NIVOLUMAB IN

HODGKIN LYMPHOMA

Dra. Shirley Quintana Truyenque

Médico Oncólogo

GLOBOCAN 2012: Hodgkin Lymphoma Incidence

and Mortality

ASR, age standardized ratio; EU, European Union; HL, Hodgkin lymphoma; US, United States. 1. King RL et al. Adv Anat Pathol. 2014;21:12-25. 2. GLOBOCAN 2012: http://globocan.iarc.fr/Pages/fact_sheets_population.aspx. Accessed October 12, 2016. 3. Townsend W et al. Lancet. 2012;380:836-847. 4. National Cancer Institute. http://seer.cancer.gov/statfacts/html/hodg.html. Accessed October 12, 2015. 5. Bosetti C et al. Ann Oncol. 2009;20:767-774.

• HL accounts for 12%–30% of all malignant lymphomas1

• Incidence has remained mostly unchanged during

the past 2 decades3

• HL incidence was stable in the US from 2002 to 20124

• HL mortality was stable in the US from 2002 to 20124

• HL mortality marginally declined in the EU from 1992 to 20025

0.0

0.5

1.0

1.5

2.0

2.5

3.0

Global EU US France Germany Japan

Estim

ate

d A

SR

s p

er

100,0

00

Incidence

HL Statistics2

Global EU US France Germany Japan

New cases (estimated, 2012) 65,950 12,431 8,601 1,757 2,017 1,061

Incidence* (estimated, 2012) 0.9 2.2 2.5 2.6 2.2 0.5

Deaths

(estimated, 2012) 25,469 2694 1,295 305 296 148

Mortality rate* (estimated, 2012) 0.3 0.3 0.3 0.3 0.2 0.1

* Estimated ASRs per 100,000. Both sexes, all ages.

Mortality rate

Hodgkin Lymphoma

BCL6, B-cell lymphoma 6 protein; CD, cluster of differentiation; cHL, classical Hodgkin lymphoma; HL, Hodgkin lymphoma; NLPHL, nodular lymphocyte-predominant Hodgkin lymphoma; PAX-5, paired box 5. 1. Eichenauer DA et al. Ann Oncol. 2011;22(suppl 6):vi55-vi58. 2. NCCN Guidelines®. HL. V3. 2016. 3. King RL et al. Adv Anat Pathol. 2014;21:12-25. 4. American Cancer Society. http://www.cancer.org/cancer/hodgkindisease/detailedguide/hodgkin-disease-what-is-hodgkin-disease. Accessed October 12, 2016. 5. Küppers R. Nat Rev Cancer. 2009;9:15-27. 6. Eberle FC et al. Cancer. 2009;15:129-137.

• HL is traditionally mai divided into 2 n categories1-3:

• HL tumors tend to contain a mixture of inflammatory cells5

• Patient prognosis differs among the cHL subtypes, with lymphocyte-depleted and

mixed cellularity subtypes having worse prognoses6

• CD20+, CD30-, CD45+, CD79a+,

BCL6+, PAX-5+; CD3-, CD15-

NLPHL is characterized by

lymphocyte-predominant cells

(popcorn cells), which are variants of Reed-

Sternberg cells4

• Nodular sclerosing: 60%–80%

• Mixed cellularity: 15%–30%

• Lymphocyte-rich: ~5%

• Lymphocyte-depleted: <1%

• CD20- (majority), CD30+, CD15+, PAX-5+

(weak); CD3-, CD45-, CD79a-

cHL is characterized by

Reed-Sternberg cells2

~95% cHL2-4 ~5% NLPHL1,2

Inflammatory Microenvironment in Hodgkin

Lymphoma

APRIL, A proliferation-inducing ligand; BCMA, B-cell maturation antigen; CCL, CC chemokine ligand; CD, cluster of differentiation; HL, Hodgkin lymphoma; IL, interleukin; NGF, nerve growth factor; PD1, programmed cell death 1; PDL1, programmed death ligand 1; RS, Reed-Sternberg; TH, T helper cell; Treg, regulatory T cells; TARC, Thymus and Activation-Regulated Chemokine; TGF, transforming growth factor; TNF, tumor necrosis factor; TRKA, tyrosine kinase receptor type 1. 1. Küppers R. J Clin Invest. 2012;122:3439-3447. 2. Küppers R. Nat Rev Cancer. 2009;9:15-27.

