immunoteràpia en el limfoma de hodgkin - academia.cat · immunoteràpia en el limfoma de hodgkin....

SCHH. Barcelona, 22 de juny de 2016

Immunoteràpia en el Limfoma de HodgkinA. Sureda

Servei d’HematologiaInstitut Català d’Oncologia - Hospitalet

The European Group for Blood and Marrow TransplantationThe European Group for Blood and Marrow TransplantationThe European Group for Blood and Marrow Transplantation

Median follow-up of survivors 50 months (75% of cases > 34 months)

OS from relapse after an ASCT. The experience of the LWP EBMT/GITMO

39.5% (95% CI: 35-44) at 3 years

0.00

0.20

0.40

0.60

0.80

1.00

0 12 24 36 48 60 72 84 96

Months from relapse

OS

29.7% (95% CI: 25-34) at 5 years

Martínez et al, Ann Oncol 2013

Chen R, et al. ASH 2015, Poster presentation from Abstract #2736

Progression free survivalOverall median PFS = 9.3 mo (95% CI: 7.1, 12.2)

PFS, progression-free survival; mo, months; ITT intention to treat; PD, progressive disease

Ongoing Phase II Study of Brentuximab VedotinPFS Per Investigator – 5 Year Follow-up

Introduction• Classical Hodgkin lymphoma (cHL) is characterized by

expression of PD-L1 and PD-L2 on malignant Reed–Sternberg cells and on inflammatory cells in the tumor microenvironment

• PD-L1 expression in cHL frequently occurs in the setting of genetic amplification of the 9p24.1 locus

• Prognosis for patients with relapsed cHL is poor

4

PD-L1 expression in cHL

Chen BJ, et al. Clin Cancer Res. 2013;19:3462–3473.Ansell SM, et al. N Engl J Med. 2015;372:311–319.

PD-L1/L2 copy gains and amplification visible by FISHCopy Gain Amplification

Inst itut Català d'OncologiaInstitut Català d’Oncologia


MHC

PD-L1

PD-1 PD-1

PD-1 PD-1

PD1 Receptor Blocking Ab

Recognition of tumour by T cell through MHC/antigen interaction mediates IFNγ release

and PD-L1/2 upregulation on tumour

T-cellreceptorT cell

receptor

PD-L1PD-L2

PD-L2

MHC

CD28 B7

T cell

NFκBOther

PI3KDendritic

cellTumour cell

IFNγIFNγR

Shp-2

Shp-2

PD-1/PD-L1 Blockade

WCLC 2013

• Nivolumab is a fully human immunoglobulin G4 monoclonal antibody targeting the programmed death-1 (PD-1) immune checkpoint pathway

June 2014

Relapsed or Refractory HL

(N = 105)

• No autoimmune disease

• No prior organ or stem cell allografting

• No prior checkpoint blockade

Endpoints

Primary• Safety and tolerability

Secondary• Best overall response

• Investigator assessed

• Objective response• Duration of response• Progression-free

survival (PFS)• Biomarker studies

Dose Expansion (3 mg/kg)

Hodgkin Lymphoma (n=23)

Non-Hodgkin lymphoma (n = 69)

Dose Escalation

Nivolumab 1 mg/kg → 3 mg/kg

Weeks 1 and 4, then every 2 weeks

Non-Hodgkin lymphoma (n = 13)

August 2012 April 2015Median Follow-up

40 weeks 76 weeksAugust 2015

Hodgkin lymphoma (n = 23)

101 weeks

7

Phase 1 Study (CA209-039) Clinical Outcomes From Extended Follow-up

Study design

Baseline Characteristics

Characteristic cHL (n = 23)

Age, median (range) 35 (20–54)

Histology, n

Nodular sclerosing 22

Mixed cellularity 1

Prior autotransplant, n (%) 18 (78)

Prior brentuximab vedotin, n (%) 18 (78)

Number of prior therapies, median (range) 5 (2–15)

