largos supervivientes con inmunoterapia: melanoma … · o no deaths related to study drug in the...
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Largos supervivientes con Inmunoterapia:
melanoma como prueba de concepto
en metastásico y adyuvancia
Dra. Ainara Soria Rivas
Oncología Médica
Sharma P, et al. Science. 2015;348:56-61.
La inmunoterapia en melanoma metastásico ha conseguido en términos de supervivencia global….
1. Impacta de modo marginal en SG.
2. Sólo ha beneficiado subgrupos específicos de enfermos.
3. Ha conseguido aumentar supervivencia global por encima de los 24 meses.
4. Son tratamientos que precisan su continuidad para mantener el beneficio indefectiblemente.
Estudios antiPD-1 tras progresión a Ipilimumab + iBRAF
CA209-037
Nivolumab
D´Angelo SP.
SMR 2014
KEYNOTE-002
Pembrolizumab
Ribas A.
SMR 2014 N 540
CA209-037
OS in All Treated Patients Censored at Start of Subsequent Anti-
PD-1 Therapy in ICC Group
9
NIVO
ICC
102 94 73 0 48 28 14 11 9 9 5 ICC
Number of Patients at Risk
268 229 207 0 177 157 137 122 112 103 71 NIVO
0
3
0
16
2
44
Time (Months)
OS
(%)
90
80
70
60
50
40
30
20
0
10
3 6 39 9 12 15 18 21 24 27 0 36 33 30
100
39%
29%
NIVO (n = 268) ICC (n = 102)
Events 172 53
Median OS, months (95% CI)
16.4 (12.9, 20.3)
11.8 (9.9, 14.4)
HR (95% CI) 0.81 (0.59, 1.11)
• In this post-hoc analysis, median OS was 4.6 months longer in NIVO vs ICC
Unresectable or Metatastic Melanoma
• Previously untreated
• 945 patients
CA209-067: Study Design CheckMate 067
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)
15
Larkin J. NEJM 2015 Larkin J. ESMO 2017
Robert C. JCO Dec 2017
DFS de enfermos con CR que discontinuaron Pembrolizumab
DFS 24 meses: 89,9%
KEYNOTE 001
Patients Alive at 3 Years – On and Off Treatment
aNIVO arm was from CheckMate 067 study only
CheckMate 069/067:
Pooled 3-Year Analysis
Still on treatment
Off treatment and never received subsequent systemic therapy
Off treatment and received subsequent systemic therapy
32.2% n = 48
41.6% n = 62
26.2% n = 39
NIVOa (n = 149)
13.4% n = 30
69.2% n = 155
17.4% n = 39
NIVO+IPI (n = 224)
8.8% n = 10
31.6% n = 36
59.6% n = 68
IPI (n = 114)
• In the NIVO+IPI arm, median duration of response was not reached with 69% of patients alive and remaining treatment free
Postow M. STIC 2017
La inmunoterapia en melanoma metastásico ha conseguido en términos de supervivencia global….
1. Impacta de modo marginal en SG.
2. Sólo ha beneficiado subgrupos específicos de enfermos.
3. Ha conseguido aumentar supervivencia global por encima de los 24 meses.
4. Son tratamientos que precisan su continuidad para mantener el beneficio indefectiblemente.
La adyuvancia con inmunoterapia en melanoma ….
1. Debe considerarse experimental, dada la inmadurez de sus datos.
2. Ha demostrado reducir en más de un 10% el riesgo de recaída de los enfermos.
3. No ha demostrado aumentar supervivencia global.
4. El interferon alfa debe seguir considerándose un estándar de tratamiento.
SLR SG
Seguimiento 6,9 años
OS 3.82 vs 2.78 y HR = 0.67 (P = .0237)
RFS 0.72 vs 0.98 y HR = 0.61 (P = .0023)
J Clin Oncol. 1996 Jan;14(1):7-17.
287 pacientes Estadios IIB,IIC,III
EORTC 18071/CA184-029: Study Design
•Stratification factors
– Stage (IIIA vs IIIB vs IIIC 1-3 positive lymph nodes vs IIIC ≥4 positive lymph nodes)
– Regions (North America, European countries, and Australia)
•Enrollment Period: June 2008 to July 2011
26
Randomized, double-blind, phase 3 study evaluating the efficacy and safety
of ipilimumab in the adjuvant setting for high-risk melanoma
INDUCTION Ipilimumab 10 mg/kg
Q3W × 4 High-risk, stage
III, completely
resected
melanoma INDUCTION
Placebo
Q3W × 4
R
MAINTENANCE
Ipilimumab 10 mg/kg
Q12W up to 3 years
MAINTENANCE
Placebo
Q12W up to 3 years
Treatment up to a maximum of 3 years, or until disease progression, intolerable
toxicity, or withdrawal
N = 475
N = 476
Week 1 Week 12 Week 24
N = 951
Q3W = every 3 weeks; Q12W = every 12 weeks; R = randomization.
aStratified by stage provided at randomization. CI = confidence interval.
