avances en el tratamiento del melanoma metastásico. 4.4.pdf · survival curves of 7,635 patients...

Avances en el tratamiento del melanoma metastásico.

José Antonio López Martín Oncología Médica H Universitario 12 de Octubre Madrid. España

2

Melanoma metastásico - 2010 • Incidencia global en ascenso • Edad de inicio menor que otros tumores • Mal pronóstico, opciones limitadas de tratamiento:

– Supervivencia 1 año ~25% / 2 años ~10%1

• No tratamientos aprobados para pacientes previamente tratados

• Ningún estudio aleatorizado ha mostrado incremento en la supervivencia

1Korn EL et al. J Clin Oncol. 2008;26:527-534

Survival curves of 7,635 patients with metastatic melanomas at distant sites (stage IV) subgrouped by (A) the site of metastatic

disease and (B) serum lactose dehydrogenase (LDH) levels.

Balch C M et al. JCO 2009;27:6199-6206 ©2009 by American Society of Clinical Oncology

Moderador

Notas de la presentación

Survival curves of 7,635 patients with metastatic melanomas at distant sites (stage IV) subgrouped by (A) the site of metastatic disease and (B) serum lactose dehydrogenase (LDH) levels. LDH values are not used to stratify patients. Curves in (A) are based only on site of metastasis. The number of patients is shown in parentheses. SQ, subcutaneous.

Hasta 2010…

Interferón alfa-2b

Quimioterapia, IL-2

ADYUV

AVANZ

Efic

Tox

Diapositiva cedida por el Dr. E. Espinosa

Desde 2010…

iBRAF, iMEK

Ipilimumab, anti-PD1

ADYUV

AVANZ

Tox

Efic

Diapositiva cedida por el Dr. E. Espinosa

Subtipos clínico-moleculares de melanoma

Modificado de Curtin JA y cols. NEJM 2005

BRAF inhibitors Vemurafenib Dabrafenib/GSK2118436 LGX818 (encorafenib)

MEK inhibitors Trametinib Cobimetinib Binimetinib Pimasertib AZD6244 TAK, BAY,

ERK inhibitor

mTOR

PI3K

Akt

PI3K inhibitors mTOR inhibitors

PTEN

100 90 80 70 60 50 40 30 20 10 0

Prog

ress

ion-

free

sur

viva

l (%

)

0 6 12 18 24

338 337

63 186

22 77

3 16

0 0

100 269

37 113

14 49

0 3

No. at risk

1.6 6.9

Hazard ratio 0.38 (95% CI: 0.32–0.46)

Log-rank p<0.001 (post-hoc) Dacarbazine

(n=338)

Vemurafenib (n=337)

BRIM-3: Vemurafenib vs DTIC (1st line) PFS (censored at crossover)

Time (months)

Dacarbazine Vemurafenib

Chapman. ASCO 2012

100 90 80 70 60 50 40 30 20 10

0

Ove

rall

surv

ival

(%)

0 6 12 18 24

Vemurafenib (n=337) Median f/u 12.5 months

Dacarbazine (n=338) Median f/u 9.5 months

338 337

173 280

79 178

24 44

0 1

244 326

111 231

50 109

4 7

9.7 13.6

BRIM-3: Vemurafenib vs DTIC (1st line) Overall survival (censored at crossover)

Hazard ratio 0.70 (95% CI: 0.57–0.87) p<0.001 (post-hoc)

Time (months)

Dacarbazine Vemurafenib

No. at risk

Chapman. ASCO 2012

On randomized study treatment at cut-off: dabrafenib 57%, DTIC 27% Median follow-up time: 4.9 months (dabrafenib 5.1 mos, DTIC 4.8 mos.)

Hauschild ASCO 2012

BREAK-3: Dabrafenib vs DTIC PFS Investigator-assessed

Vemurafenib and Dabrafenib show similar efficacy

Dabrafenib in untreated CNS metastases BRAFV600E: Maximal intracranial target lesion reduction

Cohort B

Cohort A

Kirkwood. ASCO 2012

Vemurafenib: Selected adverse events (% of patients)