• HL is characterized by an infiltration of many different cells of the immune system1,2

− RS cells represent 0.1%–2% of infiltrating cells1

− The surrounding inflammatory environment consists of T cells, B cells, and various other immune cells1,2

Adapted from Küppers et al. 2009.2

RS cell

Mast cell

CD4+ TH cell

Eosinophil

Granulocyte

CD4+ TReg cell

CD8+ TC cell

Fibroblast

Attraction through secretion

of eotaxin and CCL5

Attraction through

secretion of IL-5,

CCL5 and CCL28

Stimulation by secretion

of TNFα, and TGFβ

Inhibition through PDL1

and secretion of IL-10,

TGFβ, galectin 1

Attraction through

secretion of TARC, CCL5,

CCL20 and CCL22

Inhibition through

secretion of IL-10

Expansion

stimulated by

galectin 1 TRKA stimulation

through NGF secretion

Attraction through secretion

of TARC, CCL5, and CCL22

CD

30

CD

30

L

Attraction through

secretion of

CCL5

Stage Distribution and Survival in Hodgkin

Lymphoma

HL, Hodgkin lymphoma. 1. National Cancer Institute. Hodgkin lymphoma. http://seer.cancer.gov/statfacts/html/hodg.html. Accessed October 11, 2016.

• These stages are generalized and do not directly correlate with stages defined by Lugano classification

• Localized: Confined to primary site

• Regional: Spread to regional lymph nodes

• Distant: Cancer has metastasized

• Unknown: Unstaged

• Median age at death is 65 years

• 5-year relative survival is 86%

HL stage distribution at diagnosis 5-year relative survival

16%

40%

39%

4%

Localized

Regional

Distant

Unknown

91.5 93.1

77.3 81.9

0

20

40

60

80

100

Localized Regional Distant Unknown

IPS and Prognosis in Advanced-Stage Hodgkin

Lymphoma

FFP, freedom from progression; HL, Hodgkin lymphoma; IPS, International Prognostic Score; OS, overall survival. 1. Hasenclever D et al. N Engl J Med. 1998;339:1506-1514. 2. Moccia AA et al. J Clin Oncol. 2012;30:3383-3388.

• Higher IPS was initially associated with reduced FFP and OS in advanced-stage HL patients

treated in the 1980’s1

• Despite significant changes in HL treatment, IPS still predicts FFP and OS in recently-treated

patients2

OS according to IPS factors (N = 740)2 FFP according to IPS factors (N=740)2

1.0

0.8

0.6

0.4

0.2

0 2 4 6 8 10

Time (Years)

Fre

edom

Fro

m P

rogre

ssio

n

(Pro

babili

ty)

0

1

2

3

4

> 4

1.0

0.8

0.6

0.4

0.2

0 2 4 6 8 10

Time (Years)

Overa

ll S

urv

ival

(Pro

babili

ty)

0

1

2

3

4

> 4

6

7

8

9

• LH: LHc,( 95%), NLPHL (5%)

• Alta respuesta a quimioterapia, mayoría están curados con actuales guías de

tratamiento

• SG a 5 años

• EC I – II : 90%

• EC III : 84 %

• EC IV :65%.

• 30% de los pacientes son refractarios/recaen a la primera línea de tratamiento. (Auto

TPH)

• Aproximadamente el 30% de los pacientes con Auto TPH recaen.

• Fuente: American Cancer Society Website

10

Patología

•Sólo 1- 2 % de células malignas ( RS)(1).