Pat
ien
ts A
live
an
d W
ith
ou
t R
ecu
rren
ce
(%)
Ipilimumab Placebo
Events/patients 264/475 323/476
HR (95% CI)a 0.76 (0.64, 0.89)
Log-rank P valuea 0.0008
Median RFS,
months
(95% CI)
27.6
(19.3, 37.2)
17.1
(13.6, 21.6)
RECURRENCE FREE SURVIVAL (per IRC)
41%
30%
Years 0 1 2 3 4 5 6 7 8
0
10
20
30
40
50
60
70
80
90
100
O N Number of patients at risk 264 475 283 217 184 161 77 13 1
323 476 261 199 154 133 65 17 0
Ipilimumab
Placebo
Pat
ien
ts A
live
(%
)
aStratified by stage provided at randomization.
Ipilimumab Placebo
Deaths/patients 162/475 214/476
HR (95.1% CI)a 0.72 (0.58, 0.88)
Log-rank P valuea 0.001
SUPERVIVIENCIA GLOBAL
65%
54%
Years 0 1 2 3 4 5 6 7 8
0
10
20
30
40
50
60
70
80
90
100
O N Number of patients at risk 162 475 431 369 325 290 199 62 4
214 476 413 348 297 273 178 58 8
Ipilimumab
Placebo
SAFETY SUMMARY
Ipilimumab (n = 471)
Placebo
(n = 474)
Any Grade
Grade 3/4
Any grade
Grade 3/4
Any AE, % 98.7 54.1 91.1 26.2
Treatment-related AE, % 94.1 45.4 59.9 4.0
Treatment-related AE leading to discontinuation, %
48.0 32.9 1.5 0.6
Any immune-related AE, %
90.4 41.6 39.7 2.7
o 5 patients (1.1%) in the ipilimumab group
3 patients with colitis (2 with gastrointestinal perforations)
1 patient with myocarditis
1 patient had multiorgan failure with Guillain-Barré syndrome
o No deaths related to study drug in the placebo group
Adjuvant Therapy With Nivolumab Versus Ipilimumab After
Complete Resection of Stage III/IV Melanoma: A Randomized, Double-blind, Phase 3 Trial (CheckMate 238)
Jeffrey Weber,1 Mario Mandala,2 Michele Del Vecchio,3 Helen Gogas,4 Ana M. Arance,5
C. Lance Cowey,6 Stéphane Dalle,7 Michael Schenker,8 Vanna Chiarion-Sileni,9 Ivan Marquez-Rodas,10
Jean-Jacques Grob,11 Marcus Butler,12 Mark R. Middleton,13 Michele Maio,14 Victoria Atkinson,15
Paola Queirolo,16 Veerle de Pril,17 Anila Qureshi,17 James Larkin,18* Paolo A. Ascierto19*
1NYU Perlmutter Cancer Center, New York, New York, USA; 2Papa Giovanni XIII Hospital, Bergamo, Italy; 3Medical Oncology, National Cancer Institute, Milan, Italy; 4University of Athens, Athens, Greece; 5Hospital Clínic de Barcelona, Barcelona, Spain; 6Texas Oncology-Baylor Cancer Center, Dallas, Texas, USA; 7Hospices
Civils de Lyon, Pierre Bénite, France; 8Oncology Center Sf Nectarie Ltd., Craiova, Romania; 9Oncology Institute of Veneto IRCCS, Padua, Italy; 10General University Hospital Gregorio Marañón, Madrid, Spain; 11Hôpital de la Timone, Marseille, France; 12Princess Margaret Cancer Centre, Toronto, Ontario, Canada;
13Churchill Hospital, Oxford, United Kingdom; 14Center for Immuno-Oncology, University Hospital of Siena, Istituto Toscano Tumori, Siena, Italy; 15Gallipoli Medical Research Foundation and Princess Alexandra Hospital, Woolloongabba, and University of Queensland, Greenslopes, Queensland, Australia; 16IRCCS San Martino-IST, Genova, Italy; 17Bristol-Myers Squibb, Princeton, New Jersey, USA; 18Royal Marsden NHS Foundation Trust, London, UK; 19Istituto Nazionale Tumori
Fondazione Pascale, Naples, Italy; *Contributed equally to this study.
