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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

(2)

Ricerca Linfonodo Sentinella

(3)

Linfadenectomia

(4)

Linfadenectomia

(5)

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

(6)

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)

(7)

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

(8)

Interferon α – Meta Analysis 2017

Analisi di sottogruppo per Relapse Free Survival

Ives NJ et al, EJC 2017

(9)

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)

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)

(11)

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)

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)

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)

(14)

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)

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)

(16)

Presented By Janice Mehnert at 2019 ASCO Annual Meeting

Ad un più lungo Followup si conferma RFS

NEW NEWS ASCO 2019

(17)

PEMBROLIZUMAB IN THE ADJUVANT SETTING

EORTC 1325/KEYNOTE-054 : Study Design

Eggermont et al.. (presented at AACR 2018)

(18)

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)

(19)

KEYNOTE-054 ADVERSE EVENTS

(20)

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)

(21)

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)

(22)

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)

(23)

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)

(24)

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

(25)

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)

(26)

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

(27)

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

(28)

NEOADIUVANTE

(29)

NEOADIUVANTE: pooled analysis ASCO 2019

(30)

NEOADIUVANTE: pooled analysis ASCO 2019

(31)

NEOADIUVANTE: pooled analysis ASCO 2019

(32)

PFS OS

linea

>2°

linea

survival curves in the modern era

(33)

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)

(34)

Metastatic Melanoma Available Treatment

Immuno terapia

Terapia

Target

(35)

Dabrafenib+trametinib phase 3 trials

(36)

Normal LDH and < 3 Disease Sites identify the subgroup with best prognosis

Combi-v, Robert, ESMO 2016

(2) Quale sottogruppo ha avuto maggiore beneficio?

(37)

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)

(38)

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

(39)

ALGORITMO: QUALE PRIMA LINEA?

TT TT

(40)

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)

(41)

N-esima linea di trattamento …

(42)

N-esima linea di trattamento …

(43)

Figure 1

The Lancet Oncology 2017 18, 464-472DOI: (10.1016/S1470-2045(17)30171-7) Copyright © 2017 Elsevier LtdTerms and Conditions

N-esima linea di trattamento …

(44)

Grazie per l’attenzione

marconcini.riccardo@gmail.com

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