sergio jobim de azevedo : potenciais conflitos de interesse · sergio jobim de azevedo : potenciais...

Sergio Jobim de Azevedo : Potenciais Conflitos de Interesse• Professor, Departamento de Medicina Interna,

Faculdade de Medicina,UFRGS,Chefe, Serviço Oncologia HCPAUniversity of Miami, Dept. of Medicine, Voluntary Faculty. WJH LATP

• Consultor ( “Advisory Board Member” )Bristol-Myers Squibb, AMGEN, NovartisSchering Plough International, MSDPfizer International, Roche, Janssen

• Palestrante ( “Speaker” ): Sanofi Aventis, AstraZeneca, Janssen, MSDBristol-Myers Squibb, Roche, AMGEN, Novartis

• Patrocínio para Congresso Internacional ( “travel Grants” )Roche, Ely Lilly, AstraZeneca, Novartis, Janssen, BMS

• Coordenador UPCO Projetos de Pesquisa Clínica patrocinada ( CEP & CONEP )• Nenhuma participação acionária ou salarial

Melanoma Metastático BRAFm :

Porque a Imunoterapia deve ser o tratamento sistêmico inicial

1. A imunoterapia funciona inclusive em pacientes com mutação BRAF ; o sistema Imune Adaptativo tem memória

2. Racional Clínico : efeitos e resultados, duradouros, com possibilidade de respostas rápidas

3. Possibilidade de interromper ou “terminar” o tratamento

4. Efetividade SNC e DHL elevado

Melanoma Metastático +BRAFm :


• 1 A imunoterapia funciona em pacientes com mutação BRAF e o sistema Imune efetivo tem memória

2. Racional Clínico : efeitos e resultados, duradouros, com possibilidade de respostas rápidas inclusive em mBRAF

• 2 Possibilidade de “terminar” o tratamento ( +/- re exposição )

• 4 Efetividade SNC e DHL elevado

• 5 Segurança, tolerância e toxicidades previsíveis e manejáveis

clinicaloptions.com/oncology

Immune Checkpoint Inhibitorsclinicaloptions.com/oncology

Immune Checkpoint Inhibitors

Pts at Risk, n

Ipilimumab 1861 839 370 254 192 170 120 26 15 5 0

Pro

po

rtio

n A

live

0

0.2

0.4

0.6

0.8

1.0

Mos

0 12 24 36 48 60 72 84 96 108 120

Median OS: 11.4 mos (95% CI: 10.7-12.1)

Ipilimumab

Censored

Hodi S, et al. 2013 European Cancer Congress. Abstract LBA 24. Schadendorf D, et al. J Clin Oncol. 2015;[Epub ahead of print].

Ipilimumab: Pooled Survival Analysis From

Phase II/III Trials in Advanced Melanoma

3-yr OS rate: 22% (95% CI: 20-24)

KEYNOTE-006 (NCT01866319) Study Design

• Primary end points: PFS and OS

• Secondary end points: ORR, duration of

response, safety

Patients

• Unresectable, stage III or IV melanoma

• ≤1 previous therapy, excluding

anti–CTLA-4, PD-1, or PD-L1 agents

• Known BRAF mutation statusa

• ECOG PS 0-1

• No active brain metastases

• No serious autoimmune disease

Pembrolizumab

10 mg/kg intravenous Q2W

for 2 years

Pembrolizumab


for 2 years

R

1:1:1

Stratification Factors

• ECOG PS (0 vs 1)

• Line of therapy (first vs second)

• PD-L1 statusb (positive vs negative)

Ipilimumab


× 4 doses

aPrior anti-BRAF targeted therapy was not required for patients with normal LDH levels and no

clinically significant tumor-related symptoms or evidence of rapidly progressing disease. bDefined as

≥1% staining in tumor and adjacent immune cells as assessed by IHC (22C3 antibody).

Kaplan-Meier Estimates of Survival in Total Population

(Median Follow-Up, 33.9 mo)

ArmEvents,

nHR

(95% CI)Median, mo

(95% CI)

Pembrolizumab 278 0.70 (0.58-0.86) 32.3 (24.5-NR)

Ipilimumab 155 — 15.9 (13.3-22.0)

OS PFS per irRC by Investigator

Analysis includes all randomized patients with measurable disease at baseline who received ≥1 pembrolizumab dose.

