sergio jobim de azevedo : potenciais conflitos de interesse · sergio jobim de azevedo : potenciais...
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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 :
Porque a Imunoterapia deve ser o tratamento sistêmico inicial
• 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
10 mg/kg intravenous Q3W
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
3 mg/kg intravenous Q3W
× 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
• 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
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.
Data cutoff date: Nov 3, 2016.
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)
Data cutoff date: Nov 3, 2016.
• 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
Data cutoff date: Nov 3, 2016.
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 :
Porque a Imunoterapia deve ser o tratamento sistêmico inicial
• 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
• 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
Presented by Georgina V. Long
Intracranial Progression-Free Survival:
Intracranial Best Response All Patients (Cohorts A+B+C)
Complete ResponsePartial Response
Progressive Disease
Stable Disease
Presented by Georgina V. Long
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
Number of Patients at Risk
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
Number of Patients at Risk
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 !