8

Select Treatment-Related Adverse Events

9

Adverse Event cHL (n = 23)Any Grade,

n (%)Resolved, %

Gastrointestinal 4 (17)Diarrhea 3 (13) 100Colitis 1 (4) 100

Hepatic 2 (9)ALT increased 1 (4) 100AST increased 1 (4) 100Blood alkaline phosphatase increased 1 (4) 0

Pulmonary 1 (4)Pneumonitis 1 (4) 100

Skin 5 (22)Rash 4 (17) 100Pruritus 3 (13) 100Pruritic rash 1 (4) 100Skin hypopigmentation 1 (4) 0

Endocrine disordersHyperthyroidism 4 (17) 75

Hypersensitivity/infusion reaction 2 (9)Bronchospasm 1 (4) 100Infusion-related reaction 1 (4) 100

• All AEs were Grade 1/2 except colitis and pneumonitis which were Grade 3• There were no Grade 4 or Grade 5 AEs and no treatment-related deaths

Select Treatment-Related Adverse Events

10

Adverse Event cHL (n = 23)Any Grade,

n (%)Resolved, %

Gastrointestinal 4 (17)Diarrhea 3 (13) 100Colitis 1 (4) 100

Hepatic 2 (9)ALT increased 1 (4) 100AST increased 1 (4) 100Blood alkaline phosphatase increased 1 (4) 0

Pulmonary 1 (4)Pneumonitis 1 (4) 100

Skin 5 (22)Rash 4 (17) 100Pruritus 3 (13) 100Pruritic rash 1 (4) 100Skin hypopigmentation 1 (4) 0

Endocrine disordersHyperthyroidism 4 (17) 75

Hypersensitivity/infusion reaction 2 (9)Bronchospasm 1 (4) 100Infusion-related reaction 1 (4) 100

• All AEs were Grade 1/2 except colitis and pneumonitis which were Grade 3• There were no Grade 4 or Grade 5 AEs and no treatment-related deaths

Response Rates

Best Objective Response cHL(n = 23)

n (%) 95% CI

Objective response rate 20 (87) 66.4–97.2

CR 5 (22) 7.5–43.7

PR 15 (65) 42.7–83.6

SD 3 (13)

11

Patients (n = 23)

Perc

ent C

hang

e in

Tum

or B

urde

n

CR (22%)PR (65%)SD (13%)25

0

–25

–50

–75

–100

On treatment, ongoing responseOff treatment without disease progressiona

Progressive disease, following response or stable disease

Best Response

aMaximum clinical benefit, transplant, or toxicity 12

Durability of Response

–100

–50

0

50

100

Time Since First Treatment Date, Weeks

Perc

ent C

hang

e Fr

om B

asel

ine

in T

arge

t Les

ions

/Tum

or B

urde

n

0 6 12 18 24 30 36 42 48 54 60 66 72 78 84 90 96 102 108 114

On treatment, ongoing response

Off treatment without progression

Progressive disease, following response or stable disease

First occurrence of new lesion13

Duration of Response

14

Median DOR (95% CI): NA (15.5–NA)

Time, Months

Prob

abili

ty o

f Pat

ient

s in

Resp

onse

0.0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1.0

0 3 6 9 12 15 21 2418

18 15 12 10 9 7 2 04

No. Patients at Risk

• Median follow-up: 101 wks• Median DOR not reached

Responding Patients

15

0 8 16 24 32 40 48 56 64 72 80 88 96 104 112

17

15

201918

16

14131211

9

7654321

10

8

Patie

nts

PFS Responders Time, Weeks

• On treatment, ongoing responses

First CRFirst PRDeathOngoing response

Responding Patients

16

0 8 16 24 32 40 48 56 64 72 80 88 96 104 112

17

15

201918

16

14131211

9

7654321

10

8

Patie

nts



• 13 patients off treatment without disease progression

• 6 with maximum clinical benefit

• 5 proceeded to transplant

• 2 discontinued for toxicity


Responding Patients

17

0 8 16 24 32 40 48 56 64 72 80 88 96 104 112

17

15

201918

16

14131211

9

7654321

10

8

Patie

nts



• 13 patients off treatment without disease progression

• 6 with maximum clinical benefit

• 5 proceeded to transplant

• 2 discontinued for toxicity

• Disease progression following initial response


Progression-Free Survival

18

Median PFS (95% CI): NA (18.6–NA)