Data cutoff date: Nov 3, 2016.

ArmEvents,

nHR

(95% CI)Median, mo

(95% CI)

Pembrolizumab 369 0.56 (0.47-0.67) 8.3 (6.5-11.2)

Ipilimumab 204 — 3.3 (2.9-4.1)

100

90

80

70

60

50

40

20

0

30

10

0 4 8 12 16 20 24 28 32 36 40

Time, months

556

278

347

110

269

64

231

40

211

32

182

27

155

23

138

20

88

14

12

2

0

0

Pro

gre

ssio

n-F

ree S

urv

ival,

%

No. at risk

Pembrolizumab

31%

14%

No. at risk

Pembrolizumab

100

90

80

70

60

50

40

20

0

30

10

0 4 8 12 16 20 24 28 32 36 40

Time, months

556

278

500

212

436

169

387

145

351

122

317

111

297

103

273

94

229

77

24

10

0

0

Overa

ll S

urv

ival,

%

50%

39%

55%

42%34%

15%

Ipilimumab Ipilimumab

Analysis cut-off date: September 3, 2014.Pembrolizumab Q2W vs ipilimumab Pembrolizumab Q3W vs ipilimumab

0.1 1 10

Hazard Ratio

Overall

Male

Female

Age <65 y

Age 65 y

White race

US

Rest of world

ECOG PS 0

ECOG PS 1

557555323336234219

319318238237545543114111

443444

384377

173178

0.1 1 10

Hazard Ratio

First-line therapy

Second-line therapy

PD-L1 positive

PD-L1 negative

BRAF wild type

BRAF mutant,prior anti-BRAF

BRAF mutant,no prior anti-BRAF

No priorimmunotherapy

364366

193188

450446

96101

347348

9596

110108

537536

Favors Pembro Favors PembroFavors IPI Favors IPI

Phase III KEYNOTE-006: PFS in Pre specified Subgroups

Clinical Activity in Patients Who Received the Concurrent Regimen of Nivolumab and

Ipilimumab.

Wolchok JD et al.

N Engl J Med 2013;369:122-133.

... Combinações de inibidores de “checkpoints”

CheckMate 067 Phase 3 Trial to Evaluate the NIVO+IPI Regimen: Study Design1,2

– Randomized, double-blind, phase 3 studyto compare the NIVO+IPI regimen or NIVO alone to IPI alone

– Co-primary endpoints were PFS and OS

Unresectable orMetatastic Melanoma

• Previously untreated

• 945 patients

Treat until progressionb

orunacceptable

toxicity

NIVO 3 mg/kg Q2W +IPI-matched placebo

NIVO 1 mg/kg + IPI 3 mg/kg Q3W for 4 doses then

NIVO 3 mg/kg Q2W

IPI 3 mg/kg Q3W for 4 doses +

NIVO-matched placebo

Randomize1:1:1

Stratify by:

• PD-L1 expressiona

• BRAF status

• AJCC M stage

aVerified PD-L1 assay with 5% expression level was used for the stratification of patients; validated PD-L1 assay was used for efficacy analyses. bPatients could have been treated beyond progression under protocol-defined circumstances.PFS, progression-free survival.

n=314

n=316

n=315

1. Larkin J, et al. N Engl J Med. 2015;373:23-34. 2. Wolchok JD, et al. Presented at ASCO 2015 abstract LBA1.

Co-primary endpoints were PFS and OS

Melanoma Metastático +BRAFm :Porque a Imunoterapia deve ser o tratamento sistêmico inicial


• 2 Racional Clínico : efeitos e resultados, duradouros, com possibilidade de respostas rápidas

3. Possibilidade de interromper ou “terminar” o tratamento “sem prejuízo” , independente do motivo!

• 4 Efetividade SNC e DHL elevado• 5 Segurança, tolerância e toxicidades previsíveis e manejáveis

Horvat et l. J Clin Oncol. 2015

296 patients IPI

off protocol

85% irAE

35% steroids

10% Anti TNF

Fig 1. Patient disposition. (*) 92 patients (87.6%) remained in CR as of the data cutoff date.