Vemurafenib, n= 336 Dacarbazine, n= 282

Adverse events All Grade 3 Grade≥ 4 All Grade 3 Grade ≥4

Arthralgia 49 3 - 3 <1 - Rash 36 8 - 1 - - Fatigue 33 2 - 31 2 - Photosensitivity 30 3 - 4 - - ↑LFTs 18 7 <1 5 1 - Cutaneous SCC 12 12 - <1 <1 - Keratoacanthoma 8 6 - - - - Skin papilloma 18 <1 - - - - Nausea 30 1 - 41 2 - Neutropenia <1 - <1 11 5 3

Discontinuations due to AE: 6% Vemurafenib; 4% Dacarbazine

Chapman. ASCO 2012

Dabrafenib: Adverse Events in > 5% patients

Fotosensibilidad: dabrafenib (3%), DTIC (5%)

010203040506070

CR+PR SD PD

Assessment of Tumor Response Rate to vemurafenib: Independent Review Committee

• ORR 53% by IRC • ORR 57% by investigator assessments (INV) • RR, including unconfirmed, 69% (INV) • PR in 4 of 10 BRAFV600K patients

Res

pons

e ra

te (%

)

n=70 n=38 n=18

53% CR+PR

5% CR

29%

14%

Error bars represent 95% confidence intervals

Response and Relapse with vemurafenib 10/02/08 (Pre) 11/26/08 (2+ mo) 02/20/09 (4+ mo)

Pt #43, UCLA

melanoma

stroma

A. Ribas

Mechanisms of Resistance to BRAF Inhibitors

Survival

BRAFV600E

MEK

ERK

P

P

BRAF inh

PDGFRb or IGF1R

PI3K

AKT

Nazarian et al. Nature 2010 Villanueva et al. Cancer Cell 2010

MEK-independent progression

Nazarian et al. Nature 2010

NRASQ61

COT

Johannessen et al. Nature 2010

CRAF

Wagle et al. JCO 2011

MEK-dependent progression

Poulikakos et al. Nature 2012 Shi et al. Nature Com 2012

MEKi

PI3Ki or AKTi

A. Ribas

METRIC: Trametinib vs CT – Overall Survival

BRAFi + MEKi : Enhanced Antitumor Activity with Combination

Mea

n tu

mor

vol

ume

(m

m3 )

+ SE

M

BRAFV600E human melanoma xenograft

2000

1500

1000

500

0

0 1 0 2 0 3 0 4 0 5 0 6 0 7 0 8 0 9 0

Treatment period (days)

A375PF11 Untreated control Trametinib (0.3 mg/kg) Dabrafenib (30 mg/kg) Dabrafenib (300 mg/kg)

Dabrafenib+trametinib (30/0.3 mg/kg)

Weber. ASCO 2012

MEKi Blocks BRAFi-Induced Skin Lesions in Rats

Control BRAFi (150 mg/kg) BRAFi + MEKi (1.5 mg/kg)

BRAFi alone results in thickening & hyperkeratosis

Co-dosing with MEKi attenuates lesion formation

Weber. ASCO 2012

COMBI-d: Progression-free Survival

Presented By Keith Flaherty at 2016 ASCO Annual Meeting

COMBI-d: Overall Survival

Presented By Keith Flaherty at 2016 ASCO Annual Meeting

COMBI-v: Dabrafenib + Trametinib vs Vemurafenib Overal Survival

COMBI-v: Vemurafenib + Cobimetinib vs Vemurafenib Overal Survival

COMBI-v / Co-BRIM: Safety of the combination vs monotherapy

Ras mutated melanoma

Binimetinib vs DTIC (NEMO)

Progression-Free Survival


Progression-Free Survival by Prior Immunotherapy Stratum


GNAQ/GNA11 melanoma

c-KIT activated melanoma

Imatinib in KIT-abnormal melanoma

M1b M1c M1a

-80

-60

-40

-20

0

20

40

60

80

100

120

Guo J et al, ASCO 2010

KIT status (Exon 9:11:13:17:18: amplif) 2:14:8:3:5:3

Correlations of response and KIT aberrations

KIT Status PR SD PR+SD

KIT Amp 1/3 0/3 1/3

Exon11 2/12 8/12 10/12

Exon13 3/8 1/8 4/8

Exon17 0/3 1/3 1/3

Exon18 0/4 2/4 2/4

Multiple gene aberrations* 3/4 1/4 4/4

* 4 patients respectively harbored multiple KIT aberrations as following: (13)K642E+Amplification ; (13) I817T(T2450C); (18)F848L(T2542C) ; (11)L576P+Amplification ;