Time, Months

Prop

ortio

n of

Pat

ient

s With

out P

rogr

essi

on

0.0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1.0

0 3 6 9 12 15 21 2718No. Patients at Risk

24

23 20 13 12 11 8 1 0511

• Median follow-up: 101 wks• Median PFS not reached

Overall Survival

19

Time Since First Dose, Months

Prop

ortio

n of

Pat

ient

s Aliv

e

0.0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1.0

0 3 6 9 12 15 21 3018 24

No. Patients at Risk

23 23 23 22 21 18 2 0721 17

27

OS (N=23)

1 Year

OS rate, % (95% CI) 91 (69.5–97.8)

1.5 Years

OS rate, % (95% CI) 83 (60.1–93.1)

CheckMate 205: Overall Study Design

Cohort BCohort A Cohort C Cohort D

Brentuximab-vedotin naïve

Stop treatment if persistent CR for 1 year, if relapse, reinitiate nivo

Now enrolling

The same inclusion

criteria as cohort B.

Additionally, brentuximab vedotin prior to ASCT was

allowed.

Post-transplant

brentuximab vedotin

Registrational trial for

regulatory approval

Relapsed/refractory cHL after ASCTNewly diagnosed advanced-stage cHL

Engert A et al. EHA 2016

• Registrational phase 2 study conducted in Europe and North America

CheckMate 205: Study Design, Cohort B

Primary endpoint•ORR assessed by IRRCa

Secondary and other endpoints•IRRC-assessed DOR for complete and partial remission

•Investigator-assessed ORR and DOR

•IRRC-assessed PFS•OS•Safety•QoL•Biomarkers

aPer the 2007 International Working Group (IWG) criteria. IRRC = independent radiologic review committee

Minimum follow-up: 6 months

Single-armNivolumab 3 mg/kg

(every 2 weeks)Treatment until

disease progression or unacceptable toxicity

Prior ASCT

Brentuximab vedotin

Relapsed/refractory cHL

Inclusion criteria

• Patients could elect to discontinue nivolumab and proceed to allogeneic hematopoietic stem cell transplantation



Data shown as n (%) unless indicated otherwiseaExcluding high-dose preparative regimen prior to ASCT

Characteristic Patients(N = 80)

Age, median (range)<65 years

37 (18–72)77 (96)

SexMale 51 (64)

ECOG performance status01

42 (53)38 (48)

Previous lines of therapy,a median (range) ≥5 lines of therapy

4 (3–15)39 (49)

Previous radiation therapy 59 (74)Previous ASCT

12

80 (100)74 (93)6 (8)

Prior brentuximab vedotin therapy after ASCT 80 (100)No response to prior brentuximab vedotin 43 (54)

CheckMate 205B


Response Rates

IRRC (N = 80)

Investigator (N = 80)

Objective response rate, n (%)95% CI

53 (66)55–76

58 (73)61–82

Best overall response, n (%)Complete remissionPartial remissionStable diseaseProgressive diseaseUnable to determine

7 (9)46 (58)18 (23)6 (8)3 (4)

22 (28)36 (45)18 (23)3 (4)1 (1)

CheckMate 205B

Patients with no prior response to most recent brentuximab vedotintreatment

IRRC (N = 43)

Investigator (N = 43)

Objective response rate, n (%) 31 (72) 35 (81)


Time to and Durability of Response by IRRC

Weeks0 8 16 24 32 40 48 56

Resp

onde

rs: P

R +

CR (n

= 53

)

Censored with ongoing responseFirst partial responseFirst complete response

Median time to response,months (range)

2.1(1.6–5.7)

Median duration of response,months (95% CI)

7.8(6.6–NE)

Patients with ongoing response, n/N (%)

33/53(62%)

Transplant


Progression-Free and Overall Survival1.0

0.8

0.6

0.4

0.2

0

Prob

abili

ty o

f eve

nt

0 3 6 9 12

Median follow-up (range) 8.9 months (1.9–11.7)Median PFS (95% CI) 10.0 months (8.41–NA)PFS rate at 6 months (95% CI) 76.9% (65%–85%)Median OS Not reachedOS rate at 6 months (95% CI) 98.7% (91%–100%)