•Nodular ( cervical) en la mayoría.

•“background” inflamatorio consistente con

Linfocitos ( rosette – like ) plasmáticas,

neutrófilos e histiocitos. (2)

En un estudio retrospectivo un 98% de los

linfomas de Hodgkin clásicos fueron CD30+

(n>1200)1

RS expresan Ag CD 30 y CD 15

Immunohistochemistry shows

expression of CD30.

Inset: HRS cells3

© 2

011

Pie

r P

ao

lo P

icca

lug

a e

t a

l.

11 References: 1. Younes et al. J clin Oncol 2012 ; 30:2183-2189 . WHO classification of tumours of Haematopoietic and Lymphoid Tissues 2008.

3. Piccaluga P, et al. Adv Hematol 2011;article ID:920898.

12

Brentuximab Vedotin in Classical Hodgkin Lymphoma

1. Younes A et al. J Clin Oncol 2012;30:2183–9

Historical PFS data in patients with cHL post-ASCT suggest that the durability of response to

BV may relate to the depth of tumor response1

Median PFS, months All patients 6

CR 22 PR 5 SD 4 PD 1

0 3 6 9 12 15 18 21 24

10

20

30

40

50

60

70

80

90

100 P

rog

ress

ion

-fre

e s

urv

ival (%

)

35 33 27 26 19 17 15 5 0 CR 41 36 13 9 7 6 3 0 0 PR 22 11 3 1 1 0 0 0 0 SD 3 0 0 0 0 0 0 0 0 PD

Months

CR

PR

SD

PD

No. at risk (events)

Reprinted with permission. © (2012) American Society of Clinical Oncology. All rights reserved. Younes A et al. J Clin Oncol 2012;30(18):2183–9

PD-1 CHECKPOINT

INHIBITORS:

MECHANISM OF

ACTION

MOA of PD-1 Checkpoint Inhibitors

CD, cluster of differentiation; IFN, interferon; MOA, mechanism of action; MHC, major histocompatibility complex; NFκB, nuclear factor kappa B; PD-1, programmed cell death protein 1; PD-L1, programmed cell death ligand 1; PD-L2 programmed cell death ligand 2; PI3K, phosphatidylinositol-4,5-hisphosphate 3-kinase;Shp-2, Src-Homology domain 2 containing protein tyrosine phosphatase 2. 1. Pardoll DM. Nat Rev Cancer. 2012;12(4):252-264. 2. Brahmer JR et al. J Clin Oncol. 2010;28(19):3167-31751. 3. Menzies AM, Long GV. Ther Adv Med Oncol. 2013;5(5):278-285. 4. Brahmer JR et al. Oral presentation at ASCO 2013. 8030. 5. OPDIVO (nivolumab). US Prescribing Information. 2015.

15

Priming and activation of T-cells through MHC/antigen and CD28/B7 interactions with antigen-presenting cells1

Recognition of tumor by T-cell through MHC/antigen interaction mediates IFNγ release and PD-L1/2

upregulation on tumor1

Adapted from Pardoll 2012.1

• Nivolumab is a fully human, IgG4 PD-1 receptor-blocking monoclonal antibody2-4

• Nivolumab binds to the PD-1 receptor and blocks its interaction with PD-L1 and PD-L2, releasing PD-1

pathway-mediated inhibition of the immune response, including the anti-tumor immune response5

MHC

PD-L1

PD-1 PD-1

PD-1 PD-1

Nivolumab blocks the PD-1 receptor

T-cell receptor

T-cell receptor

PD-L1 PD-L2

PD-L2

MHC

CD28 B7

T-cell

NFκB

Other

PI3K Dendritic

cell Tumor

cell

IFNγ

IFNγR

Shp-2

Shp-2

RS cells have developed

mechanisms that exploit the

programmed death-1 (PD-1)

pathway and serve to evade

immune detection.

