TRATAMIENTO DE COMBINACIÓN: ¿EL NUEVO ESTÁNDAR?
Dr. Iván Márquez Rodas
Hospital General Universitario Gregorio Marañón
23-6-2017
COI • Honorarios, asesoría: BMS, NOVARTIS, GSK,
AMGEN, MSD, MERCK, ROCHE, PIERRE FABRE, INCYTE, BIONCOTECH
• Participación en ensayos 067, 511, 742 y 915 con el regimen de combinación ipilimumab+nivolumab
RESUMEN
• Inicios y racional de la combinación: Fase I
• CA209-067: resultados comunicados en AACR 2017
• ¿Algún subgrupo? – PD-L1, LDH, BRAF
• Subpoblaciones especiales – Melanoma de mucosas
– Melanoma ocular
– Metástasis cerebrales
RACIONAL PRECLINICO
Ribas 2012 NEJM Curran et al. Proc Natl Acad Sci USA 2010 Chiste de Nacho Melero, ASCO 2013
Cinturón y tirantes…*
FASE I
¿Es necesario un fase III? *
Wolchok NEJM 2013 * Pregunta de la audiencia, ASCO 2013
21/52 respuestas (42%) 16/21 respuestas mayores de 80% (76%) 5/21 respuestas completes (24%) 53% efectos secundarios grado 3-4 21% discontinuaciones
# 1: Overall Survival Data not Seen Before in Melanoma (3 Year Rates From Phase I Clinical Trial)
Cohorts 1–3
Cohort 8
All concurrent cohorts
63 60 57 54 51 48 45 42 39 36 33 30 27 24 21 18 15 12 9 6 3 0
0.0
0.1
0.2
0.3
0.4
0.5
0.6
0.7
0.8
0.9
1.0
Months
Pro
bab
ility
of
Surv
ival
0 1 1 2 4 4 5 10 14 21 26 35 39 41 41 41 42 45 47 49 52 53 Cohorts 1–3
0 0 0 0 0 0 0 0 0 0 0 0 0 0 17 25 28 30 32 35 40 41 Cohort 8
21 26 35 39 41 58 66 70 75 79 84 92 94 All concurrent cohorts 0 1 1 2 4 4 5 10 14
Number of patients at risk
Died/treated, n/N
Median OSa, mo (95% CI)
Cohorts 1–3 18/53 NR (39.8–NR)
Cohort 8 14/41 NR (20.0–NR)
All concurrent cohorts 32/94 43.9 (39.8–NR)
Cohorts 1–3: 85%
Cohorts 1–3: 68%
Sznol 2015 Melanoma Bridge
Larkin 2015 NEJM
FASE III
• Objetivo co-primario: SLP • Superior a ipilimumab y (de forma exploratoria) a
nivolumab – Tasas de respuesta – SLP – Toxicidad
• Por tanto, los datos de supervivencia global son fundamentales
Overall Survival Results From a Phase III Trial of Nivolumab Combined With Ipilimumab in
Treatment-naïve Patients With Advanced Melanoma (CheckMate 067)
James Larkin,1 Vanna Chiarion-Sileni,2 Rene Gonzalez,3 Piotr Rutkowski,4 Jean-Jacques Grob,5
C. Lance Cowey,6 Christopher D. Lao,7 Dirk Schadendorf,8 Pier Francesco Ferrucci,9 Michael Smylie,10
Reinhard Dummer,11 Andrew Hill,12 John Haanen,13 Michele Maio,14 Grant McArthur,15 Dana Walker,16
Linda Rollin,16 Christine Horak,16 F. Stephen Hodi,17,* Jedd D. Wolchok18,*
1Royal Marsden Hospital, London, UK; 2Oncology Institute of Veneto IRCCS, Padua, Italy; 3University of Colorado Cancer Center, Denver, CO,
USA; 4Maria Sklodowska-Curie Memorial Cancer Center & Institute of Oncology, Warsaw, Poland; 5Hospital de la Timone, Marseille, France; 6Texas Oncology-Baylor Charles A. Sammons Cancer Center, Dallas, TX, USA; 7University of Michigan, Ann Arbor, MI, USA; 8Department of
Dermatology, University of Essen, Essen, Germany; 9European Institute of Oncology, Milan, Italy; 10Cross Cancer Institute, Alberta, Canada; 11Universitäts Spital, Zurich, Switzerland; 12Tasman Oncology Research, QLD, Australia; 13Netherlands Cancer Institute, Amsterdam, The
Netherlands; 14University Hospital of Siena, Siena, Italy; 15Peter MacCallum Cancer Centre, Victoria, Australia; 16Bristol-Myers Squibb,
Princeton, NJ, USA; 17Dana-Farber Cancer Institute, Boston, MA, USA; 18Memorial Sloan-Kettering Cancer Center and Weill Cornell Medical College, New York, NY, USA; *Contributed equally to this study.