76.9%

PFS (24/80 events)

CheckMate 205

PFS per IRRC assessment

Months

98.7%OS (3/80 events)


Adverse Events

• Serious AEs (SAEs) included pyrexia, tumor progression, arrhythmia, infusion reaction, septic meningitis, and pneumonia (≤4% each)

• *One patient experienced a grade 5 SAE of multi-organ failure due to Epstein Barr virus–positive T-cell lymphoma

Total patients with an event (%) Any grade Grade 3–4

Any AE 79 (99) 32 (40)Treatment-related AE 72 (90) 20 (25)Treatment-related AE leading to discontinuation:

Autoimmune hepatitisIncreased ALT and ASTMulti-organ failure*

3 (4)

111

2 (3)

110

Treatment-related serious AE 5 (6) 0Treatment-related death 0 0

CheckMate 205B


Pruritus

Diarrhea

Nausea

Arthralgia

Pyrexia

Rash

Infusion-related reaction

Fatigue

Treatment-Related AEs in ≥10% of Patientsa

Patients (n)80400

Any grade

aWithin 30 days of last dose

CheckMate 205B

Grade 3–4

6020Engert A et al. EHA 2016

0 20 40 60 80

Skin

Gastrointestinal

Hypersensitivity/infusion reaction

Endocrine

Hepatic

Pulmonary

Renal

Select AEs (immune-related, any cause)

• Drug-related pneumonitis reported in 2 patients (grade 2 and grade 3) between first dose and 35 days after last dose

• Majority of events were manageable, with resolution occurring when immune-modulating medications were administered

Patients (n)

Any gradeResolved Grade 3–4

CheckMate 205B



OPDIVO ®(Nivolumab)

OPDIVO (nivolumab) is indicated for the treatment of patients with cHL that has relapsed or progressed afterASCT and post-transplantation BV. This indication isapproved under accelerated approval based on overallresponse rate. Continued approval for this indication maybe contingent upon verification and description of clinicalbenefit in confirmatory trials.


The PD-1 and PD-L1/L2 Pathway to Be Continued• PD-1 is an immune checkpoint

receptor1

• Binding of PD-1 by its ligands PD-L1 or PD-L2 leads to downregulation of T-cell function1

• This mechanism is usurped by many tumors1

• PD-1 blockade through mAb therapy can restore effective anti-tumor immunity2,3

• Pembrolizumab is a humanized anti-PD1 mAb with activity in multiple malignancies4,5

30

1. Keir ME et al. Annu Rev Immunol. 2008; 2. Pardoll DM. Nat Rev Cancer. 2012; 3. Topalian et al. N Engl J Med. 2012. 4. Garon et al. N Engl J Med. 2015; 5. Robert et al. Lancet. 2014.

KEYNOTE-087: Study Design

31

Cohort 1 (N = 60)R/R cHL who

progressed after ASCT and subsequent BV

therapy

Progressive Disease

Pembrolizumab 200 mg Q3W

Cohort 2 (N = 60)R/R cHL who failed

salvage chemotherapy, ineligible for ASCT and

failed BV therapy

Cohort 3 (N = 60)R/R cHL who failed

ASCT and not treated with BV post transplant

Survival Follow-Up

• Primary end point: ORR (central review)• Secondary end points: ORR (investigator review), PFS, OS

• Prespecified interim analysis, based on investigator-assessed response, performed after 30 patients in all 3 cohorts reached first response assessment

CT scans repeated Q12W PET repeated at W12, W24, to confirm CR or PD, and as clinically indicated

Chen R et al. EHA 2016


32

Characteristic(N = 30 in each cohort)

Cohort 1 Progressed after

ASCT and subsequent BV

therapy%

Cohort 2Failed salvage chemotherapy,

ineligible for ASCT and failed BV therapy

%

Cohort 3 Failed ASCT and not treated with BV post

transplant%

Age, median (range) 36 (19-64) 33 (20-71) 30 (18-67)