Durable Complete Responses after Discontinuation of Pembro in Patients

with MM JCO 36: 1668-1674, June 2018KeyNote 001 – Pembrolizumab, open label phase 1b multiple cohorts, median follow up 43 mo; 24 mo DFS 90,9%

Fig 2. Time to response and durability of response from the start of therapy in complete responders who

discontinued pembrolizumab and proceeded to observation (n = 67).

Durable Complete Responses after Discontinuation of Pembro in Patients with MMJCO 36: 1668-1674, June 2018 KeyNote 001 ( open label phase 1b multiple cohorts, median follow up 43 mo )

Fig 3. Disease-free survival (A) from time of experiencing complete response (CR) in all patients who achieved CR (n = 105) and (B) from time of

discontinuation of pembrolizumab in patients who discontinued after CR for reasons other than progression (n = 89).

DFS at 24 mo: 90,9% DFS at 24 mo: 85,9%

Interrupção IT

por Toxicidade

IPI 3mg + NIVO 1mg :

Análise Combinada

CM 069 ( fase 2 , 95 pac )

CM 067 ( fase 3 , 314 pac)

Dirk Schadendorf;

Jedd D. Wolchok;

Stephen Hodi; et al

JCO 35:3807-14 , 2017

Fig 2. Time to and duration of response in patients who discontinued treatment because of

adverse events during the induction phase of treatment.

IPI 3mg + NIVO 1mg :

Análise Combinada

CM 069 e CM 067

Fig 3. (A) Progression-free survival and (B) overall survival for patients who discontinued treatment because of adverse events

(AEs) during the induction phase and for patients who did not discontinue because of AEs. Differences between the two subgroups

were not statistically significant for either progression-free survival or overall survival.

Disposition of Patients Who Completed Protocol-Specified Time on Pembrolizumaba (median follow-up, 9.7 mo)

aIncludes patients completing ≥21.6 months of treatment.bFrom end of pembrolizumab treatment.

cBoth deaths were a result of PD. Data cutoff date: Nov 3, 2016.

104 (19%) completed pembrolizumab

24 (23%) CR 68 (65%) PR 12 (12%) SD

• 23 ongoing responses

• 1 PDb

• 1 received second course

of pembrolizumab

• 64 ongoing responses

• 4 PDb

• 3 received second course

of pembrolizumab

• 10 ongoing SD

• 2 deathsb,c

556 patients received

pembrolizumab

Treatment Exposure and Response Duration in Patients Who

Completed Protocol-Specified Time on Pembrolizumab (n = 104)

Length of each bar represents time to the last scan. Dotted line represents time of protocol-specified pembrolizumab discontinuation.


Time, months0 4 8 12 16 20 24 28 32 36 40

PR

PD

CR

Patient with CR or PR

Patient with SD

Patient with ongoing CR or PR

Death

100

90

80

70

60

50

40

30

20

10

00 2 4 6 8 10 12 14

104 96 95 86 67 30 6 0

Time, months

Pro

gre

ss

ion

-Fre

e S

urv

ival,

%

No. at risk

PFS (irRC, investigator) From Last Pembrolizumab Dose to PD or

Death in Patients Who Completed Protocol-Specified Time on

Pembrolizumab (n = 104)


• 102 (98%) patients were alive after a

median of 9.7 months after completing

pembrolizumab treatment

Patients who completed protocol-specified time on pembrolizumab, n

Estimated PFS, % (95% CI)

Median PFS

104 91 (80-96) NR

100

90

80

70

60

50

40

30

20

10

0

0 2 4 6 8 10 12 14

61 61

No. at risk

PR 68

SD 12

CR 24

55 40 17 4 0

12 11 9 9 4 1 0

23 23 22 18 9 1 0

Pro

gre

ss

ion

-Fre

e S

urv

ival,

%

Time, months


Best Response n

Estimated PFS, %(95% CI)