30
CA209-238: Study Design
ESMO 2017
Patients with high-risk, completely resected stage
IIIB/IIIC or stage IV melanoma
•Enrollment period: March 30, 2015 to November 30, 2015
Follow-up
Maximum treatment duration of
1 year
NIVO 3 mg/kg IV Q2W and
IPI placebo IV Q3W for 4 doses
then Q12W from week 24
IPI 10 mg/kg IV Q3W for 4 doses
then Q12W from week 24 and
NIVO placebo IV Q2W
1:1
n = 453
n = 453
Stratified by:
1) Disease stage: IIIB/C vs IV M1a-M1b vs IV M1c
2) PD-L1 status at a 5% cutoff in tumor cells
Primary endpoint: RFS: time from randomization until first recurrence (local, regional, or distant metastasis), new primary melanoma, or death
Secondary endpoints OS, Safety and tolerability, RFS by PD-L1 tumor expression, HRQoL
Current interim analysis: Primary endpoint (RFS), safety, and HRQoL ;DMFS (exploratory)
Duration of follow-up: minimum 18 months; 360 events
Stage IIIB, IIIC, or stage IV melanoma by the American Joint Committee on Cancer 2009 classification, 7th edition Complete regional lymphadenectomy or resection was required within 12 weeks of randomization
Acral or Mucosal Melanomas were allowed
CARACTERÍSTICAS BASALES
• Most of the patients had cutaneous melanoma (85%), and 4% had acral and 3% had mucosal melanoma
• All 905 patients are off treatment; median doses were 24 (1-26) in the NIVO group and 4 (1-7) in the IPI group
• 397 patients completed 1 year of treatment (61% of the NIVO group and 27% of the IPI group)
NIVO (n = 453)
IPI (n = 453)
Median age, years 56 54
Male, % 57 59
Stage, IIIB+IIIC, % 81 81
Macroscopic lymph node involvement (% of stage IIIB+IIIC) 60 58
Ulceration (% of stage IIIB+IIIC) 42 37
Stage IV, % 18 19
M1c without brain metastases (% stage IV) 17 17
PD-L1 expression ≥5%, % 34 34
BRAF mutation, % 41 43
LDH ≤ ULN, % 91 91
ESMO 2017
Primary Endpoint: RFS R
FS (
%)
Months
0
10
20
30
40
50
60
70
80
90
100
0 6 12 18 24 27 3 9 15 21
453 353 311 249 5 0 399 332 291 71 NIVO
453 314 252 184 2 0 364 269 225 56 IPI
Number of patients at risk
NIVO
IPI
NIVO IPI
Events/patients 154/453 206/453
Median (95% CI) NR
NR (16.6, NR)
HR (97.56% CI) 0.65 (0.51, 0.83)
Log-rank P value
<0.0001
66%
53%
71%
61%
ESMO 2017
PD-L1 Expression Level <5% PD-L1 Expression Level ≥5%
NIVO IPI
Events/patients 114/275 143/286
Median (95% CI) NR 15.9 (10.4, NR)
HR (95% CI) 0.71 (0.56, 0.91)
NIVO IPI
Events/patients 31/152 57/154
Median (95% CI) NR NR
HR (95% CI) 0.50 (0.32, 0.78)
Subgroup Analysis of RFS: PD-L1 Expression Level
RFS
(%
)
Months
0
10
20
30
40
50
60
70
80
90
100
0 6 12 18 24 27 3 9 15 21
NIVO
IPI
275 204 171 129 3 0 242 189 159 41 NIVO
286 184 139 100 2 0 219 153 124 31 IPI
Number of patients at risk
RFS
(%
)
Months
152 130 122 105 2 0 135 125 114 26 NIVO
154 120 105 78 0 0 133 108 93 21 IPI
Number of patients at risk
64%
54%
0
10
20
30
40
50
60
70
80
90
100
0 6 12 18 24 27 3 9 15 21
NIVO
IPI
82%
74%
ESMO 2017
Stage III Stage IV
Subgroup Analysis of RFS: Disease Stage
RFS
(%
)
Months
0
10
20
30
40
50
60
70
80
90
100
0 6 12 18 24 27 3 9 15 21
367 290 257 203 3 0 322 272 239 58 NIVO
366 259 208 152 1 0 299 223 186 45 IPI
