Melanoma:

o que este tumor nos ensinou na

imunoterapia

Rafael Aron Schmerling

Potenciais Conflitos de Interesse
Bristol-Myers Squibb Consultoria, honorários, pesquisa, patrocínio

Lilly Consultoria, honorários

Merck Sharp & Dome Consultoria, honorários, patrocínio

Novartis Consultoria, pesquisa

Pierre Fabre Consultoria, pesquisa

ROCHE Consultoria, honorários, pesquisa

Sanofi Consultoria, honorários

UNITED Medical Honorários

Imunoterapia pode curar ?
Interleucina-2
Sobrevida em Pacientes com Resposta Completa

N 182

TR 14,8%

RC 6,6%

CR Duradoura 5,5%

Duração de 12 – 148+
Resposta Mediana 80+

Rosemberg et al, Ann Surg 228:307-319, 1998

HD-IL2 com resposta duradoura - CWG
Probabilidade de Resposta
1.0

0.8
N=17
0.6

0.4 N=43

0.2 N=26

0.0
0 12 24 36 48 60 72 84 96 108 120
Meses
All responders CR PR

Atkins et al, J Clin Oncol 17:2105-2116, 1999

IL-2 Alta Dose, na população geral
Sobrevida Global

Atkins et al, J Clin Oncol 17:2105-2116, 1999

Como melhorar o resultado?
 Camundongo deficiente de CTLA-4
wt 50x -/- 50x -/- 100x
miocardio

Timo Baço
pâncreas

Miocardio Pulmão
Waterhouse et al, Science 1995
Tivoli et al, Immunity 1995
Camundongo deficiente de PD1

Nishimura et al, Science 2001; 291:319-22

Acesso Expandido, 4846 pacientes
1861 pacientes em protocolos de pesquisa

1.0
0.9
0.8
Median OS, months (95% CI): 9.5 (9.0–10.0)
Proportion Alive

0.7
0.6
0.5 3-year OS rate, % (95% CI): 21 (20–22)
0.4
0.3
0.2
0.1 Ipilimumab
CENSORED
0.0
0 12 24 36 48 60 72 84 96 108 120
Months
Patients at Risk
Ipilimumab 4846 1786 612 392 200 170 120 26 15 5 0

Schadendorf D, et al. Eur J Cancer 2013;49(suppl 2): abstract 24LBA

“Pseudo-Progressão”

Pré Ipi Ipi x2 Ipi x3 Ipi x4

Cortesia, Dr. A.C. Buzaid

Como melhorar, ainda mais,
o resultado?
Anti PD1

Robert et al. Lancet, 2014

 Keynote 002: Pembrolizumab vs. QT pós Ipi
Sobrevida Livre de Progressão Rate Mea
Median Rate at HR
Arm at 9 n,a P
(95% CI), mo 6 mo (95% CI)
mo mo

100 2.9 0.57

Progression-Free Survival, %

Pembro 2 Q3W 34% 24% 5.4 <0.0001

(2.8-3.8) (0.45-0.73)
90 Pembro 10 2.9 0.50
80 Q3W (2.8-4.7)
38% 29% 5.8
(0.39-0.64)
<0.0001

70 Chemotherapy
2.7
16% 8% 3.6 — —
60 (2.5-2.8)

50
40
30
20
10
0
0 2 4 6 8 10 12 14 16 18
Time, months
180 153 74 53 26 9 4 2 0 0
181 158 82 55 39 15 5 1 1 0
179 128 43 22 15 4 2 1 0 0
aRestrictedmean PFS time based on 12 months of follow-up.
Analysis cut-off date: May 12, 2014. Ribas et al. Lancet Oncol 2015; 16:908-18
 crossover from the chemotherapy to one of the pembrolizumab arms in KEYNOTE-002 0.0
• Second stage:
– OS for the patients who switched from the chemotherapy control group to the pembrolizumab 0 50 100 150 200
2 mg/kga rmwa sa dj
ustedba sedon th er esul
ts from thef irststage,andth en combi
nedw ith
OBJECTIVES unadjusted OS data from other study patients to estimate the treatment effect Time, weeks