Abstract Number CT075
Larkin AACR 2017
Unresectable or
Metatastic Melanoma
• Previously untreated
• 945 patients
CA209-067: Study Design CheckMate 067: Study Design
Treat until
progression or
unacceptable
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
Randomize
1:1:1
Stratify by:
• BRAF status
• AJCC M stage
• Tumor PD-L1 expression <5% vs ≥5%*
N=314
N=316
N=315
Randomized, double-blind,
phase III study to compare NIVO+IPI
or NIVO alone to IPI alone*
*The study was not powered for a comparison between NIVO and NIVO+IPI
Database lock: Sept 13, 2016 (median follow-up ~30 months in both NIVO-containing arms)
10
¿Cuántos hubiesen sido necesarios para alcanzar ese poder estadístico?
Larkin AACR 2017
Study Endpoints: NIVO+IPI or NIVO vs IPI
• Co-primary endpoints:
– PFS and OS (intent-to-treat population)
• Secondary and exploratory endpoints:
– ORR by RECIST v1.1
– Efficacy by tumor PD-L1 expression level
– Safety profile (in patients who received ≥1 dose of study drug)
• Current analysis:
– Per protocol, a total of 644 deaths were projected to occur at 28 months (99% power to detect a HR of 0.65 for each NIVO-containing arm vs IPI)
• However, the actual number of deaths was 28% lower than anticipated (95% power to detect a HR of 0.65 vs IPI)
– The study was not powered for a comparison between NIVO+IPI and NIVO
11 Larkin AACR 2017
NIVO+IPI (N=314)
NIVO (N=316)
IPI (N=315)
ORR, % (95% CI)* 58.9 (53.3–64.4) 44.6 (39.1–50.3) 19.0 (14.9–23.8)
Best overall response — %
Complete response 17.2 14.9 4.4
Partial response 41.7 29.7 14.6
Stable disease 11.5 9.8 21.3
Progressive disease 23.6 38.6 51.1
Unknown 6.1 7.0 8.6
Median duration of response, months (95% CI)
NR (NR–NR) 31.1 (31.1–NR) 18.2 (8.3–NR)
Updated Response To Treatment
*By RECIST v1.1; NR = not reached.