Guo J et al, ASCO 2010

70%

Paradigmas de tratamiento farmacológico del melanoma avanzado

Diana= sistema inmune

Diana=tumor Inmunoterapia Tratamiento Anti-diana

Cortesía del Dr. Ribas

Melero … Ascierto. Clin Cancer Res 2013

Ipilimumab en melanoma avanzado: Supervivencia en ensayos de Fase 2

O´Day et al. ASCO 2009: 9033

Hodi, NEJM 2010 Robert, NEJM 2011

Supervivencia global

IPILIMUMAB vs vacuna (pretratados) o DTIC (1ª Línea)

41

Eventos adversos relacionados con activación linfocitaria (irAEs)

Moderador


La diapositiva muestra un sarpullido relacionado con la inmunidad de un paciente tratado con ipilimumab

Pooled survival analysis from all phase I-III, including BMS EAP

Nivo CA209-003

Hodi, SMR 2014

Nivolumab CA209-003

52% IPI previo, 17% iBRAF previo Mediana seguimiento 15 m.

Respuestas 33%

Pembro KEYNOTE 001: resultado global

Daud, ASCO 2015, abs 9005

Pembrolizumab KEYNOTE 001

Pembrolizumab (MK-3475)

Hamid NEJM 2013.

Ribas SMR 2014 Ribas A. Lancet Oncol.2015

Pembrolizumab tras Ipilimumab KEYNOTE-002

Respuestas 21-25% frente a 4%

Nivolumab tras Ipilimumab CHEKMATE-037

Weber, Lancet 2015

Nivolumab Resp. 31%

DTIC o Taxol-Carbo Resp. 10%

Nivolumab vs DTIC en 1ª Línea (BRAFwt)

Robert, NEJM 2014

Supervivencia global

Pembrolizumab vs ipilimumab (1ª Línea) KEYNOTE-006

Robert C, N Engl J Med. 2015;372(26):2521-2532. 1. Ficha técnica de KEYTRUDA™ (pembrolizumab). Julio de 2015.

Grupo de tratamiento RRIb

(IC del 95%)

Valor P c

Pembro 10 mg/kg cada 2 semanas

0,63 (0,47, 0,83) 0,00052


0,69 (0,52, 0,90) 0,00358

Ipilimumab — —

Tiempo, meses

100

90

80

70

60

50

40

30

20

10

0

Supe

rviv

enci

a gl

obal

, %

0 2 4 6 8 10 12 14 16 18

Kaplan-Meier OS (población IT)

212 202

279 277 278

266 266 242

248 251 212

233 238 188

219 215 169 157

177 158 117

67 71 51

N.º en riesgo 19 18 17

0 0 0

74% 68%

58%

Fecha de corte de los datos para el análisis: 3 de marzo de 2015.

12

Pembrolizumab vs Ipilimumab KEYNOTE-006: PFS

Grupo de tratamiento RRIc

(IC del 95%)

Valor P d


0,58 (0,46, 0,72) <0,00001


0,58 (0,47, 0,72) <0,00001

Ipilimumab — —

100

90

80

70

60

50

40

30

20

10

0

Supe

rviv

enci

a lib

re d

e pr

ogre

sión,

%

0 2 4 6 8 10 12 14 Tiempo, meses

Fecha de corte de los datos para el análisis:

3 de septiembre de 2014.

Kaplan-Meier PFS (población IT)

279 231 147 98 49 7 2 0 277 235 133 95 53 7 1 1 278 186 88 42 18 2 0 0

N.º en riesgo

47%

46%

27%

6

Robert C, N Engl J Med. 2015;372(26):2521-2532. 1. Ficha técnica de KEYTRUDA™ (pembrolizumab). Julio de 2015.

Nivolumab vs Ipilimumab 1ª Línea CHECKMATE 067

NIVO + IPI (N=314)

NIVO (N=316)

IPI (N=315)

Mediana SLP, meses (95% CI)

11.5 (8.9–16.7)

6.9 (4.3–9.5)

2.9 (2.8–3.4)

HR (99.5% CI) vs. IPI

0.42 (0.31–0.57)*

0.57 (0.43–0.76)*

--

HR (95% CI) vs. NIVO

0.74 (0.60–

0.92)** -- --

No. at Risk 314 NIVO + IPI 173 151 65 11 1 219 0 316 NIVO 147 124 50 9 1 177 0 315 IPI 77 54 24 4 0 137 0