Keynote 002: Pembrolizumab vs. QTafterpós Ipibaseline in the crossover

• To adjust for the confounding in OS for the control group introduced by crossover from the chemotherapy CI=conf
idencei
nter
val
;PD =pr
ogr
essi
vedi
sea
se.
to one of the pembrolizumab arms Table 1. Patient Baseline Characteristics
Figure 4. Kaplan-Meier curves of overall survival in the pembrolizumab 2 mg/kg arm using
• To compare and validate adjusted OS results using multiple approaches with a historical control Pembrolizumab Pembrolizumab
Figure 3. Kaplan-Meier curves of overall survival secondary Characteristic
2 mg/kg Q3W
n = 180
10 mg/kg Q3W
n = 181
Chemotherapy
n = 179
various approaches to adjust for crossover confounding.
1.0
METHODS Age, median (range), years 62.0 (15-87) 60.0 (27-89) 63.0 (27-87)
ITT control
Pembrolizumab 2 mg/kg
versus noncrossover groups (compared with Kaplan-Meier curves for the treatment group Two-stage adjusted control

Sobrevida Globalsince randomization).

Male, % 58 60 64 0.8
Study design and patients RPSFT-adjusted control
ECOG PS,a % Historical control
• KEYNOTE-002 was a randomized, controlled, phase 2 study of pembrolizumab compared with
investigator’s choice of chemotherapy in patients with advanced melanoma refractory to ipilimumab 0 54 54 55

Probability
0.6
(Figure 1) 1 44 46 45
BRAF status, %
Figure 1. Study design. Mutant
1.0 24 22 23
0.4

Patients
• Advanced melanoma
Pembrolizumab
2 mg/kg IV Q3W
Wild type
LDH level,b %
76 78 77
0.2
Noncrossover (after PD)
gned to receive
• PD within 24 weeks after
≥2 IPI doses
• Previous BRAF or MEK
Normal
Eleva ted( ≥1
10% ULN)
55
43
58
40
60
38 Crossover control (after PD)
0.0

, or chemotherapy
inhibitor (if BRAF mutant)
• ECOG PS 0-1
• Resolution of IPI-related AEs
R
1:1:1
Pembrolizumab
10 mg/kg IV Q3W M stage, %
M0 1 <1 <1 0 Pembrolizumab 2 mg/kg (from randomization)
50 100 150
• No chronic systemic steroid
therapy (>10 mg/day
prednisone or equivalent)
Pembrolizumab
2 mg/kg IV Q3W M1a 0.8 8 5 7 Time, weeks
• No active autoimmune
disease
Investigator's
choice
chemotherapy
PD
Crossover
eligible
M1b
M1c
8
83
12
82
9
83
95% CI
ITT = intention-to-treat population; RPSFT = rank-preserving structural failure time.

Stratification factors
Pembrolizumab
ECOG PS = Eastern Cooperative Oncology Group performance status; LDH = lactate dehydrogenase; Q3W = every 3 weeks; ULN = upper Table 2. Hazard Ratios of Overall Survival for Pembrolizumab Compared With Chemotherapy
10 mg/kg IV Q3W
limit of normal.
• Paclitaxel + carboplatin aECOG PS was missing for 2 patients. Using Various Approaches to Estimate the Treatment Effect of Crossover

ertopembr
oli
zumab
• ECOG PS (0 vs 1) • Paclitaxel bLDH level was unknown or missing for 11 patients.
• LDH (normal vs elevated) • Carboplatin Pembrolizumab 2 mg/kg Pembrolizumab 10 mg/kg

Probability
• BRAF status (mutant vs • Dacarbazine vs chemotherapy vs chemotherapy
wild type) • Temozolomide
0.6
Figure 2. Disposition of chemotherapy control group from KEYNOTE-002 with respect to
treatment switching. HR 95% CI HR 95% CI
AE = adverse event; ECOG PS = Eastern Cooperative Oncology Group performance status; IPI = ipilimumab; IV = intravenously;
LDH = lactate dehydrogenase; PD = progressive disease; Q3W = every 3 weeks; R = randomization. ITT 0.86 0.67-1.10 0.74 0.57-0.96
Chemotherapy RPSFT 0.79 0.50-1.03 0.67 0.45-0.85
Treatments and assessments control group
• Patients were randomly assigned 1:1:1 to receive pembrolizumab 2 or 10 mg/kg Q3W or investigator’s n = 179 2-stage 0.58 0.44-0.78 0.51 0.38-0.67
choice of chemotherapy (paclitaxel plus carboplatin, paclitaxel, carboplatin, dacarbazine, or CI=conf
idencei
nter
val
;H R =hazar
dra
ti
o;I
TT =i
ntenti
on-
to-
tr
eatpopul
a ti
on;RPSFT =r
ank
-pr
eser
vingstr
uctur
alf
ail
ureti
me.
temozolomide) 2 mg/kg vs. QT 10mg/kg vs. QT
brolizumab 2 mg/kg
• Individual treatment assignment between pembrolizumab and chemotherapy was open label;
assignment of pembrolizumab dose was masked to investigators and patients
0.4
Crossed over to Crossed over to Did not cross over CONCLUSIONS
pembrolizumab 2 mg/kg pembrolizumab 10 mg/kg n = 81
• Pa ti
ents i
n th ech emoth erapyg roupw i thdocumenteda ndconf irmeddi sea sepr
og ression a torafter n = 53 • Various appr
oaches tocrossovera dj
ustmenty i
eldedsimil
a resti
ma tes oftheOS benef itof
n = 45
week 12 who met the relevant eligibility criteria could cross over to receive pembrolizumab after a pembrolizumab compared with chemotherapy as measured by HR, although the magnitudes of the
HR IC 95%
washout period of at least 28 days from the last dose of chemotherapy HR IC 95% esti
ma tedbenefi
tvaried
– Patients who crossed over were randomly assigned to receive 1 of the 2 pembrolizumab doses in a – Among the 3 approaches evaluated, results from the 2-stage approach were closest to the

