SUPERNOVAE IN ONCOLOGIA V Edizione
Algoritmo terapeutico nel melanoma
Riccardo Marconcini
U.O. Oncologia Medica 2 Universitaria Azienda Ospedaliero Universitaria Pisana
PISA, 20 Settembre 2019
Ricerca Linfonodo Sentinella
Linfadenectomia
Linfadenectomia
IMMUNOTHERAPY (Checkpoints inhibitors)
TARGETED THERAPIES
Metastatic Setting Adjuvant Setting
LOCAL DISEASE
Surgery of primary melanoma + Lymphonodes
Evaluation of adjuvant treatment
METASTATIC DISEASE
Melanoma:
Area di RIcerca
Drugs used in metastatic setting have been experimented in the adjuvant setting
Riassumendo in meno di 15 minuti…
… tutti i nuovi studi nel setting adiuvante:
Utilizzavano AJCC 7° edizione
(entrata in uso l’8°)
Prevedevano la linfadenectomia
(MSLTII ne ridimensiona l’uso)
Riassumendo… pT3bT4 N0
➢ lo stadio IIC ha un rischio di ricaduta > IIIA
➢ ma non ci sono attualmente dati per terapia adiuvante
➢ l’unico studio che includeva Stadio II era BRIM 8 (vemurafenib) risultato negativo
➢ studio in corso con Pembrolizumab vs Placebo in stadi IIB IIC
➢IFN può ancora avere un ruolo nei casi con primitivo ulcerato
Interferon α – Meta Analysis 2017
Analisi di sottogruppo per Relapse Free Survival
Ives NJ et al, EJC 2017
Riassumendo… STADIO IIIA
➢ Gli studi hanno incluso soltanto stadi IIIA con coinvolgimento linfonodale metastatico >1 mm
In particolare gli studi che hanno coinvolto lo stadio IIIA sono:
- COMBI AD (Dabrafenib+Trametinib vs placebo) disponibile attualmente in eap- studi clinici
- Keynote-054 Pembrolizumab vs placebo - attualmente non disponibile in Italia
➢ Lo studio Checkmate 238 non includeva gli stadi IIIA e
l’evidenza dell’uso di Nivolumab in questo stadio è quindi più
limitata
10
COMBI-AD: RFS by Subgroup
è opportuno trattare gli stadi IIIA (7 th edition)?
Macrometastasis and no ulceration (n = 201) Micrometastasis and no ulceration (n = 165)
0.01 0.10 1.00
0.51 0.37
0.52 0.51 0.33
0.43 0.49 0.43
0.44
10.00 HR
Favors Dabrafenib Plus Trametinib Favors Placebo
V600K (n = 78) V600E (n = 792) Male (n = 482) Female (n = 388)
< 65 years (n = 712)
≥ 65 years (n = 158) Disease stage IIIA (n = 154) Disease stage IIIB (n = 356) Disease stage IIIC (n = 347) Micrometastasis (n = 309) Macrometastasis (n = 319)
Macrometastasis and ulceration (n = 116) Micrometastasis and ulceration (n = 143)
1 Nodal metastatic mass (n = 360) 2–3 Nodal metastatic masses (n = 308)
≥4 Nodal metastatic masses (n = 145)
0.45 0.50 0.44 0.38
0.51 0.55 0.43
0.48 0.54
GV Long et al NEJM 2017 (presented by Hauschild at ESMO 2017)
Riassumendo… STADIO > IIIB
➢ BRAF wt: Nivolumab adj per 1 anno (Checkmate 238)
➢ BRAF v600 mutato:
Ad oggi il beneficio è evidente sia per Terapie Target che Immunoterapia (disponibili tramite eap
DabrafenibTrametinib – e Nivolumab fino 30.6.19)
Il dibattito su quale trattamento preferire è aperto
Valutare nel singolo paziente
vantaggi/svantaggi in relazione a : -Comorbidità
- posologia/schedula
N.B. Con D+T, studio con popolazione dedicate e con maggior followup.
N.B. Attenzione alle tossicità rare e permanenti da Imunotp
12
BID, twice daily; DMFS, distant metastasis–free survival; ECOG, Eastern Cooperative Oncology Group; FFR, freedom from relapse; OS, overall survival; QD, once daily; RFS, relapse-free survival. aOr until disease recurrence, death, unacceptable toxicity, or withdrawal of consent; bPatients were followed for disease recurrence until the first recurrence and thereafter for survival;
cThe study will be considered complete and final OS analysis will occur when ≈ 70% of randomized patients have died or are lost to follow-up; dNew primary melanoma considered as an event.