0 6 9 12 15 18 3 21

NIVO NIVO + IPI

IPI

Meses

1.0

0.9

0.8

0.7

0.6

0.5

0.4

0.3

0.2

0.1

0.0

Prop

orti

on a

live

and

prog

ress

ion-

free

Sup. libre progresión

Larkin, NEJM 2015

Talimogene Laherparepvec - T-VEC (Amgen) OncoVex-GMCSF (Biovex)

1 Liu BL, et al. Gene Therapy. 2003;10:292-303.

• Herpes simplex virus type 1 (HSV-1)

• engineered to selectively replicate in tumor cells and to express h-GM-CSF

– ICP34.5 deletion (neurovirulence factor)

– ICP47 deletion

– Insertion of GM-CSF

– Created in JS1 virus strain

ICP34.5

pA hGM-CSF CMV

ICP34.5 ICP47

CMV hGM-CSF pA

Talimogene laherparepvec (JS1/ICP34.5-/ICP47-/hGM-CSF)

HSV: Herpes simplex virus; ICP: Infected cell protein; CMV: Cytomegalovirus promoter

Moderador


Talimogene laherparepvec is an oncolytic herpes simplex virus type 1 (HSV-1) strain engineered to replicate selectively in tumor cells and to express GM-CSF. Talimogene laherparepvec has deletions in HSV genes ICP34.5 and ICP47. In addition, two copies of human GM-CSF gene under the control of the cytomegalovirus (CMV) promoter (for high levels of gene expression) have been inserted into the virus. Talimogene laherparepvec was created in the highly virulent JS1 strain for increased potency compared to cultured viruses that may have lost some of their virulence through repeated propagation in the laboratory. This virus was formally named JS1/34.5-/47-/GM-CSF or OncoVEXGM-CSF 2 Liu Bl, Robinson M, Han Z-Q et al., ICP34.5 deleted herpes simplex virus with enhanced oncolytic, immune stimulating, and anti-tumor properties. Gene Therapy. 2003;10:292-303. Hu JC, Coffin RS, Davis CJ et al.: A Phase I study of OncoVEXGM-CSF, a second-generation oncolytic herpes simplex virus expressing granulocyte macrophage colony-stimulating factor. Clin Cancer Res. 2006; 12(22), 6737–6747

Talimogene Laherparepvec: Oncolytic Immunotherapy Platform

Local Effect: Tumor Cell Lysis

Systemic Effect: Tumor-Specific Immune Response

Selective viral replication in tumor tissue

Tumor cells rupture for an oncolytic effect

Systemic tumor-specific immune response

Death of distant cancer cells

Product is not suitable for systemic administration. This mechanism of action is investigational. 1. Varghese S, et al. Cancer Gene Ther. 2002;9:967-978. 2. Hawkins LK, et al. Lancet Oncol. 2002;3:17-26. 3. Fukuhara H, et al. Curr Cancer Drug Targets. 2007;7:149-155. 4. Sobol PT, et al. . Mol Ther. 2011;19:335-344. 5. Liu BL, et al. Gene Ther. 2003;10:292-303. 6. Melcher A, et al. Mol Ther. 2011;19:1008-1016. 7. Fagoaga OR In: McPherson RA, Pincus MR, eds. Henry’s Clinical Diagnosis and Management by Laboratory Methods, 22nd ed. Philadelphia, PA: Elsevier; 2011:933-953. 8. Dranoff G. Oncogene. 2003;22:3188-3192.