l group after disease

double-blind manner Crossed over despite
violating ≥1 qualifying
No disease
progression
Disease progression
n = 50 • Th
historical control using the Korn method7
eKEYNOTE- 002 studysati
sfi
edma nyofthekeyattr
ibutes f
orsuccessf
uli
mpl ementa
ti
on of
Crossover modeling
mutation
ITT status,
0,86 and
0,67 – 1,10 0,74
• Both the 2-stage method3,4 and the rank-preserving structural failure time (RPSFT) method5,6 were 0,57-0,96
0.2crossover condition
n = 12
n = 31
the2-
stagea
mechanism
ppr
oach ,incl
udi
ngaw el
l-def
inedsecondaryba seli
neandacl eartr
eatmentsw i
tch

applied to the survival times for patients in the chemotherapy control arm for OS crossover adjustment
• As thebestvali
datedapproachforthi
s study,the2-
stageappr
oa chi
ndicatedasigni
fi
cantandr
obust
• 2-stage method:
COG) performance
– In thefirststage, sur vi
va lti
mef r
om th eseconda ryba seli
netodea thw a s modeledtodeter
the treatment effect in the chemotherapy control group between patients who switched to
mi
ne
Met all qualifying
crossover conditions
Eligible for crossover
n = 35
tr
ea tmentef
fectofOS benef
itw i
thpembr oli
zuma bcompar
edw ithchemoth er
apy

n = 41
ssion
RPSFT 0,50 – 1,03
pembrolizumab compared with those who did not switch
0,79 0,67
• Based on the estimated switching effect, the survival times of the patients in the control
0,45 – 0,85 REFERENCES
group who switched to pembrolizumab were adjusted
• The unadjusted survival times of the patients in the control group who did not switch to
0.0 Survived beyond
28 days after last
1. Ribas A et al. Lancet Oncol. 2015;16(8):908-918.
2. Hamid O et al. Presented at: European Society for Medical Oncology (ESMO) 2016 Congress; October 7-11, 2016;
Copenhagen, Denmark. Abstr 1107O.
chemotherapy dose
pembrolizumab were combined with those of the patients in the pembrolizumab arms for an n = 34 3. Latimer NR et al. Med Decis Making. 2014;34(3):387-402.

2-stage 0,58 0,44 – 0,78

estimate of the treatment effect in the second-stage analysis
0,51 0,38 – 0,67 4. Latimer NR et al. Stat Methods Med Res. 2014. [Epub ahead of print]. doi: 10.1177/0962280214557578.
5. Robins JM. Encyclopedia of Biostatistics. Chichester, England: John Wiley & Sons; 1998:4372-4389.

e pembrolizumab
– This approach is particularly suitable for oncology trials because time of progression can be a
natural candidate for the secondary baseline, which tends to happen shortly before switching
treatment when disease states of the patients are similar
Crossover-adjusted overall survival
0 50
6. Hernán MA et al. Pharmacoepidemiol Drug Saf. 2005;14(7):477-491.