CheckMate 205 Update With Minimum 12-Month Follow-Up:

A Phase 2 Study of Nivolumab in Patients With

Relapsed/Refractory Classical Hodgkin Lymphoma

John Timmerman,1 Andreas Engert,2 Anas Younes,3 Armando Santoro,4 Philippe Armand,5

Michelle Fanale,6 Graham P. Collins,7 Voravit Ratanatharathorn,8 John Kuruvilla,9

Jonathon B. Cohen,10 Kerry J. Savage,11 Marek Trneny,12 Jan Paul de Boer,13 Margaret Shipp,14 Scott

Rodig,15 Pier Luigi Zinzani,16 Kazunobu Kato,17 Anne Sumbul,17 and Stephen Ansell,18 on behalf of

the CheckMate 205 Investigators

1University of California, Los Angeles, CA, USA; 2University Hospital of Cologne, Cologne, Germany; 3Memorial Sloan Kettering Cancer Center, New

York, NY, USA; 4Humanitas Cancer Center – Humanitas University, Rozzano–Milan, Italy; 5Dana-Farber Cancer Institute, Boston, MA, USA; 6University of Texas MD Anderson Cancer Center, Houston, TX, USA; 7Oxford Cancer and Haematology Centre, Churchill Hospital, Oxford, UK;

8Barbara Ann Karmanos Cancer Institute, Detroit, MI, USA; 9Princess Margaret Cancer Centre and University of Toronto, Toronto, Canada; 10Winship

Cancer Institute—Emory University, Atlanta, GA, USA; 11British Columbia Cancer Agency, Vancouver, Canada; 12Charles University in Prague and

General University in Prague, Prague, Czech Republic; 13LLPC-HOVON Netherlands Cancer Institute, Amsterdam, Netherlands; 14Dana Farber

Cancer Institute, Boston, MA, USA; 15Brigham and Women's Hospital, Boston, MA, USA; 16Institute of Hematology “Seràgnoli”, University of

Bologna, Bologna, Italy; 17Bristol-Myers Squibb, Princeton, NJ, USA; 18Mayo Clinic, Rochester, MN, USA

Presented at the 58th Annual Meeting and Exposition of the American Society of Hematology; San Diego, CA; December 5, 2016

1110

CheckMate 205: Nivolumab in R/R or Newly

Diagnosed cHL

*Inclusion criteria specific to Cohorts A, B, and C of this study. a. Primary disclosure at ASH 2016, with minimum follow-up of 9 months. b. Update at ASH 2016, with minimum follow-up of 12 months. 1. Clinicaltrials.gov. NCT02181738. Accessed December 21, 2016. 2. BMS Internal Data. HL 205 Overview. 3. BMS Internal Data. CA209205 Cohort D Intro. 4. Timmerman J et al. Presentation at ASH 2016. Abstract 1110. 5. Zinzani PL et al. Presentation at ISHL 2016. Abstract T022. 6. Armand P et al. Poster presentation at ASCO 2016. Abstract TPS7573.

17

NCT021817381-3: noncomparative, multicohort, single-arm, open-label, phase 2 study of nivolumab in patients with cHL

Key Inclusion Criteria

• ≥18 years of age

• ECOG ≤1

• Received prior high-dose conditioning chemotherapy followed by autoSCT*

• May be BV-naïve or may have had prior BV treatment*

• Newly diagnosed and previously untreated cHL (Cohort D)

• No prior alloSCT

Cohort Aa,4, n = 63 BV-naïve, failure of autoSCT

Cohort Bb,4, n = 80 Failure of autoSCT and BV

Cohort C5, n = 100 Failure of BV before and/or after autoSCT

Cohort D6 Newly diagnosed advanced-stage cHL

Nivolumab 3 mg/kg IV q2w

Nivolumab 3 mg/kg IV q2w

Nivolumab 3 mg/kg IV q2w

Primary endpoints:

IRRC-assessed ORR; Incidence of grade 3-5 AEs (Cohort D)