Oncology

Moderador


Selective viral replication in cancer cells A genetically modified virus invades both normal and cancer cells1 Genetic modifications of the virus result in selective replication in tumor tissue; healthy cells remain unharmed2 Tumor cells rupture for an oncolytic effect Viral replication causes tumor cells to lyse, releasing viruses and tumor-specific antigens (TSAs)1,3 The engineered immunomodulatory cytokine GM-CSF is locally expressed2 Progeny virions invade other local tumor cells, repeating the process and resulting in robust tumor lysis4 Systemic tumor-specific immune response The release of TSAs and GM-CSF in the local environment initiates a cascade of events3,5-7 Local inflammation Increased HLA class II expression Enhanced dendritic cell activity, including proliferation, maturation, and migration Death of distant cancer cells GM-CSF stimulates a systemic, T cell-mediated, tumor-specific immune response—providing the basis for its potential as a systemic anticancer therapy2 References: 1. Hawkins LK, Lemoine NR, Kirn D. Oncolytic biotherapy: a novel therapeutic platform. Lancet Oncol. 2002;3:17-26. 2. Fukuhara H, Todo T. Oncolytic herpes simplex virus type 1 and host immune responses. Curr Cancer Drug Targets. 2007;7:149-155. 3. Sobol PT, Boudreau JE, Stephenson K, Wan Y, Lichty BD, Mossman. KL. Adaptive antiviral immunity is a determinant of the therapeutic success of oncolytic virotherapy. Mol Ther. 2011;19:335-344. 4. Liu BL, Robinson M, Han Z-Q, et al. ICP34.5 deleted herpes simplex virus with enhanced oncolytic, immune stimulating, and anti-tumour properties. Gene Ther. 2003;10:292-303. 5.Melcher A, Parato K, Rooney CM, Bell JC. Thunder and lightning: immunotherapy and oncolytic viruses collide. Mol Ther. 2011;19:1008-1016. 6. Fagoaga OR. Human leukocyte antigen: the major histocompatibility complex of man. In: McPherson RA, Pincus MR, eds. Henry’s Clinical Diagnosis and Management by Laboratory Methods, 22nd ed. Philadelphia, PA: Elsevier; 2011:933-953. 8. Dranoff G. GM-CSF-secreting melanoma vaccines. Oncogene. 2003;22:3188-3192.

Baseline Midway through treatment After 4 months of treatment

= Lesion injected

Examples of Responses Seen With Talimogene Laherparepvec

1 Senzer NN, et al. J Clin Oncol. 2009;27:5763-5771.

Moderador


These photographs show example areas of cutaneous response in patient 603 at baseline, 6 weeks (midway through treatment), and after 4 months of treatment. By 4 months, lesions both in the injected and uninjected areas had completely resolved or appeared as flat, pigmented areas. Biopsies taken at 8 months demonstrated that these areas contained no melanoma. Senzer NN, Kaufman HL, Amatruda T, et al. Phase II clinical trial of a granulocyte-macrophage colony-stimulating factor-encoding, second-generation oncolytic herpes virus in patients with unresectable metastatic melanoma. J Clin Oncol. 2009;27:5763-5771.

Midway through treatment After 4 months of treatment

Uninjected area



Moderador


These photographs show additional example areas of cutaneous response in patient 603 at 6 weeks and after 4 months of treatment. By 4 months, lesions in uninjected areas had completely resolved or appeared as flat, pigmented areas. Biopsies taken at 8 months demonstrated that these areas contained no melanoma. Senzer NN, Kaufman HL, Amatruda T, et al. Phase II clinical trial of a granulocyte-macrophage colony-stimulating factor-encoding, second-generation oncolytic herpes virus in patients with unresectable metastatic melanoma. J Clin Oncol. 2009;27:5763-5771.

3 months

6 months

Response in the liver – uninjected



Moderador


These computed tomography images of the liver were taken at 3 months and 6 months for another patient (patient 703). Areas inside the black circles are matched sites of lesions during therapy. By 6 months after injection of cutaneous lesions, the lesions in the liver had resolved. Senzer NN, Kaufman HL, Amatruda T, et al. Phase II clinical trial of a granulocyte-macrophage colony-stimulating factor-encoding, second-generation oncolytic herpes virus in patients with unresectable metastatic melanoma. J Clin Oncol. 2009;27:5763-5771.

Ove

rall

Surv

ival

0%

10%

20%

30%

40%

50%

60%

70%

80%

90%

100%

Months

0 5 10 15 20 25 30 35 40

GM-CSF T-VEC

141 295

101 229

63 154

25 62

3

10

Log Rank: P = 0.07* HR: 0.79 (0.61, 1.02)

45

19.0 (16.0, 24.0) months

23.3 (19.4, 29.7) months

Median (95% CI)

GM-CSF (N = 141)

T-VEC (N = 295)

OPTIM_ TVEC Interim Overall Survival

Interim OS data represent 85% of the required 290 events

Survival T-VEC GM-CSF Difference %

24-month 49.6% 41.3% 8.3

36-month 40.6% 27.8% 12.8

Difference: 4.3 months

*P-value is not significant at the planned nominal 0.0001

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Kaufman HL et al. LBA and oral presentation at SMR 2013 Annual Meeting, November 17 – 20, Philadelphia, PA