100
7. Korn EL et al. J Clin Oncol. 2008;26(4):527-534.
150 200
n combi
nedw i th
• The survival curve of patients in the chemotherapy control group who crossed over to pembrolizumab
• RPSFT method: 2 mg/kg after disease progression is similar to that of patients who were originally allocated to this
– This method assumes that treatment has a multiplicative effect on a patient’s survival by using the pembrolizumab dose at study start (Figure 3)
• Of the approaches evaluated, the results from the 2-stage method were most appropriate when
Tempo,
Time, weeks semanas
ACKNOWLEDGMENTS
t accelerated failure time model
– Ag r
idsea rchoverpossi bleva l
ues w a s usedtodeter mi
neth etr ea tmentef f
ectthatsa
ti
sfi
edthe
compared with the historical control (Figure 4)
• HRs were similar between the pembrolizumab 2 mg/kg and 10 mg/kg doses (Table 2)
The authors thank the patients and their families and all investigators and site personnel. Editorial assistance was
provided by Tricia Brown, MS, and Payal Gandhi, PhD, of the ApotheCom oncology team (Yardley, Pennsylvania,
constraint that counterfactual survival times are independent of treatment group
aRestricted mean PFS time based on effect
12 months of follow-up. USA) and was funded by Merck & Co., Inc., Kenilworth, New Jersey, USA. The study was funded by Merck & Co., Inc.,
– This approach depends on an assumption of a common treatment
CIwere
=c onf i dencei
nter
val
;PD =pr
ogr
essi
vedi
sease.
Kenilworth, New Jersey, USA.
• The resulting adjusted
Analysis cut-off survivaldate:
curves for May 12, using
chemotherapy 2014.various approaches
against a historical literature-based benchmark using the Korn algorithm
validated
7 Ribas et al. Lancet Oncol 2015; 16:908-18
Nivolumab vs DTIC – BRAF selvagem, 1ª linha

Robert et al. N Engl J Med. 2015;372(4):320-30.

KeyNote 001: Pembrolizumabe – 5 anos

Hamid et al. ASCO, 2018

KeyNote 001: Pembrolizumabe – 5 anos

Hamid et al. ASCO, 2018

KeyNote 006: Pembrolizumabe vs. Ipilimumab
Sobrevida Global Follow Up Mediano 45,9m

Robert et al. ASCO, 2018

KeyNote 006: Pembrolizumabe vs. Ipilimumab
Sobrevida Livre de Progressão Follow Up Mediano 45,9m

Robert et al. ASCO, 2018

KeyNote 006: Pembrolizumabe vs. Ipilimumab
Duração de Resposta Follow Up Mediano 45,9m

Robert et al. ASCO, 2018

KeyNote 006: Pembrolizumabe vs. Ipilimumab
Resposta Follow Up Mediano 45,9m

Robert et al. ASCO, 2018

Como a resposta impacta no
tratamento?
KeyNote 001: Até quando tratar?
Pacientes com Resposta Completa

90% @ 2y 86% @ 2y

Robert et al. J Clin Oncol, 2018

KeyNote 001: Até quando tratar?
Pacientes com 94+ semanas de tratamento

Robert et al. ASCO, 2018

Conseguimos melhorar,
ainda mais, o resultado?

Combinações
CheckMate 067: Ipi/Nivo, Nivo vs. Ipi
Nivo+Ipi Nivo Ipi
314 316 315

PFSm, meses (IC95%) 11,5 (9,7-19,3) 6,9 (5,1-9,7) 2,9 (2,8-3,2)

HR (IC95%) vs Ipi 0,43 (0,35-0,52) 0,55 (0,45-0,66) ---

HR (IC95%) vs Nivo 0,78 (0,64-0,96)* --- ---

Wolchok et al. N Engl J Med, 2017

 CheckMate 067: Ipi/Nivo, Nivo vs. Ipi
Nivo+Ipi Nivo Ipi
314 316 315

OSm, meses (IC95%) NR (38,2-NR) 37,6 (29,1-NR) 19,9 (16,9-24,6)

HR (IC95%) vs Ipi 0,55 (0,45-0,69) 0,65 (0,53-0,80) ---

Ipi HR (IC95%) vs Nivo 0,85 (0,68-1,07)* --- ---

Nivo Ipi
Nivo

RC 19% 16% 5% 64%

RP 39% 28% 14% 59%

45%
DE 12% 10% 22%

PD 24% 38% 50%

N/A 6% 8% 9%

Wolchok et al. N Engl J Med 2017 ;377(14):1345-1356

CheckMate 067: Ipi/Nivo, Nivo vs. Ipi
• With an additional 19 months of follow-up, safety was consistent with the initial report1
NIVO+IPI NIVO IPI
(N=313) (N=313) (N=311)
Any Any Any
Patients reporting event, % Grade 3-4 Grade 3-4 Grade 3-4
Grade Grade Grade
Treatment-related adverse
95.8 58.5 86.3 20.8 86.2 27.7
event (AE)
Treatment-related AE leading
39.6 31.0 11.5 7.7 16.1 14.1
to discontinuation
Treatment-related death, n (%) 2 (0.6)a 1 (0.3)b 1 (0.3)b