Combi-AD: Study design
Key eligibility criteria
• Completely resected, high-risk stage IIIA (lymph node metastasis > 1 mm), IIIB, or IIIC cutaneous melanoma
• BRAF V600E/K mutation
• Surgically free of disease ≤ 12 weeks before randomization
• ECOG performance status 0 or 1
• No prior radiotherapy or systemic therapy
R A N D O M I Z A T I O N
Stratification
• BRAF mutation status (V600E, V600K)
• Disease stage (IIIA, IIIB, IIIC)
1:1
Dabrafenib 150 mg BID + trametinib 2 mg
QD (n = 438)
2 matched placebos (n = 432)
Treatment: 12 monthsa
Follow-upb until end of studyc
• Primary endpoint: RFSd
• Secondary endpoints: OS, DMFS, FFR, safety
N = 870
(Presented by Hauschild A. at ESMO 2017)
13
COMBI-AD:
Relapse-free survival (primary endpoint)
438 413 405 392 382 373 355 336 325 299 282 276 263 257 233 202 194 147 116 110 66 52 42 19 7 2 0 432 387 322 280 263 243 219 203 198 185 178 175 168 166 158 141 138 106 87 86 50 33 30 9 3 0 0
Months From Randomization
Dabrafenib plus trametinib Placebo
No. at Risk
0 0.0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1.0
2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 32 34 36 38 40 42 44 46 48 50 52
Proportion Alive and Relapse Free
1 y, 88%
2 y, 67%
3 y, 58%
1 y, 56%
2 y, 44%
3 y, 39%
NR, not reached.
Group
Events, n (%)
Median (95% CI), mo
HR (95% CI) Dabrafenib plus
trametinib 166 (38) NR
(44.5-NR) 0.47 (0.39-0.58);
P < .001
Placebo 248 (57) 16.6
(12.7-22.1)
P = .0000000000000153
GV Long et al NEJM 2017 (presented by Hauschild at ESMO 2017)
COMBI-AD:
Distant metastasis–free survival
438 413 407 390 381 373 353 336 327 302 285 278 265 258 235 203 195 146 116 110 66 52 42 19 7 2 0 432 392 330 282 265 247 221 206 201 187 179 176 169 168 159 144 140 107 88 87 51 33 30 9 3 0 0
Proportion Alive and Distant Metastasis Free
1 y, 91%
2 y, 77%
3 y, 71%
1 y, 70%
2 y, 60%
3 y, 57%
0.0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1.0
0 2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 32 34 36 38 40 42 44 46 48 50 52 Months From Randomization
Dabrafenib plus trametinib Placebo
No. at Risk
Group
Events, n (%)
Median (95% CI), mo
HR (95% CI) Dabrafenib
plus trametinib
110 (25) NR
(NR-NR) 0.51 (0.40-0.65);
nominal P < .001
Placebo 152 (35) NR
(41.2-NR)
GV Long et al NEJM 2017 (presented by Hauschild at ESMO 2017)14
15
COMBI-AD:
Overall survival (first interim analysis)
438 426 416 414 408 401 395 387 381 376 370 366 362 352 328 301 291 233 180 164 105 82 67 28 12 5 0 432 425 415 410 401 386 378 362 346 337 328 323 308 303 284 269 252 202 164 152 94 64 51 17 7 1 0
0 0 0
0.0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1.0
2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 32 34 36 38 40 42 44 46 48 50 52 54
Proportion Alive
1 y, 97%
2 y, 91%
3 y, 86%
1 y, 94%
2 y, 83%
3 y, 77%
aPrespecified significance boundary (P = .000019).