• At the 18-month DBL, the CR rate for NIVO+IPI, NIVO and IPI was 12.1%, 9.8% and 2.2%, respectively
12
Database lock: Sept 13, 2016, minimum f/u of 28 months
Larkin AACR 2017
Updated Progression-Free Survival
50%
43%
18%
43%
37%
12%
Perc
en
tag
e o
f P
FS
Months
0
10
20
30
40
50
60
70
80
90
100
0 3 6 9 12 15 18 36 30 24 33 27 21
0 IPI
NIVO+IPI (N=314) NIVO (N=316) IPI (N=315)
Median PFS, mo (95% CI) 11.7
(8.9–21.9) 6.9
(4.3–9.5) 2.9
(2.8–3.2)
HR (95% CI) vs. IPI 0.42
(0.34–0.51) 0.54
(0.45–0.66) --
HR (95% CI) vs. NIVO 0.76
(0.62–0.94) -- --
Pro
gre
ss
ion
-fre
e S
urv
iva
l (%
)
5 16 27 30 33 35 43 46 58 77 136 315
Patients at risk:
0 NIVO 16 62 88 97 103 107 112 120 132 151 178 316
0 NIVO+ IPI 16 71 104 110 118 125 132 137 156 176 218 314
NIVO+IPI
NIVO
IPI
8 Database lock: Sept 13, 2016, minimum f/u of 28 months
Larkin AACR 2017
Overall Survival
Months Patients at risk:
73%
74%
67%
64%
59%
45%
Pe
rce
nta
ge
of
PF
S
0
10
20
30
40
50
60
70
80
90
100
0 3 6 9 12 15 18 39 30 24 33 27 21
Ove
rall S
urv
iva
l (%
)
36
0 IPI 34 104 129 136 149 164 182 205 228 254 285 315 4
0 NIVO 55 157 175 181 191 201 213 230 244 265 292 316 3
0 NIVO+IPI 49 170 192 198 200 209 221 226 247 265 292 314 7
*P<0.0001
NIVO+IPI (N=314) NIVO (N=316) IPI (N=315)
Median OS, mo (95% CI) NR NR
(29.1–NR) 20.0
(17.1–24.6)
HR (98% CI) vs. IPI 0.55
(0.42–0.72)* 0.63
(0.48–0.81)* --
HR (95% CI) vs. NIVO 0.88
(0.69–1.12) -- --
NIVO+IPI
NIVO
IPI
14
Database lock: Sept 13, 2016, minimum f/u of 28 months
Igualdad de beneficio al año, 5% más de beneficio a los 2 años, pendientes de 3 años… Larkin AACR 2017
¿QUÉ PASARÁ A LOS TRES AÑOS?
18
12
43
37
50
43
0
10
20
30
40
50
60
70
80
1 AÑO 2 AÑOS
SLP
ipilimumab nivolumab ipi+nivo
15
67
45
74
59
73
64
0
10
20
30
40
50
60
70
80
1 AÑO 2 AÑOS
SG
ipi SG nivo SG ipi+nivo SG
Deconstrucción con mótivos académicos, a partir de Larkin AACR 2017
16
YA SÉ QUE NO TIENE NADA QUE VER…
Von Minckwitz NEJM 2017
NIVO+IPI (N=314)
NIVO (N=316)
IPI (N=315)
Any subsequent therapy, n (%)* 129 (41) 169 (54) 225 (71)
Systemic therapy 100 (32) 140 (44) 196 (62)
Anti-PD-1 agents 30 (10) 32 (10) 132 (42)
Anti-CTLA-4 19 (6) 83 (26) 12 (4)
BRAF inhibitors 40 (13) 57 (18) 68 (22)
MEK inhibitors 30 (10) 38 (12) 39 (12)
Investigational agents** 8 (3) 6 (2) 15 (5)
Median time to subsequent systemic therapy, mo (95% CI)
NR (NR‒NR) 26.8 (18.0‒NR) 8.5 (7.3‒9.7)
2 year % of pts free of subsequent therapies
65.8 53.8 24.7
Subsequent Therapies: All Randomized Patients
17