Secondary endpoints:

DOR, CRR, CR duration, PRR, PR duration, Investigator-assessed ORR

and DOR; Treatment discontinuation rate (Cohort D), Incidence of grade 3-

5 AEs (Cohort D)

Start Date: July 2014

Estimated Primary Completion Date: January 2017

Sponsor: BMS

Status: Ongoing, but not recruiting participants

Until disease progression, toxicity, or alloSCT

Until disease progression, toxicity, or alloSCT

Nivolumab 240 mg IV q2w

Nivolumab 240 mg + Doxorubicin 25 mg/m2 + Vinblastine 6 mg/m2 + Dacarbazine 375 mg/m2 q2w

12 doses 4 doses

Until disease progression, toxicity, persistent CR for 1 year, or alloSCT

Nivolumab in Classical Hodgkin Lymphoma

1. Younes A et al. Lancet Oncol 2016;17:1283–94

In CheckMate 205 Cohort B,

post-ASCT and BV, with minimum

follow-up of 6 months, nivolumab

showed clinically meaningful

efficacy1:

– IRRC ORR: 66%

– Median PFS: 10 months

– DOR: 8 months

Nivolumab may induce durable

responses, including PRs

Months

1.0

0.8

0.6

0.4

0.2

0.0

Pro

bab

ilit

y o

f P

FS

0 3 6 9 12

77%

80 70 36 10 0

No. of patients at risk

Reproduced from Younes A et al. Lancet Oncol 2016;17:1283–94 (page 1289),

Copyright (2016), with permission from Elsevier

CheckMate 205: Study Design, Cohorts A and B

Primary endpoint • ORR by IRRC

Additional endpoints

• Duration of response

• Duration of CR/PR

• PFS by IRRC

• OS

• Safety

1. Younes A et al. Lancet Oncol 2016;17:1283–94

Nivolumab 3 mg/kg IV Q2W

Treatment until

disease progression or

unacceptable toxicity

Patients could elect to

discontinue nivolumab and

proceed to

allogeneic (allo)‐HSCT

Cohort B

n = 80

Cohort A

n = 63

BV naïve

post-ASCT

BV treated

post-ASCT1

FDA approval

May 2016

ASH 2016:

Primary disclosure

Minimum follow-up 9

months

ASH 2016:

Update

Minimum follow-up

12 months

Phase 2 study conducted in Europe and North America

Baseline Characteristics

Characteristic BV post-ASCT

Cohort B (n = 80)1

Age, median (range), years 37 (18–72)

Male, n (%) 51 (64)

ECOG performance status, n (%)

0

1

42 (53)

38 (48)

Previous lines of therapy, median (range)

Prior BV therapy after ASCT, n (%)

4 (3–15)

80 (100)

Treatment between ASCT and nivolumab, n (%)

Systemic cancer therapy

Radiotherapy only

Neither

80 (100)

0

0

1. Younes A et al. Lancet Oncol 2016;17:1283–94

Drug-Related Adverse Events

Patients with an AE (≥10%) BV post-ASCT

Cohort B (n = 80)

Any grade Grade 3–4

Drug-related AE, n (%) 73 (91) 24 (30)

Fatigue 23 (29) 0

Diarrhea 11 (14) 0

Infusion-related reaction 16 (20) 0

Rash 12 (15) 1 (1)

Nausea 10 (13) 0

Cough 3 (4) 0

Headache 3 (4) 0

Arthralgia 12 (15) 0

Lipase increased 10 (13) 6 (8)

Pyrexia 11 (14) 0

Pruritus 10 (13) 0

Drug-related serious AE, n (%) 5 (6) 1 (1)

No treatment-related deaths reported in either cohort

Best Change in Target Lesions Cohort B: Nivolumab After BV Post-ASCT

Asterisks ( * ) represent responders

95% of evaluable patients showed a reduction in tumor burden

Best

red

ucti

on

fro

m b

aselin

e

in t

arg

et

lesio

n (

%)

* * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * –100

–75

–50

–25

0

25

50

75

100

Patients

* * * * *

Duration of Response by Best Response Cohort B: Nivolumab After BV Post-ASCT

OR

CR

PR

0 3 6 9 12 15

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0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1.0

Pro

bab

ilit

y o

f re

sp

on

se

Months

6 5 5 3 2 0

48 39 31 22 10 0

54 44 36 25 12 0

No. of patients at risk

CR

PR

OR

Database lock Oct 2015 Apr 2016

Median follow-up, mo

(range)

9

(2–12)

15

(2–19)

ORR, n (%) 53 (66) 54 (68)

Median DOR, mo

(95% CI)

8

(7, NR)

13

(9, NR)

Median DOCR, mo

(95% CI)

5

(NR, NR)

NR

(5, NR)

Median DOPR, mo

(95% CI)

8

(7, NR)

13

(8, NR)

Progression-Free Survival by Best Response Cohort B: Nivolumab After BV Post-ASCT

CR

PR

SD

PD

18 0 3 6 9 12 15

0.0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1.0

Pro

bab

ilit

y o

f P

FS

Months

0 6 6 5 4 2 1

0 48 47 37 30 16 3

0 17 16 10 6 4 0

0 7 1 0 0 0 0

No. of patients at risk

CR

PR

SD

PD

Database lock Apr 2016

Median PFS, mo

(95% CI)

15

(11, NR)

Median PFS in CR, mo

(95% CI)

NR

(8, NR)

Median PFS in PR, mo

(95% CI)

15

(11, NR)

Median PFS in SD, mo

(95% CI)

12

(6, NR)

12-month OS, % 95

Median PFS prolonged by

5 months with extended follow-up

0

10

20

30

40

50

60

70

80

90

100

Patients

, %

73% 70% 72% 88%

CR: 17%

PR: 56%

CR: 18%

PR: 52%

CR: 12%

PR: 60%

PR: 50%

CR: 38%

BV Before and After

AutoSCT

(n = 8)

Overall

(N = 100)a

BV Before AutoSCT

(n = 33)

BV After AutoSCT

(n = 57)b

CheckMate 205C – Best Response (IRRC)

a. Includes 2 patients for whom order of BV relative to autoSCT could not be determined: 1 had a CR and 1 had a PR. b. Response could not be determined in 4 patients who had no postbaseline tumor assessments before or on day of subsequent therapy. autoSCT, autologous stem cell transplant; BV, brentuximab vedotin; CR, complete remission; IRRC, independent radiologic review committee; ORR, objective

response rate; PD, progressive disease; PR; partial remission; SD, stable disease. 1. Zinzani PL et al. Presentation at ISHL 2016. Abstract T022. 25

SD 17 (17) 7 (21) 9 (16) 1 (13)

PD 6 (6) 3 (9) 3 (5) 0

ORR:

CheckMate 205C – Time to Response and DOR

autoSCT, autologous stem cell transplant; BV, brentuximab vedotin; CI, confidence interval; CR, complete remission; DOR, duration of response; NE, not evaluable; PR, partial remission. 1. Zinzani PL et al. Presentation at ISHL 2016. Abstract T022.

26

Median time to response,

months (range)

2.1

(0.8-6.5)

Median duration of response,

months (95% CI)

7.0

(6.7-NE)

Patients still on treatment (among

all treated), n/N (%)

70/100

(70)

Median duration of follow-up

(among all treated), months

(range)

8.8

(1.4-13.5)

BV before and

after autoSCT

Time, weeks

BV after

autoSCT

0 64 56 48 40 32 24 16 8

Resp

on

ders

: P

R +

CR

(n

= 7

3)

BV before

autoSCT

Censored with ongoing response

First PR

First CR

Subsequent transplant (n = 9)

Censored

Trials With AlloSCT After Nivolumab for R/R HL

a. Patients in CheckMate-039 received nivolumab 3 mg/kg at week 1, at week 4, and then every 2 weeks.

alloSCT, allogeneic stem cell transplant; autoSCT, autologous stem cell transplant; BV, brentuximab vedotin; cHL, classical Hodgkin lymphoma; HL, Hodgkin lymphoma; IV,

intravenously; R/R, relapsed/refractory.