Stage IIIB/IIIC/IVM1a disease: HR 0.56; 95% CI: 0.38-0.81 Descriptive Log Rank p = 0.002

Interim OS by Stage at Enrollment Stage IIIB/C

Stage IV M1a

Hazard Ratio = 0.46 (0.26, 0.83) Descriptive Log Rank p=0.008

Median (95% CI)

T-VEC (N=88) NE (NE, NE) mos

GM-CSF (N=43) 24.3 (18.6, NE) mos

Hazard Ratio = 0.67 (0.41, 1.10) Descriptive Log Rank p = 0.11

Median (95% CI)

T-VEC (N=75) 25.8 (18.1, NE) mos

GM-CSF (N=43) 19.0 (13.3, 29.6) mos

88 87 81 75 68 46 25 10 4 0

0 5 10 15 20 25 30 35 40 45

0%

20%

40%

60%

80%

100%

Kapl

an-M

eier

Per

cent

GM-CSF 88 87 81 75 68 46 25 10 4 0

Study Month

Number of Patients at Risk:

75 70 65 54 43 29 17 9 2 0

0 5 10 15 20 25 30 35 40 45 Study Month

0%

20%

40%

60%

80%

100%

75 70 65 54 43 29 17 9 2 0 43 41 32 26 20 13 7 3 1 0 43 41 32 26 20 13 7 3 1 0

Number of Patients at Risk: Kapl

an-M

eier

Per

cent

T-VEC

GM-CSF T-VEC

43 37 33 29 22 14 9 3 0 43 37 33 29 22 14 9 3 0

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Interim OS by Stage at Enrollment Stage IV M1b

Stage IV M1c


Median (95% CI)

T-VEC (N=64) 13.5 (11.8, 19.4) mos

GM-CSF (N=26) 13.2 (6.1, 26.4) mos


Median (95% CI)

T-VEC (N=67) 12.6 (9.1, 17.3) mos

GM-CSF (N=29) 16.2 (10.2, 32.1) mos

0 5 10 15 20 25 30 35 40 45 Study Month

0%

20%

40%

60%

80%

100%

Kapl

an-M

eier

Per

cent

Number of Patients at Risk: 67 57 40 28 23 15 10 5 2 0 67 57 40 28 23 15 10 5 2 0 29 26 21 17 10 8 4 3 1 0 29 26 21 17 10 8 4 3 1 0 GM-CSF

T-VEC

|

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|

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0 5 10 15 20 25 30 35 40 45

0%

20%

40%

60%

80%

100%

Kapl

an-M

eier

Per

cent

Study Month

Number of Patients at Risk: 64 55 43 29 20 15 10 7 2 0 64 55 43 29 20 15 10 7 2 0 26 21 15 12 11 7 5 3 1 0 26 21 15 12 11 7 5 3 0 GM-CSF

T-VEC

|

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Interim OS by Line of Therapy

Second-line or greater

Hazard Ratio = 0.49 (0.33, 0.74) Descriptive Log Rank p < 0.001

Median (95% CI) T-VEC (N=138) NE (24.5, -) mos GM-CSF (N=65) 16.7 (12.8, 21.1) mos


Median (95% CI)

T-VEC (N=157) 17.1 (14.3, 22.5) mos

GM-CSF (N=76) 23.7 (16.2, 32.4) mos

0 5 10 15 20 25 30 35 40

0%

20%

40%

60%

80%

100%

Kapl

an-M

eier

Per

cent

Study Month


0 5 10 15 20 25 30 35 40 Study Month

0%

20%

40%

60%

80%

100%

Kapl

an-M

eier

Per

cent


45

157 139 114 89 69 55 35 26 10 0 157 139 114 89 69 55 35 26 10 0 76 69 57 49 40 29 22 12 3 0 76 69 57 49 40 29 22 12 3 0

13 8 13 0 11 5 9 7 8 5 5 0 2 7 5 0 6 5 5 6 4 4 3 5 2 3 1 3 3 0 GM-CSF

T-VEC

GM-CSF T-VEC

First-line

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Melanoma, volumen mutacional y efecto de ipilimumab

Snyder, NEJM 2014

Melanoma- NRAS e inmunoterapias Best Response to Any Line of Immune Therapy, n (%)