*Patients may have received more than 1 subsequent therapy (e.g. radiation, surgery and systemic therapies)
**Other than investigational immunotherapy, BRAF inhibitors, and MEK inhibitors
Larkin AACR 2017
18
Los pacientes del CHECK-MATE 067 no podían participar en este ensayo
Pero tenían acceso a pembro…
Schadendorf ASCO 2017
CHECK-MATE 064
19 Weber Lancet 2016
IPI POST NIVO ENSAYO 066
20 Atkinson SMR 2015
Subgroup
Patients Unstratified Hazard Ratio Unstratified Hazard Ratio (95% CI)
NIVO+IPI NIVO PFS OS PFS OS
Overall 314 316 0.77 0.89
<65 years 185 198 0.74 0.81
≥65 years 129 118 0.82 0.99
BRAF Mutant 102 98 0.60 0.71
BRAF Wild-type 212 218 0.86 0.97
ECOG PS = 0 230 237 0.79 0.91
ECOG PS = 1 83 78 0.72 0.82
M0/M1a/M1b 129 132 0.67 0.84
M1c 185 184 0.83 0.90
LDH ≤ ULN 199 197 0.72 0.89
LDH > ULN 114 112 0.79 0.86
LDH > 2 x ULN 37 37 0.70 0.71
PD-L1 ≥5% 68 80 0.87 1.05
PD-L1 <5% 210 208 0.73 0.84
PFS and OS Subgroup Analyses (All Randomized Patients) Descriptive comparison between NIVO+IPI and NIVO
21
NIVO+IPI NIVO
2 0 1
NIVO+IPI NIVO
2 0 1
Larkin AACR 2017
OS
(%
)
Months
0
10
20
30
40
50
60
70
80
90
100
0 39 36 33 30 27 24 21 18 15 12 9 6 3
NIVO+IPI NIVO IPI
0 IPI 215 3 21 67 82 87 96 106 118 134 147 166 194
0 NIVO 218 2 38 105 119 124 127 134 144 155 163 179 199
0 NIVO+IPI 212 5 31 108 120 126 127 133 142 144 157 170 194
61%
57%
42%
BRAF Wild-type
OS
(%
)
Months
0
10
20
30
40
50
60
70
80
90
100
0 39 36 33 30 27 24 21 18 15 12 9 6 3
NIVO+IPI NIVO IPI
0 IPI 100 1 13 37 47 49 53 58 64 71 81 88 91
0 NIVO 98 1 17 52 56 57 64 67 69 75 81 86 93
0 NIVO+IPI 102 2 18 62 72 72 73 76 79 82 90 95 98
71%
62%
OS in Patients with BRAF Wild-type and Mutant Tumors
22
51%
NIVO+IPI NIVO IPI
Median, mo
(95% CI)
NR
NR
(26.4‒NR)
24.6
(17.9‒31.0)
HR (95% CI)
vs NIVO
0.71
(0.45‒1.13) -- --
NIVO+IPI NIVO IPI
Median, mo
(95% CI)
NR
(27.6‒NA)
NR
(25.8‒NR)
18.5
(14.8‒23.0)
HR (95% CI) vs
NIVO
0.97
(0.74‒1.28) -- --
BRAF Mutant
Patients at risk: Patients at risk:
Larkin AACR 2017
NIVO+IPI (N=314)
NIVO (N=316)
IPI (N=315)
Any subsequent therapy, n (%)* 129 (41) 169 (54) 225 (71)
Systemic therapy 100 (32) 140 (44) 196 (62)
Anti-PD-1 agents 30 (10) 32 (10) 132 (42)
Anti-CTLA-4 19 (6) 83 (26) 12 (4)
BRAF inhibitors 40 (13) 57 (18) 68 (22)
MEK inhibitors 30 (10) 38 (12) 39 (12)
Investigational agents** 8 (3) 6 (2) 15 (5)
Median time to subsequent systemic therapy, mo (95% CI)
NR (NR‒NR) 26.8 (18.0‒NR) 8.5 (7.3‒9.7)
2 year % of pts free of subsequent therapies
65.8 53.8 24.7
Subsequent Therapies: All Randomized Patients
23