• Most select AEs were managed and resolved within 3-4 weeks (85–100% across organ
categories)
• ORR was 70.7% for pts who discontinued NIVO+IPI due to AEs, with median OS not
reached
aCardiomyopathy (NIVO+IPI, n=1); Liver necrosis (NIVO+IPI, n=1). Both deaths occurred >100 days after the last treatment.
bNeutropenia (NIVO, n=1); colon perforation (IPI, n=1).1
Larkin J, et al. NEJM 2015;373:23‒34
Metástases Cerebrais
Pacientes sem Tratamento
População Total
Prévio

Ipi+Nivo Nivo Ipi+Nivo Nivo

Nivo* (n:16)
(n:35) (n:25) (n:27) (n:19)

Resposta Intracraniana 46% 20% 6% 56% 21%

Resposta Completa 17% 12% 0 19% 11%

Resposta Parcial 29% 8% 6% 37% 10%

Doença Estável 11% 0 13% 11% 0

Progressão de Doença 40% 76% 81% 30% 74%

* Sintomáticos ou com Comprometimento Meníngeo

Long et al, Lancet Oncol 2018

Ipi e Nivo em Metástases Cerebrais
Ipi-Nivo Nivo

População
Total RO-IC 46% RO-IC 20%

Ipi-Nivo Nivo

RO-IC 56% RO-IC 21%

BRAF/MEK-I
Naive

Long et al, Lancet Oncol 2018

Ipi e Nivo em Metástases Cerebrais
População BRAF/MEK-I
Total Naive

Long et al, Lancet Oncol 2018

T-VEC + Pembrolizumabe

wk

Ribas et al. Cell, 2017

Conseguimos melhorar,
ainda mais, o resultado?

Seleção de Pacientes
PD-L1 em Melanoma

Daud et al. J Clin Onco, 2016

PD-L1 em Melanoma

Sobrevida Livre de Progressão conforme o status de PD-L1

Wolchok et al. ASCO, 2016

PD-L1 em Melanoma

Resposta conforme o status de PD-L1

Wolchok et al. ASCO, 2016

NGS e Imunoterapia
Análise retrsopectiva

Johnson et al, Cancer Immunol Res. 2016 Nov;4(11):959-967

Perfil de Expressão Gênica e Imunoterapia

Distribuição de 18 genes do
perfil de expressão gênica
dividido entre respondedores
e não-respondedores

Hamid et al. ASCO, 2018

No Pain, No Gain?
Toxicidade e Eficácia – anti PD1

Freeman-Keller M et al. Clin Cancer Res 2015; 22:886-94

Toxicidade e Eficácia - Vitiligo

Freeman-Keller M et al. Clin Cancer Res 2015; 22:886-94

 Toxicidade e Eficácia – anti PD1

Número
de eventos

Gravidade
dos eventos

Weber J et al. J Clin Oncol 2017; 35:785-92

Toxicidade e Eficácia

Weber J et al. J Clin Oncol 2017; 35:785-92

e Adjuvância?...
Ipilimumabe – Sobrevida Global

Eggermon et al. N Engl J Med, 2016

 Sobrevida Livre de Recidiva
Nivolumabe vs Ipilimumabe

Sobrevida
Livre de Recidiva

Nivo Ipi

12 m 70,5% 60,8%

18 m 66,4% 52,7%

Weber et al. N Engl J Med, 2017

Pembrolizumbe vs. Placebo

Eggermont et al, N Engl J Med 2018

Potenciais Conflitos de Interesse
Imunoterapia promove sobrevida prolongada
Padrão de resposta fora do “habitual”
Claramente superior a quimioterapia
Possibilidade real de sustentação do ganho após a interrupção do tratamento
Combinações potencializam resposta. Sem um papel totalmente definido
Possibilidade de tratamento de metástases cerebrais
Seleção de pacientes “clínica” e por “biomarcadores” precisa ser otimizada
Toxicidade está relacionada a resposta
Imunoterapia Adjuvante oferece melhora de SG com Ipi e SLD (por ora) com anti-PD1
Obrigado

@MelanomaSarcoma