Number of patients at risk
72%
62%
RFS
(%
)
Months
0
10
20
30
40
50
60
70
80
90
100
0 6 12 18 24 27 3 9 15 21
82 59 51 43 2 0 73 56 49 12 NIVO
87 55 44 32 1 0 65 46 39 11 IPI
Number of patients at risk
63%
58%
NIVO IPI
Events/patients 120/367 163/366
Median (95% CI) NR NR (16.6, NR)
HR (95% CI) 0.65 (0.52, 0.83)
NIVO IPI
Events/patients 33/82 43/87
Median (95% CI) NR (15.9, NR) 16.8 (8.5, NR)
HR (95% CI) 0.70 (0.45, 1.10)
NIVO
IPI
NIVO
IPI
ESMO 2017
BRAF Mutant BRAF Wild type
NIVO IPI
Events/patients 63/187 84/194
Median (95% CI) NR NR (16.1,
NR)
HR (95% CI) 0.72 (0.52, 1.00)
NIVO IPI
Events/patients 67/197 105/214
Median (95% CI)
NR 16.6 (12.3,
NR)
HR (95% CI) 0.58 (0.43, 0.79)
Subgroup Analysis of RFS: BRAF Mutation Status
RFS
(%
)
Months
0
10
20
30
40
50
60
70
80
90
100
0 6 12 18 24 27 3 9 15 21
NIVO
IPI
187 142 126 102 2 0 159 135 118 32 NIVO
194 142 112 78 1 0 155 118 100 26 IPI
Number of patients at risk
RFS
(%
)
Months
0
10
20
30
40
50
60
70
80
90
100
0 6 12 18 24 27 3 9 15 21
197 154 137 108 2 0 175 145 127 26 NIVO
214 140 111 80 1 0 174 122 96 22 IPI
Number of patients at risk
NIVO
IPI
72%
57%
68%
63%
36 ESMO 2017
Exploratory Endpoint: DMFS for Stage III Patients
DM
FS (
%)
Months
0
10
20
30
40
50
60
70
80
90
100
0 6 12 18 24 27 3 9 15 21
369 309 280 214 3 0 335 292 264 62 NIVO
366 284 239 176 1 0 312 254 217 51 IPI
Number of patients at risk
NIVO
IPI
NIVO IPI
Events/patients 93/369 115/366
Median (95% CI) NR NR
HR (95% CI) 0.73 (0.55, 0.95)
Log-rank P value 0.0204
80%
73%
ESMO 2017
Safety Summary
• There were no treatment-related deaths in the NIVO group
• There were 2 (0.4%) treatment-related deaths in the IPI group (marrow aplasia and
colitis), both >100 days after the last dose
AE, n (%)
NIVO (n = 452) IPI (n = 453)
Any grade Grade 3/4 Any grade Grade 3/4
Any AE 438 (97) 115 (25) 446 (98) 250 (55)
Treatment-related AE 385 (85) 65 (14) 434 (96) 208 (46)
Any AE leading to discontinuation
44 (10) 21 (5) 193 (43) 140 (31)
Treatment-related AE leading to discontinuation
35 (8) 16 (4) 189 (42) 136 (30)
ESMO 2017
Treatment-Related Select Adverse Events
AE, n (%)
NIVO (n = 452) IPI (n = 453)
Any grade Grade 3/4 Any grade Grade 3/4
Skin 201 (44.5) 5 (1.1) 271 (59.8) 27 (6.0)
Gastrointestinal 114 (25.2) 9 (2.0) 219 (48.3) 76 (16.8)
Hepatic 41 (9.1) 8 (1.8) 96 (21.2) 49 (10.8)
Pulmonary 6 (1.3) 0 11 (2.4) 4 (0.9)
Renal 6 (1.3) 0 7 (1.5) 0
Hypersensitivity/infusion reaction 11 (2.4) 1 (0.2) 9 (2.0) 0
Endocrine
Adrenal disorder 6 (1.3) 2 (0.4) 13 (2.9) 4 (0.9)
Diabetes 2 (0.4) 1 (0.2) 1 (0.2) 0
Pituitary disorder 8 (1.8) 2 (0.4) 56 (12.4) 13 (2.9)
Thyroid disorder 92 (20.4) 3 (0.7) 57 (12.6) 4 (0.9)
ESMO 2017
NIVOLUMAB + IPILIMUMAB
NIVOLUMAB
Melanomas III-B or III-C or III-D AJCC 8th edition
CHECKMATE-915
Primary endpoint: RFS
La adyuvancia con inmunoterapia en melanoma ….
1. Debe considerarse experimental, dada la inmadurez de sus datos.
2. Ha demostrado reducir en más de un 10% el riesgo de recaída de los enfermos.
3. No ha demostrado aumentar supervivencia global.
4. El interferon alfa debe seguir considerándose un estándar de tratamiento.