*Patients may have received more than 1 subsequent therapy (e.g. radiation, surgery and systemic therapies)
**Other than investigational immunotherapy, BRAF inhibitors, and MEK inhibitors
Larkin AACR 2017
OS by Tumor PD-L1 Expression, 5% Cutoff
24
NIVO+IPI NIVO IPI
Median OS, mo
(95% CI)
NR
(31.8–NR)
NR
(23.1–NR)
18.5
(13.7–22.5)
HR (95% CI)
vs NIVO
0.84
(0.63–1.12) ─ ─
PD-L1 Expression Level <5%
OS
(%
)
Months
0
10
20
30
40
50
60
70
80
90
100
0 39 36 33 30 27 24 21 18 15 12 9 6 3
Patients at risk:
202 0 IPI 2 18 63 78 81 90 100 108 125 140 158 179
208 0 NIVO 2 34 99 110 112 118 123 133 144 151 169 189
210 0 NIVO+IPI 7 34 116 127 130 131 139 144 146 163 178 194
NIVO+IPI NIVO IPI
Median OS, mo
(95% CI) NR NR
28.9
(18.1–NR)
HR (95% CI)
vs NIVO
1.05
(0.61–1.83) ─ ─
PD-L1 Expression Level ≥5%
OS
(%
)
Months
0
10
20
30
40
50
60
70
80
90
100
0 39 36 33 30 27 24 21 18 15 12 9 6 3
Patients at risk:
75 0 IPI 1 13 33 39 40 43 46 55 61 65 67 72
80 0 NIVO 1 18 49 54 57 58 61 63 68 73 75 79
68 0 NIVO+IPI 0 11 35 44 45 45 45 50 52 55 56 63
55%
63%
41%
72%
68%
54%
• ORR of 73.5% for NIVO+IPI and 58.8% for NIVO • ORR of 56.2% for NIVO+IPI and 42.3% for NIVO
Larkin AACR 2017
De 5% a 8% De 5% a -4%
<1% PD-L1 NIVO+IPI NIVO IPI
Median OS, mo
(95% CI)
NR
(26.5–NR)
23.5
(13.0–NR)
18.6
(13.7–23.2)
HR (95% CI)
vs NIVO
0.74
(0.52–1.06) ─ ─
≥1% PD-L1 NIVO+IPI NIVO IPI
Median OS, mo
(95% CI) NR NR
22.1
(17.1–29.7)
HR (95% CI)
vs NIVO
1.03
(0.72–1.48) ─ ─
OS
(%
)
Months
0
10
20
30
40
50
60
70
80
90
100
0 39 36 33 30 27 24 21 18 15 12 9 6 3
60%
49%
41%
OS
(%
)
Months
0
10
20
30
40
50
60
70
80
90
100
0 39 36 33 30 27 24 21 18 15 12 9 6 3
113 0 IPI 1 10 32 43 44 50 57 61 71 79 87 96
117 0 NIVO 2 16 50 55 57 59 62 65 73 76 86 103
123 0 NIVO+IPI 4 18 66 72 74 74 79 82 82 91 102 113
164 0 IPI 2 21 64 74 77 83 89 102 115 126 138 155
171 0 NIVO 1 36 98 109 112 117 122 131 139 148 158 165
155 0 NIVO+IPI 3 27 85 99 101 102 105 112 116 127 132 144
67%
67%
48%
Similar Outcomes Were Observed at a 1% Cutoff
25
PD-L1 Expression Level <1% PD-L1 Expression Level ≥1%
Patients at risk: Patients at risk:
• ORR of 65.2% for NIVO+IPI and 55.0% for NIVO • ORR of 54.5% for NIVO+IPI and 35.0% for NIVO
Larkin AACR 2017
Safety Summary • With an additional 19 months of follow-up, safety was consistent with the initial report1
• 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
26
NIVO+IPI (N=313)
NIVO
(N=313) IPI
(N=311)
Patients reporting event, % Any Grade Grade 3-4 Any Grade Grade 3-4 Any Grade Grade 3-4
Treatment-related adverse event (AE)