1. Armand P et al. Presentation at ASH 2016. Abstract 3502.

CheckMate-039

(phase 1)

Nivolumab 3 mg/kg IV every 2 weeksa

Patients could discontinue nivolumab and proceed to

alloSCT, either directly or after systemic therapy

AlloSCT

n = 5

CheckMate 205 (phase 2)

Relapsed cHL after autoSCT

Cohort A

n = 63

Cohort B

n = 80

Cohort C

n = 100

AlloSCT

n = 6

AlloSCT

n = 11

AlloSCT

n = 18

BV-naïve

BV before

and/or after

autoSCT

BV after

autoSCT

n = 23

Relapsed HL with ≥1

previous systemic

cancer therapy

Conclusion

En pacientes no tratados previamente con BV y tratados con BV,

Nivolumab demostró:

• Alta ORR (68%)

• Respuestas duraderas y PFS independientemente de la

profundidad de la respuesta, incluso en pacientes con PR o SD

• Un perfil de seguridad aceptable.

Nivolumab ofrece una opción de tratamiento favorable para los

pacientes con linfoma de Hodgkin que progresa después de ASCT

LOCAL APPROVAL MAY

BE REQUIRED BEFORE

EXTERNAL USE. REFER

TO LOCAL GUIDELINES.

Table of Contents

PD-1 Checkpoint

Inhib i tors : MOA

Pseudo-Progression as

Response to Immuno-

Oncology Therapies

Nivolumab: Ongoing

BMS-Sponsored Clinical

Trials

CTLA-4 Checkpoint

Inhib i tors : MOA

Nivolumab: ISRs

Summary

29

LOCAL APPROVAL MAY

BE REQUIRED BEFORE

EXTERNAL USE. REFER

TO LOCAL GUIDELINES.

Table of Contents

PD-1 Checkpoint

Inhib i tors : MOA

Pseudo-Progression as

Response to Immuno-

Oncology Therapies

Nivolumab: Ongoing

BMS-Sponsored Cl in ical

Tr ia ls

CTLA-4 Checkpoint

Inhib i tors : MOA

Nivolumab: ISRs

Summary

30

Previous version (v3.2016)

31

HODG-E Versión actualizada (v1.2017)

• Nivolumab es una opcion para pts con

LH r/r post TAMO y post BV post-

transplante

CASO CLÍNICO:

LINFOMA DE HODGKIN R/R

Filiación

• Varón de 39 años, químico-farmaceútico.

– Elabora productos con soda caústica e hipoclorito de sodio.

– Contacto TBC (+) (hermano con TBC en dos años de tratamiento)

• Antecedentes: DM2 (2014) en tto. con Metformina.

• No antecedentes oncológicos.

• Antecedente familiar: tía materna con cáncer de mama.

Cuadro Clínico:

• TE: 3 m.

– Síntomas principales: tos productiva en incremento, disnea, sudoración vespertina, hiporexia, baja de peso (15 kilos).

• Examen físico: ECOG 1

– Adenopatías en hemicuello derecho (G II) de hasta 2 cm.

– Pulmones: roncos bilaterales.

FI: Octubre 2014

Estudio anatomopatológico • Biopsia de Ganglio cervical derecho:

Neoplasia linfoide compatible con Linfoma Hodgkin Clásico. • CD30: Positivo

• CD15(-/+)

• CD3: Negativo

• CD20: Negativo

• EMA: Negativo

• EBV: Negativo

• Biopsia de mediastino: Fragmentos de tejido conectivo con proceso inflamatorio crónico con algunos eosinofilos, fibrosis e histiocitos.