NRAS Mutant (n = 60)

BRAF Mutant (n = 53)

Wild Type (n = 116)

P

Value*

CR/PR 19 (32) 12 (23) 22 (19) .068

SD/ PD 41 (68) 41 (77) 94 (81)

CR/PR/SD 30 (50) 16 (30) 34 (29) .004

PD 30 (50) 37 (70) 82 (71)

Response to First-line Immune Therapy

CR/PR 17 (28) 8 (15) 19 (16) .037

SD/PD 43 (72) 45 (85) 97 (84)

CR/PR/SD 27 (45) 13 (25) 31 (27) .006

PD 33 (55%) 40 (75) 85 (73)

Johnson DB, et al. Cancer Immunol Res. 2015;3:288-295. *Pearson χ2 test P value for NRAS-mutant vs non-NRAS-mutant pts.

Expresión intratumoral de PD-L1 y respuesta a anti-PD1/PD-L1

Mahoney KM, et al. Oncology. 2014;28:39-48.

Setting Treatment Objective Response Rate, %

Assay (mAb) Unselected PD-L1+ PD-L1–

Solid tumors (n = 42) Nivo 21 36 0 Tumor (5H1)

Melanoma (n = 44) Nivo 32 67 19 Tumor (28-8)

Tumor (28-8) Melanoma (n = 34) Nivo 29 44 17 Melanoma (n = 113) Pembro 40 49 13 Tumor (22C3) NSCLC (n = 129) Pembro 19 37 11 Tumor (22C3) HNSCC (n = 55) Pembro 18 46 11 Tumor (22C3) Melanoma (n = 411) Pembro 40 49 13 Tumor (22C3) Solid tumors (n = 94) MPDL 21 36 13 TIL Melanoma (n = 30) MPDL 29 27 20 TIL NSCLC (n = 53) MPDL 23 46 15 TIL Bladder (n = 65) MPDL 26 43 11 TIL Solid tumors (n = 179) MEDI 11 22 4 NR (SP263)

Moderador


PD-L1, programmed death ligand 1; PD-1, programmed death 1; NSCLC, non-small cell lung cancer; HNSCC, head and neck squamous cell carcinoma.

Melanoma - PD-L1 tumoral y nivolumab

100

90

80

70

60

0

50

40

30

20

10

0 3 6 9 12 15 18 Meses

Nivolumab PD-L1+

Dacarbacina PD-L1+

Nivolumab PD-L1- (<5%)

Dacarbacina PD-L1-

Dacarbacina PD-L1-

Nivolumab PD-L1-

Dacarbacina PD-L1+

Nivolumab PD-L1+

74 128 74

126

69 108 64

107

56 88 44 78

39 63 30 52

18 26 11 11

1 7 1 2

0 0 0 0

%SG 1 año (95% CI)

82 (69–89)

67 (58–75)

52 (37–65)

37 (26–48)

Mediana SG (95% CI)

Nivolumab PD-L1+ NA

Nivolumab PD-L1- NA

Dacarbacina PD-L1+ 12,4 (9,2–NA)

Dacarbacina PD-L1- 10,2 (7,6–11,8)

Modificado de Long, SMR 2014

Gajewski, Curr Opin Immun 2011

Infiltrado celular inmuno-inflamatorio del tumor

FENOTIPO NO INFLAMADO: Alta expresión de marcadores vasculares, macrófagos, fibroblastos + Escasa inflamacion, quimioquinas y linfocitos = Escaso tráfico celular inmune

FENOTIPO INFLAMADO: Alta densidad de señales de inmunidad natural, quimioquinas para reclutamiento de células T, células T activadas específicas de tumor Pero dominan los reguladores negativos

Melanoma - Supervivencia (PFS, OS) con pembrolizumab, según score de firma

génica de IFN-γ

A Ribas. ASCO 2015

MM ALGORITHM 2016 ? (be aware that this may change shortly…)

METASTATIC MELANOMA

BRAF wild type

BRAF mutated

NIVOLUMAB PEMBROLIZUMAB

iBRAF+iMEK INMUNOTHERAPY 2L

???????

1st LINE THERAPY 2nd LINE THERAPY

iBRAF+iMEK iBRAFor iMEK

vs

NIVOLUMAB PEMBROLIZUMAB

avances en el tratamiento del melanoma metastásico. 4.4.pdf · survival curves of 7,635 patients...

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