MedianPFS

CR 24 95 (69-99) NR

PR 68 91 (74-97) NR

SD 12 83 (48-96) NR

PFS (irRC, investigator) From Last Pembrolizumab Dose to PD or

Death in Patients Who Completed Protocol-Specified Time on

Pembrolizumab (n = 104) (cont)

Melanoma Metastático +BRAFm :



• 2 Racional Clínico : efeitos e resultados, duradouros, com possibilidade de respostas rápidas

• 3 Possibilidade de “terminar” o tratamento ( +/- re exposição )

4. Efetividade em melanoma no SNC e DHL elevado

• 5 Segurança, tolerância e toxicidades previsíveis e manejáveis

Efficacy and Safety of Nivolumab Plus Ipilimumab in Patients with Melanoma Metastatic to the Brain: Results of the Phase II Study CheckMate 204

• Exclusion criteria included neurological symptoms; steroids > 10 days; WBRT; prior treatment with checkpoint inhibitors; leptomeningeal disease

• Original planned enrollment of 110 asymptomatic patients

NIVO1 mg/kg

Q3W × 4

+

IPI3 mg/kgQ3W × 4

NIVO

3 mg/kg

Q2W

Treat until progression

or unacceptabl

e toxicity (maximum of 24 months)a

Induction Maintenance•≥ 1 measurable,

unirradiated MBM

(0.5-3.0 cm)

•Prior SRT in ≤3

MBM

•Previous treatment

with BRAFi/MEKi

permitted

Key

eligibilities

Response to Treatment – All Patients (N = 75)

28

Global Intracranial Extracranial

Best overall response, n (%)

Complete response 4 (5) 16 (21) 5 (7)

Partial response 36 (48) 25 (33) 32 (43)

Stable disease 4 (5) 4 (5) 2 (3)

Progressive diseasea 18 (24) 18 (24) 16 (21)

Not evaluableb 13 (17) 12 (16) 20 (27)

Objective response rate, % (95% CI) 53 (41−65) 55 (43−66) 49 (38−61)

Clinical benefit ratec, % (95% CI) 59 (47−70) 60 (48−71) 52 (40−64)aConfirmed and unconfirmed progressive disease

bIncludes unconfirmed responses

cClinical benefit rate = complete response + partial response + stable disease ≥ 6 months

PFS

Events/patients Median (95% CI)

Intracranial 24/75 NR (7.5‒NR)

Extracranial 15/75 NR (NR‒NR)

Global 25/75 NR (6.5‒NR)

Months

PF

S (

%)

100

90

80

70

60

50

40

30

10

0

20

Number of patients at risk

0 181512963 21

67%

Intracranial 151014305075 0

Intracranial

151014315275Extracranial 0

Extracranial

151014294975Global 0

Global

10

A Randomized Phase 2 Study of Nivolumab or Nivolumab plus Ipilimumab in Patients with

Melanoma Brain Metastases. A Random. Ph 2 Study :

The Anti-PD1 Brain Collaboration (ABC)

Presented by Georgina V. Long

CPreviously treated or symptomatic or

leptomeningeal, with MRI progression

n=15

Nivolumab 3mg/kg Q2W

ANo prior local brain Rx & asymptomatic

n=30

Nivolumab 1mg/kg + Ipilimumab 3mg/kg

Q3W X4→ Nivolumab 3mg/kg Q2WR 1:1

Primary Endpoint: Intracranial Response Rate ≥ week 12

Secondary Endpoints: Extracranial Response Rate

Overall Response Rate

PFS (Intracranial, Extracranial, Overall)

OS

BNo prior local brain Rx & asymptomatic

n=30

Nivolumab 3mg/kg Q2W

• Melanoma Brain Metastases

≥ 5mm & < 40mm

• No previous

Anti-CTLA-4

Anti-PD-1 or -PD-L1 agents

• Previous BRAFi+MEKi allowed

• ECOG PS 0-2

• No serious autoimmune disease

• No corticosteroids (Cohort C < 10mg prednisone allowed)

Best Intracranial RECIST Response

A: Ipi+NivoN=26

B: NivoN=25

C: Nivo☨

N=16

Intracranial Response, n (%) 11 (42%) 5 (20%) 1 (6%)

