days 17 24 31 38

CT-011 1 2 3 4

n = 30

RituximabIf ≥SD, continue 8 more

infusions every 4 weeks

Weeks 0 4 8 12 16

Slides Courtesy of Jason Westin

Pidilizumab Plus Rituximab for 30 Relapsed FL: Pt Features

Feature Type % of Pts

FLIPI 1 Low 41

Int 24

High 35

FLIPI 2 Low 24

Int 48

High 28

Prior Therapies Median # (Range) 1 (1-4)

Prior Rituximab 100

Prior Chemotherapy 69

# Prior R Doses 6

Pidilizumab Plus Rituximab for

Relapsed FL: Best Response

No. of Patients (%)

Enrolled 30

Evaluable 29

Overall response 19 (66)

Complete response 15 (52)

Partial response 4 (14)

Tumor Regression 25 (86)

• Median time to response was 88 days

• ORR did not correlate with FLIPI1 or FLIPI2 score, amount of prior

rituximab, prior chemotherapy, or duration of prior response (p>0.05)

PFS

0 5 10 15 200

20

40

60

80

100

Months

n = 29, 9 PD events 2 treated patients withdrew are censored at last restage date

Median PFS = 635 days

Median follow up = 14 months

Med PFS All = 21.1 mo

Med PFS Responders = NR

PFS correlated with both FLIPI (l/i vs h, NR vs 12.6mo) and

FLIPI2 (l/i vs h, NR vs 13.5mo, p = 0.0344). OS = 100%.

Pidilizumab Plus Rituximab for Relapsed FL:

PFS Results







• Brentuximab Vedotin Plus ABVD or AVD for

Untreated Advanced HL

SGN-35 Mechanism of Action: Brentuximab Vedotin

• SGN-35 antibody-drug conjugate

– CD30-targeted antibody (cAC10) conjugated to an auristatin (MMAE), an anti-tubulin agent

• Selectively induces apoptosis in HL and ALCL cells:

– Binds to CD30

– Becomes internalized

– Releases MMAE

-

-

ADC traffics to

lysosome

Enzymatic

linker cleavage

releases MMAE

from ADC

MMAE binds

tubulin

G2/M cell

cycle arrest

& apoptosis

-

SGN-35

Binds

CD30

Endocytosis

ADC traffics to lysosome

Enzymatic cleavage

releases MMAE from ADC

Binds tubulin

G2/M cell Cycle

arrest and

apoptosis

SGN-35 Antibody-

toxin conjugate

Phase 2 Brentuximab Vedotin for Rel/Ref HL Post Auto SCT

Feature %

ECOG 1 59

Primary Ref to initial TX 71

Refractory to last TX 42

Best Resp to last TX CR 12

PR 34

SD 23

PD 25

2 Prior ASCTs 11

• 102 pt, med age 31 (15-77), med prior TXs 3.5 (1-13),

time from ASCT to Relapse 6.7 mo (0-131)

Younes et al. NEJM 363: 1812- 1821, 2010.

Parameter Result

OR 75%

CR 34%

PR 41%

Med Dur

Resp CRs

6.7 mo

(3.6-14.8)

Med Dur

Resp PRs

5.6 mo

(5-9)

Med OS 22.4 mo

Phase II Brentuximab for HL Relapsed after AutoSCT: Long-Term Survivors

Gopal et al. Blood 122: 2013 (abst).

• 102 patients entered, dosed at 1.8 mg/kg q 3 wk for

up to 16 cycles

• Results: ORR=75%, CR=34%, 3 yr OS rate=54%

• Med OS Rates: CR = NR, PR = 31.6 mo, SD = 20.6 mo,

PD = 10.2 mo

Younes et al. JCO 30: 2183-2189, 2012.

PFS Results OS Results

CRss

• 5 Sequential Cohorts

• Dose-limiting toxicities were defined as any cycle 1 toxicity

requiring > 7 delay in ABVD or AVD

Brentuximab Vedotin (“A”) Plus ABVD or AVD for Newly Diagnosed Advanced HL

Connors et al. ASH 2014 # 292

ABVD + A, N=25

Cohort 1 (0.6 mg/kg) N=6

Cohort 2 (0.9 mg/kg) N=13 ABD + A, N=26

Cohort 3 (1.2 mg/kg) N= 6 Cohort 4 (1.2 mg/kg) N=6

Expansion (1.2 ng/kg) N=26

BV Plus ABVD or AVD for Untreated Advanced HL: Patients

Younes et al. Lancet Oncology 14: 1348-1356, 2013.

Feature ABVD + A N=25 (%) AVD + A N=26 (%)

ECOG 1 48 58

Stage IIA Bulky 0 12

IIB 16 15

IIIA 20 12

IIIB 16 19

IV 48 42

Bulky Disease 80 54

IPS 0-3 72 77

4-7 28 23

• Updated Results

Brentuximab Vedotin Plus ABVD or AVD forNewly Diagnosed Advanced Stage HL

Parameter ABVD + A (N=24) AVD + A (N=256

Med F/U (mo) 41 (9-51) 31 (9-35)

CR (%) 95 96

PET 2 Neg 100 92

3 yr FFS (%) 83 96

3 yr OS 92 100

Any Pulm Event (%) 44 0

Toxicity 36 0

Interstitial Lung 4 0

Pneumonitis 4 0

Gr 1-3 PN 72 73

Connors et al. ASH 2014 # 292 Phase III Randomized Trial Underway









• Phase I/II Brentuximab Plus Bendamustine for

Relapsed Refractory HL

Phase I/II Brentuximab Plus Bendamustine for Relapsed/Refractory HL

• For a total of 54 patients, 48 are evaluable

• Features:

• Comparisons of Therapy

• 20 pts went to SCT with good collections,1 relapsed

Disease Status Dur Prior Resp Patients (%)

Primary Refractory Not applicable 27 (50)

Relapsed < 1 Yr 10 (19)

Relapsed > 1 Yr 17 (31)

Studies ORR (%) CR (%) MED PFS

BV Alone 75 34 12 mo for CRs

BV + Benda 96 83 NR for ORRs

LaCasce et al. ASH 2014 # 293









• Phase I/II Brentuximab Plus Bendamustine for

Relapsed Refractory HL

• Phase Brentuximab Plus Dacarbazine for

Untreated HL in Patients > 60

Phase I Brentuximab Plus Dacarbazine for Untreated HL in Patients > 60

• Pts > 60 have higher risks of toxicity with standard chemotherapy

• Study (Part 1): BV (1.8 mg/kg) alone for older pts.

– If well tolerated, dacarbazine added to BV

• With BV alone, 19/27 (70%) entered CR, 6 (22%) PR.

– Median PFS was only 10.5 mo

– Neuropathy: Sensory in 7, Motor in 2

• Part 2: BV+Dacarbazine (375 mg/m2 day 1)

– 15/18 (93%) respond, with 83% still on treatment

– Median PFS NR

– Neuropathy: Sensory Neuropathy 33%, Nausea in 33%

Forero-Torres et al. ASH 2014 # 294 Planned: BV and Bendamustine!!

PD-1 and Anti-CD30 Antibodies for Hodgkin Lymphoma:

An ASH Update

F B Hagemeister, MD

Department of Lymphoma/Myeloma

M. D. Anderson Cancer Center

Beijing, China, Feb 1, 2015

6 frederick

Documents

pd ligandstwo antipd

tumor cells pd

activation of pd

copies of pd

pdl2 tcells

pdl2 patterns

pdl2 interaction

phase brentuximab