95.8 58.5 86.3 20.8 86.2 27.7
Treatment-related AE leading to discontinuation
39.6 31.0 11.5 7.7 16.1 14.1
Treatment-related death, n (%) 2 (0.6)a 1 (0.3)b 1 (0.3)b
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
1. Larkin J, et al. NEJM 2015;373:23‒34.
27 Presented By MS Carlino at 2017 ASCO Annual Meeting
61% ORR, 15% CR
PEMBRO 2 MG/KG + IPI 1 MG/KG
CHECK-MATE 511: fase III IPI 1 NIVO 3 VS IPI 3 NIVO 1
COMBINACIÓN EN SITUACIONES ESPECIALES
MTS SNC
28
A Randomized Phase 2 Study of Nivolumab
or Nivolumab plus Ipilimumab in Patients
with Melanoma Brain Metastases:
The Anti-PD1 Brain Collaboration (ABC)
Georgina V. Long, Victoria Atkinson, Alexander M. Menzies, Serigne Lo,
Alexander Guminski, Michael P. Brown, Maria Gonzalez, Katrina Diamante,
Shahneen Sandhu, Richard A. Scolyer, Louise Emmett, Grant A. McArthur.
Presented by Georgina V Long
Intracranial Response C
ha
nge
fro
m B
ase
line (
%)
All Patients
Drug
Treatment
Naive
Cohort A: Nivo+Ipi Cohort B: Nivo alone
-50
-100
50
100
0
150
200
* * * * * * * * * * * *
* * * *
IC RR = 42%
IC RR = 50%
IC RR = 20%
IC RR = 21%
* Deceased prior to week 12 assessment
200
-50
-100
50
100
0
150
* * * * *
Presented by Georgina V. Long
Efficacy and Safety of Nivolumab Plus Ipilimumab in Patients with Melanoma Metastatic to the Brain:
Results of the Phase II Study CheckMate 204
Hussein Tawbi,1 Peter Forsyth,2 Alain Algazi,3 Omid Hamid,4 F. Stephen Hodi,5 Stergios Moschos,6 Nikhil Khushalani,2 Rene Gonzalez,7 Christopher Lao,8 Michael Postow,9 Michael B. Atkins,10 Marc Ernstoff,11 Igor Puzanov,11 Ragini Kudchadkar,12 Reena Thomas,13 Ahmad Tarhini,14 Joel Jiang,15
Alexandre Avila,15 Sheena Demelo,15 Kim Margolin16
1University of Texas, MD Anderson Cancer Center, Houston, TX, USA; 2Moffitt Cancer Center and Research Institute, Tampa, FL, USA; 3University of California-San Francisco, San Francisco, CA, USA; 4The Angeles Clinic and Research Institute, Los Angeles, CA, USA;
5Dana-Farber Cancer Institute, Boston, MA, USA; 6University of North Carolina Lineberger Comprehensive Cancer Center, Chapel Hill, NC, USA; 7University of Colorado Comprehensive Cancer Center, Aurora, CO, USA; 8University of Michigan, Ann Arbor, MI, USA;
9Memorial Sloan Kettering Cancer Center and Weill Cornell Medical College, New York, NY, USA; 10Georgetown-Lombardi Comprehensive Cancer Center, Washington DC, USA; 11Roswell Park Cancer Institute, Buffalo, NY, USA; 12Winship Cancer Institute of
Emory University, Atlanta, GA, USA; 13Stanford University Hospital, Palo Alto, CA, USA; 14University of Pittsburgh Medical Center, Pittsburgh, PA, USA; 15Bristol-Myers Squibb, Princeton, NJ, USA; 16Department of Medical Oncology, City of Hope, Duarte, CA, USA.