Months From Randomization
Group
Events, n (%)
Median (95% CI), mo
HR (95% CI) Dabrafenib plus
trametinib 60 (14) NR
(NR-NR) 0.57
(0.42-0.79);
P = .0006a
Placebo 93 (22) NR
(NR-NR)
Dabrafenib plus trametinib Placebo
No. at Risk
GV Long et al NEJM 2017 (presented by Hauschild at ESMO 2017)
Presented By Janice Mehnert at 2019 ASCO Annual Meeting
Ad un più lungo Followup si conferma RFS
NEW NEWS ASCO 2019
PEMBROLIZUMAB IN THE ADJUVANT SETTING
EORTC 1325/KEYNOTE-054 : Study Design
Eggermont et al.. (presented at AACR 2018)
KEYNOTE-054: RFS (PRIMARY END POINT)
Eggermont A.M.M., et al., N Engl J Med. 2018 Apr 15. doi: 10.1056 (presented at AACR 2018)
KEYNOTE-054 ADVERSE EVENTS
CA209-067: Study Design
Nivolumab in the adjuvant setting CA209-238: Study Design
20
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
Weber et al NEJM 2017 (presented at ESMO 2017)
•
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)21
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
CA209-238: Baseline Patients Characteristics
Weber et al NEJM 2017 (presented at ESMO 2017)
Primary Endpoint: RFS
RFS (%)
Months
0 10 20 30 40 50 60 70 80 90 100
0 3 6 9 12 15 18 21 24 27
453 399 353 332 311 291 249 71 5 0
NIVO
453 364 314 269 252 225 184 56 2 0
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%
CA209-238: RFS (primary endpoint)
Weber et al NEJM 2017 (presented at 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)
RFS (%)
Months 0
10 20 30 40 50 60 70 80 90 100
0 3 6 9 12 15 18 21 24 27
NIVO IPI
275 242 204 189 171 159 129 41 3 0
NIVO
286 219 184 153 139 124 100 31 2 0
IPI
Number of patients at risk
RFS (%)
Months
152 135 130 125 122 114 105 26 2 0
NIVO
154 133 120 108 105 93 78 21 0 0
IPI
Number of patients at risk
9 64%
54%
0 10 20 30 40 50 60 70 80 90 100
0 3 6 9 12 15 18 21 24 27
NIVO IPI
82%
74%
CA209-238 - Subgroup Analysis of RFS:
PD-L1 Expression Level
Weber et al NEJM 2017 (presented at ESMO 2017)
Stage III Stage IV
10
RFS (%)
Months 0
10 20 30 40 50 60 70 80 90 100
0 3 6 9 12 15 18 21 24 27
367 322 290 272 257 239 203 58 3 0
NIVO
366 299 259 223 208 186 152 45 1 0
IPI
Number of patients at risk
72%
62%
RFS (%)
Months 0
10 20 30 40 50 60 70 80 90 100
0 3 6 9 12 15 18 21 24 27
82 73 59 56 51 49 43 12 2 0
NIVO
87 65 55 46 44 39 32 11 1 0
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
CA209-238 - Subgroup Analysis of RFS:
Disease Stage
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)
RFS (%)
Months 0
10 20 30 40 50 60 70 80 90 100
0 3 6 9 12 15 18 21 24 27
NIVO IPI
187 159 142 135 126 118 102 32 2 0
NIVO
194 155 142 118 112 100 78 26 1 0
IPI
Number of patients at risk
RFS (%)
Months 0
10 20 30 40 50 60 70 80 90 100
0 3 6 9 12 15 18 21 24 27
197 175 154 145 137 127 108 26 2 0
NIVO
214 174 140 122 111 96 80 22 1 0
IPI
Number of patients at risk NIVO IPI
72%
57%
68%
63%
25
CA209-238 - Subgroup Analysis of RFS:
BRAF Mutation Status
Weber et al NEJM 2017 (presented at ESMO 2017)
Riassumendo… STADIO IV resecato
Stage IV
10
RFS (%)
Months 0
10 20 30 40 50 60 70 80 90 100
0 3 6 9 12 15 18 21 24 27
82 73 59 56 51 49 43 12 2 0
NIVO
87 65 55 46 44 39 32 11 1 0
IPI
Number of patients at risk
63%
58%
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
Solo lo studio Checkmate 238 includeva pazienti con metastasi radicalmete asportate
Nivolumab disponibile in eap solo fino al 30.6.19
IMMUNOTHERAPY (Checkpoints inhibitors)
TARGETED THERAPIES
Metastatic Setting Adjuvant Setting
LOCAL DISEASE
Surgery of primary melanoma + Lymphonodes
Evaluation of adjuvant treatment
METASTATIC DISEASE
Melanoma Patient Hystory:
Research Areas
Drugs used in metastatic setting have been experimented in the adjuvant setting
NEOADIUVANTE
NEOADIUVANTE: pooled analysis ASCO 2019
NEOADIUVANTE: pooled analysis ASCO 2019
NEOADIUVANTE: pooled analysis ASCO 2019
PFS OS
1°
linea
>2°
linea
survival curves in the modern era
• Landscape depends on local reimbursement and other regional access restrictions
• For practical considerations it does not capture patients with brain metastasis
• Third line with ipilimumab following a-PD-1 mono could be considered
Ipilimumab BRAFi MEKi
BRAFi MEKi 1stline of
treatment
2ndline of treatment
Ipilimumab
Clin. Trial Ipi/Chemo
BRAFi MEKi
PD
PD PD
Ipilimumab
Chemo BSC
PD PD
BRAF mutated
Assessment of BRAFmt status
Disease evaluation
BRAF wild type
Clinically stable
Clinical deterioration
Clinically stable
Clinical deterioration
Ipilimumab Ipilimumab a-PD-1
a-PD-1 mono a-PD-1 mono mono
a-PD-1 mono
a-PD-1 mono
Promotion of non-authorised molecules cannot begin before regulatory approval or any local specific decision.