CR 4 (15%) 3 (12%) 0

PR 7 (27%) 2 (8%) 1 (6%)

SD 2 (8%) 1 (4%) 4 (25%)

PD 12 (46%) 18 (72%) 11 (69%)

NE* 1 (4%) 1 (4%) 0

NE = Not Evaluable

*Pts who deceased prior to wk 12 = PD☨Leptomeningeal, previous local treatment or symptoms

• Median duration of intracranial response not reached in any arm


Intracranial Progression-Free Survival:

Intracranial Best Response All Patients (Cohorts A+B+C)

Complete ResponsePartial Response

Progressive Disease

Stable Disease


Checkmate 067 - Combination: Influence of LDH

Larkin et al. SMR 2016

NIVO + IPI (n = 269)

NIVO(n = 316)

IPI(n = 230)

Median PFS, months (95% CI)

NR (11.7, NR)

11.3(7.7, 20.2)

4.1(3.1, 5.1)

HR (95% CI)NIVO+IPI over NIVO or IPI

–0.7

(0.6, 0.9)0.4

(0.3, 0.5)

NIVO+IPI (n = 138)

NIVO(n = 191)

IPI(n = 126)

Median PFS, months (95% CI)

5.2(2.9, 9.6)

2.7(2.6, 3.2)

2.6(2.6, 2.8)

HR (95% CI) NIVO+IPI over NIVO or IPI

–0.8

(0.6, 1.0)0.5

(0.4, 0.6)

NIVONIVO+IPI IPI

LDH ≤ ULN LDH > ULN

269 213 172 149 131 125 106 67 28 2NIVO+IPI 0

Time (Months)

PF

S (

%)

100

90

80

70

60

50

40

30

20

0

10

3 6 9 12 15 18 21 24 270 30

Number of Patients at Risk

316 213 173 155 133 118 105 51 10 0NIVO 0

230 126 71 53 43 37 24 15 5 0IPI 0

60%

50%47%

35%

23%

17%

71%

56% 54%

138 74 59 53 44 43 36 18 4 0NIVO+IPI

Time (Months)

PF

S (

%)

100

90

80

70

60

50

40

30

20

0

10

3 6 9 12 15 18 21 24 270


191 74 58 51 49 42 37 15 5 0NIVO

126 32 16 12 7 6 4 3 1 0IPI

34%29%

28%

15%

7% 6%

47%

38%35%

PFS in Patients With BRAF Mutations and LDH > ULN

34

NIVO+IPI

(n = 23)

NIVO

(n = 25)

IPI

(n = 23)

Median PFS, months (95% CI) NR (4.2, NR) 2.8 (2.6, 6.7) 2.8 (2.6, 5.8)

HR (95% CI) NIVO+IPI over

NIVO or IPI– 0.4 (0.2, 0.9) 0.3 (0.1, 0.6)

Time (Months)

100

90

80

70

60

50

40

30

20

0

10

3 6 279 12 15 18 21 240

NIVO+IPI

NIVO

IPI


23 19 15 013 12 12 9 3 2NIVO+IPI

25 10 8 07 7 7 6 2 0NIVO

23 8 5 04 2 2 2 1 1IPI

PF

S (

%)

Melanoma Metastático BRAFm : CONCLUSÕES

A Imunoterapia deve ser o tratamento sistêmico inicial

• 1 A imunoterapia funciona em pacientes com mutação BRAF; sistema Imune efetivo tem memória

• 2 Racional Clínico : efeitos e resultados, duradouros,com possibilidade de respostas rápidas

• 3 Possibilidade de interromper ou “terminar” o tratamento

• 4 Efetividade SNC e DHL elevado

Melanoma Metastático +BRAFm : CONCLUSÕES

A Imunoterapia deve ser o tratamento sistêmico inicial

5. Segurança, tolerância e toxicidades previsíveis e manejáveis

6. Combinações TKI e Imunoterapias são experimentais

7. Os resultados randomizados não estão disponíveis

Obrigado pela atenção !

sergio jobim de azevedo : potenciais conflitos de interesse · sergio jobim de azevedo : potenciais...

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