Abstract Number 9507
Response to Treatment – All Patients (N = 75)
32
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
COMBINACIÓN EN SITUACIONES ESPECIALES
LDH ELEVADA
33
PFS in Patients With LDH > 2x ULN
34
NIVO+IPI
(n = 43)
NIVO
(n = 58)
IPI
(n = 31)
Median PFS, months (95% CI) 2.6 (1.7, 2.9) 2.1 (1.9, 2.6) 2.3 (1.7, 2.6)
HR (95% CI) NIVO+IPI over
NIVO or IPI – 0.7 (0.5, 1.1) 0.5 (0.3, 0.9)
43 14 12 0 11 8 8 6 1 0 NIVO+IPI
Time (Months)
PF
S (
%)
100
90
80
70
60
50
40
30
20
0
10
3 6 27 9 12 15 18 21 24 0
Number of Patients at Risk
58 13 9 0 5 5 5 5 4 2 NIVO
31 2 0 0 0 0 0 0 0 0 IPI
10%
17%
10%
20%
18%
29%
NIVO+IPI
NIVO
IPI
Larkin SMR 2016
PFS in Patients With BRAF Mutations and LDH > ULN
35
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 27 9 12 15 18 21 24 0
NIVO+IPI
NIVO
IPI
Number of Patients at Risk
23 19 15 0 13 12 12 9 3 2 NIVO+IPI
25 10 8 0 7 7 7 6 2 0 NIVO
23 8 5 0 4 2 2 2 1 1 IPI
PF
S (
%)
Larkin SMR 2016
IPI+NIVO LDH >1x… NR, aprox 57% en 1 año
NIVO LDH >1x… 2,8, aprox 30% en 1 año
36
No. at risk
Normal LDH, Disease Sites < 3
Normal LDH, Disease Sites ≥ 3
LDH > 1 x ULN
LDH > 2 x ULN
PFS by LDH and Number of Disease Sitesa
a Factors identified by the regression tree analysis.
0.0
0
.2
0.4
0
.6
0.8
1
.0
0 12 24 36
237 149 53 8
161 69 23 2
149 40 9 0
70 4 0 0
PF
S P
rob
ab
ility
Months
Normal LDH, Disease Sites < 3
Normal LDH, Disease Sites ≥ 3
LDH >1-≤ 2 x ULN
LDH > 2 x ULN
PRESENTED BY GV LONG AT SMR 2015
LDH>2 x, 5,5 meses, 8% al año
LDH >1x, <2x, 7,4 meses, 32% al año
OTRA FORMA DE VERLO, BRAF Y LDH ELEVADA
PFS MEDIANA (mo) PFS % AÑO PFS % 2 AÑOS
IPI+NIVO NR ?? 57 ?? ?? ??
NIVO 2,8 ?? 30 ?? ?? ??
BRAF+MEK 7,4 5,5*
32 8*
18 2*
37 *Valores para LDH>2, no disponibles inmuno
LONG SMR 2015
Long Lancet Oncol 2016
Larkin SMR 2016
COMBINACIÓN EN SITUACIONES ESPECIALES
MELANOMA MUCOSAS
38
D`Angelo 2016 JCO
AGREGACIÓN DE DATOS DE PACIENTES CON MELANOMA DE MUCOSAS N=136 (86 NIVO, 35 IPI+NIVO, 36 IPI) Ensayos 066, 067, 069, 038, 037
D`Angelo 2016 JCO
6 meses combo PFS vs 3 meses monoterapias 37% ORR para combo vs 23% nivo y 8 ipi%
COMBINACIÓN EN SITUACIONES ESPECIALES
MELANOMA UVEAL
41
MELANOMA UVEAL
42 Piulats ASCO 2017
16% respuestas
CONCLUSIONES • La combinación de ipilimumab y nivolumab es superior en PFS y OS a
ipilimumab
• Pero no es superior (en este momento) en OS a nivolumab – En estudio no diseñado para ello
• Un 5% más probabilidad de OS frente a nivolumab a los dos años; mediana de duración respuesta no alcanzada
• Más del doble de discontinuaciones (39,6 vs 16,1%)
• Falta de tamaño muestral podría compensarse con seguimiento más largo y estudios agregados
– Permitirán análisis de subgrupos para decision de tratamiento
• Mucosas
• BRAF+ y LDH elevada
• LDH elevada
• PD-L1 ?
• Ocular?
• No se puede definir como estándar (si nos acogemos a la RAE), pero es una opción más a considerar, teniendo en cuenta los pros y los contras
MUCHAS GRACIAS
I´ll see you again in 25 years…
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