Advanced Melanoma Expected Algorithm: Post
anti-PD-1 Mono Authorisation (EUROPE)
Metastatic Melanoma Available Treatment
Immuno terapia
Terapia
Target
Dabrafenib+trametinib phase 3 trials
Normal LDH and < 3 Disease Sites identify the subgroup with best prognosis
Combi-v, Robert, ESMO 2016
(2) Quale sottogruppo ha avuto maggiore beneficio?
Presented by: Jeffrey Weber
0
0 6 12 18 24 30 36 42 48 54 60 66
20 40 60 80 100
0
19 16 12 10 9 8 8 5 3 3 3 0
12 9 0 0 0 0 0 0 0 0 0 0 12 12 12 12 9 8 7 7 5 3 3 1 0
19 19 18 15 15 14 14 13 10 9 9 3 0 20
40 60 80 100
Time From Randomization, months Time From Randomization, months
0 6 12 18 24 30 36 42 48 54 60 66 72
Progression-Free Survival, % Overall Survival, %
Progression-Free Survival Overall Survival
Patients at risk, n Patients at risk, n
25% 25%
8% 8%
57%
42%
51%
31%
74%
58%
47%
8%
Long Followup phase II PFS - OS
In LDH ≤ ULN and < 3 Metastatic Sites (ITT)
COMBI-v: Best Response
Best Confirmed Response
Dabrafenib + Trametinib (n = 352)
Vemurafenib (n = 352)a Overall response rate, n (%)
[95% CI]
236 (67) [62-72]
187 (53) [48-58]
Complete response (CR), n (%) 68 (19) 41 (12)
Partial response (PR), n (%) 168 (48) 146 (41)
Stable disease (SD), n (%) 83 (24) 109 (31)
Progressive disease, n (%) 22 (6) 37 (11)
Not evaluable, n (%) 11 (3) 18 (5)
aOne patient in the vemurafenib arm did not have a measurable target lesion at baseline.
Response rate
ALGORITMO: QUALE PRIMA LINEA?
TT TT
• Landscape depends on local reimbursement and other regional access restrictions
• For practical considerations it does not capture patients with brain metastasis
• Third line with ipilimumab following a-PD-1 mono could be considered
Ipilimumab BRAFi MEKi
BRAFi MEKi 1stline of
treatment
2ndline of treatment
Ipilimumab
Clin. Trial Ipi/Chemo
BRAFi MEKi
PD
PD PD
Ipilimumab
Chemo BSC
PD PD
BRAF mutated
Assessment of BRAFmt status
Disease evaluation
BRAF wild type
Clinically stable
Clinical deterioration
Clinically stable
Clinical deterioration
Ipilimumab Ipilimumab a-PD-1
a-PD-1 mono a-PD-1 mono mono
a-PD-1 mono
a-PD-1 mono
Promotion of non-authorised molecules cannot begin before regulatory approval or any local specific decision.
Advanced Melanoma Expected Algorithm: Post
anti-PD-1 Mono Authorisation (EUROPE)
N-esima linea di trattamento …
N-esima linea di trattamento …
Figure 1
The Lancet Oncology 2017 18, 464-472DOI: (10.1016/S1470-2045(17)30171-7) Copyright © 2017 Elsevier LtdTerms and Conditions