Terapia adiuvante

MELANOMA Terapia Adiuvante

Riccardo Marconcini

U.O. Oncologia medica 2 Universitaria Ospedale S. Chiara - Pisa

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

3

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. ^a Or until disease recurrence, death, unacceptable toxicity, or withdrawal of consent; ^b Patients were followed for disease recurrence until the first recurrence and thereafter for survival;

c The study will be considered complete and final OS analysis will occur when ≈ 70% of randomized patients have died or are lost to follow-up; ^d New 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 months^a

Follow-up^b until end of study^c

• Primary endpoint: RFS^d

• Secondary endpoints: OS, DMFS, FFR, safety

N = 870

(Presented by Hauschild A. at ESMO 2017)

4

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 1 16 1 10 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) 5

6

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%

a Prespecified 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 = .0006^a

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

11 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)

12

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 (presented at ESMO 2017)

Stage III Stage IV

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

Weber et al (presented at ESMO 2019)

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%

15

CA209-238 - Subgroup Analysis of RFS:

BRAF Mutation Status

Weber et al (presented at ESMO 2019)

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)

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

23

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

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

Setting Metastatico Setting Adiuvante

MALATTIA LOCALE Chirurgia del primitivo +

linfonodi locoregionali

Valutazione di trattamento

adiuvante

MALATTIA METASTATICA

CONCLUSION

 BRAF + MEK i hanno un ruolo definito nel setting adiuvante per i melanomi in stadio III BRAF v600 mutati (Dabrafenib e Trametinib: FDA Breakthrough Therapy designation)

AntiPD1 sono stati studiati con successo nel setting adiuvante –

indipendentemente dallo status di BRAF (Nivolumab studiato nei melanoma in stadio IIIB-C e IV resecato, Pembrolizumab negli stadi III)

Ipilimumab ha mostrato minor efficacia di Nivolumab

IFN oramai limitata indicazione (ancora un ruolo negli stadi pT3b pT4b N0?)

 Setting Neo Adiuvante è una nuova area di ricerca

 Melanoma BRAF mutato in stadio III necessita di fattori predittivi di risposta per scegliere tra

terapie target e immunocheckpoint inibitori

Grazie per l’attenzione

marconcini.riccardo@gmail.com