• Biopsia de Hueso y Médula ósea: Infiltrada por linfoma Hodgkin

Extensión de enfermedad

Evaluación de riesgo SCORE PRONOSTICO

INTERNACIONAL (IPS) (enfermedad avanzada)

Albúmina: 3.5 (<4)

Hemoglobina: 10.4 (<10.5g/dl) Varón (Varón)

Edad: 39 años (>45)

Estadio clínico: IV (EC IV)

Leucocitos: 5400 mm3 (> 15000 y linfopenia <8%)

Linfocitos: 20% (linfocitos <8%, < 600/mm3)

DIAGNÓSTICO: Linfoma de Hodgkin clásico EC IV B IPS AR

Tratamiento:

• Dic 2014- May 2015: Inicia tratamiento con ABVDX 6 con respuesta parcial.

• Jun 2015 - Nov 2015: ICE X 4 con enfermedad estable al inicio y luego progresión de enfermedad.

PET-SCAN (nov 2015)

• Lesiones hipermetabólica de reciente aparición en pared torácico antero-inferior de lado izquierdo y pubis.

• Aumento de la actividad metabólica en pelvis.

• Aumento de actividad metabólica en grupo cervical IIA derecho.

Tratamiento de 3° línea:

• Dic 2015- May 2016: Brentixumab 1.8 mg/kg c/3 sem con mejoría clínica y estabilización de la enfermedad.

– Crecimiento clínico de adenopatía cervical derecha hasta 3 cm.

– Nódulos subcutáneos en región anterior de tórax (1x1cm)

– Dolor en tórax superior derecho que se irradia a brazo.

– VSG 75 mm/h (aumento)

PET-SCAN

• Incremento del numero y metabolismo de adenopatías supra e infra diafragmática y de lesiones Oseas.

• Lesiones hipermetabólica de reciente aparición pulmonar, hepático, esplénico y pleural bilateral.

Tratamiento de 4° línea: • Jul 2016- Set 2016: GEMOX x 3

– Hospitalización por IRA asociada a progresión de enfermedad y proceso neumónico.

– ECOG 3, MEG, en silla de ruedas, disnea, tos persistente dolor torácico.

– Tomografías: Derrame pleural y pericárdico.

Tratamiento de 5° línea:

• Oct 2016: Nivolumab 240 mg/día c/2 sem. – Después del 1er curso se evidencio mejoría clínica significativa.

(disminución de la tos, disnea y dolor torácico)

– Eventos adversos: no se reportó.

– Disminución leve de las adenopatías cervicales, así como las lesiones subcutáneas

Tratamiento de 5° línea: NIVOLUMAB

Hasta la actualidad ha recibido 24 cursos – Después del primer curso se evidencio mejoría clínica significativa.

– Eventos adversos: disminución de peso, dolor articular esporádico, tendencia al llanto (Sd. Depresivo)

– Clínicamente no se palpan adenopatías y lesiones subcutáneas en resolución.

PET actual Jul 2017

• Remisión de la mayoría de las lesiones hepáticas, pulmonares, óseas y adenopatías a nivel supra e infra diafragmático.

• Persiste imagen hipermetabólica

en la región pre-esternal izquierda (SUV 3.1) y lingular (SUV MAX 5.3).

• Disminución del metabolismo

reportadas en el bazo (SUV 5.6, previo 6.8).

Línea del tiempo

1° línea ABVD 2° Línea

ICE

3° línea Brentuximab

4° línea GEMOX

5° línea Nivolumab

Octubre 2014

R parcial Progresión Hepática,

esplénica y ósea

Octubre 2017

EE, Progresión Nódulos subcutáneos en región anterior de

tórax

Progresión Derrame pleural y

pericárdico

R parcial

RC clínica Asintomático

RP. Metabólica

JULIO 2016

JULIO 2017