Age >65 0 20 3Lines of systemic therapy, median (range)

5 (3-12) 4 (1-10) 3 (2-10)

Primary refractory 23 50 50

Prior radiation therapy 47 27 43

Bulky lymphadenopathy† 7 10 3

Baseline B symptoms 23 20 23

Bone marrow involvement 0 10 3

Prior brentuximab failure 100 100 40‡

†Bulky disease was defined as a mass larger than a third of transthoracic diameter at any level of thoracic vertebrae, or single site of disease in any area that is 10 centimeters or greater in diameter.‡Patients received BV therapy prior to transplant. Data cutoff: April 8, 2016


Best Overall Response, Investigator Review

33

†One patient in Cohort 2 had no assessment. The patient had symptomatic deterioration, with subsequent clinical progression.‡For complete remission, a residual mass was permitted for patients who were negative on PET scanning. Data cutoff: April 8, 2016

Cohort 1 Progressed after

ASCT and subsequent BV

therapyn (%)

Cohort 2†

Failed salvage chemotherapy,

ineligible for ASCT and failed BV therapy

n (%)

Cohort 3 Failed ASCT and not treated with BV post

transplantn (%)

% (95% CI) % (95% CI) % (95% CI)

Overall response rate 73 (54-88) 83 (65-94) 73 (54-88)

Complete remission‡ 27 (12-46) 30 (15-49) 30 (15-49)

Partial remission 47 (28-66) 53 (34-72) 43 (26-63)

Stable disease 17 (6-35) 7 (1-22) 13 (4-31)

Progressive disease 10 (2-27) 7 (1-22) 13 (4-31)


Primary Refractory Disease†

N = 37

% (95% CI)

Overall response rate 78 (62-90)

Complete remission‡ 35 (20-53)

Partial remission 43 (27-61)

Stable disease 11 (3-25)

Progressive disease 8 (2-22)

Best Overall Response, Investigator Review

34

†Defined as failure to achieve complete or partial remission to frontline therapy‡For complete remission, a residual mass was permitted for patients who were negative on PET scanning.Data cutoff: April 8, 2016 Chen R et al. EHA 2016

0 5 10 15 20 25 30 35 40Weeks

®®

®®®®®®®®®

®®®®

®®®

®®®®

®®

®

35Data cutoff: April 8, 2016

Treatment Exposure: Cohort 1Progressed after ASCT and subsequent BV therapy

• Median number of treatment cycles: 9 (range, 4-13)

• 19 patients who responded were still on pembrolizumab treatment

*

Treatment OngoingComplete ResponsePartial ResponseProgressive DiseaseLast Dose



Treatment Exposure: Cohort 2Failed salvage chemotherapy, ineligible for ASCT and failed BV therapy



*


0 5 10 15 20 25 30 35 40Weeks

®

®®®®®®

®®

®®

®®

®®®®

®



Treatment Exposure: Cohort 3Failed ASCT and not treated with BV



*


0 5 10 15 20 25 30 35 40 45Weeks

®®®®®

®

®®®

®®®®®®®®

®®®®

®®®

®®

®


Treatment-Related Adverse Events

38

≥5% of patientsTotal Population

N = 90%

Any gradePyrexia 13

Diarrhea 10

Neutropenia 8

Fatigue 8

Cough 8

Hypothyroidism 7

Dry skin 6

Nausea 6

AEs of Clinical InterestTotal Population

N = 90%

Rash, all grade 1† 4

Pneumonitis, all grade 2 2

Colitis, grade 3 1

• Four patients (4%) experienced grade 3/4 AEs• No treatment related deaths were observed• Two discontinuations due to treatment-related AEs (pneumonitis and

infusion reaction)

†Includes erythematous rash. Data cutoff: April 8, 2016 Chen R et al. EHA 2016


• The advent of check point inhibitors (nivolumab, pembrolizumab) will be changing the therapeutic landscape of patients with relapsed / refractory HL

• High response rates / durable remissions• Manageable toxicity profile• The impact on SCT indications / toxicities remains to be seen• All data in relapsed / refractory patients support a quick

clinical development to earlier phases of the disease

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