TRATAMIENTO DE COMBINACIÓN: ¿EL NUEVO ESTÁNDAR?

Dr. Iván Márquez Rodas

Hospital General Universitario Gregorio Marañón

23-6-2017

COI • Honorarios, asesoría: BMS, NOVARTIS, GSK,

AMGEN, MSD, MERCK, ROCHE, PIERRE FABRE, INCYTE, BIONCOTECH

• Participación en ensayos 067, 511, 742 y 915 con el regimen de combinación ipilimumab+nivolumab

RESUMEN

• Inicios y racional de la combinación: Fase I

• CA209-067: resultados comunicados en AACR 2017

• ¿Algún subgrupo? – PD-L1, LDH, BRAF

• Subpoblaciones especiales – Melanoma de mucosas

– Melanoma ocular

– Metástasis cerebrales

RACIONAL PRECLINICO

Ribas 2012 NEJM Curran et al. Proc Natl Acad Sci USA 2010 Chiste de Nacho Melero, ASCO 2013

Cinturón y tirantes…*

FASE I

¿Es necesario un fase III? *

Wolchok NEJM 2013 * Pregunta de la audiencia, ASCO 2013

21/52 respuestas (42%) 16/21 respuestas mayores de 80% (76%) 5/21 respuestas completes (24%) 53% efectos secundarios grado 3-4 21% discontinuaciones

# 1: Overall Survival Data not Seen Before in Melanoma (3 Year Rates From Phase I Clinical Trial)

Cohorts 1–3

Cohort 8

All concurrent cohorts

63 60 57 54 51 48 45 42 39 36 33 30 27 24 21 18 15 12 9 6 3 0

0.0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1.0

Months

Pro

bab

ility

of

Surv

ival

0 1 1 2 4 4 5 10 14 21 26 35 39 41 41 41 42 45 47 49 52 53 Cohorts 1–3

0 0 0 0 0 0 0 0 0 0 0 0 0 0 17 25 28 30 32 35 40 41 Cohort 8

21 26 35 39 41 58 66 70 75 79 84 92 94 All concurrent cohorts 0 1 1 2 4 4 5 10 14

Number of patients at risk

Died/treated, n/N

Median OSa, mo (95% CI)

Cohorts 1–3 18/53 NR (39.8–NR)

Cohort 8 14/41 NR (20.0–NR)

All concurrent cohorts 32/94 43.9 (39.8–NR)

Cohorts 1–3: 85%

Cohorts 1–3: 68%

Sznol 2015 Melanoma Bridge

Larkin 2015 NEJM

FASE III

• Objetivo co-primario: SLP • Superior a ipilimumab y (de forma exploratoria) a

nivolumab – Tasas de respuesta – SLP – Toxicidad

• Por tanto, los datos de supervivencia global son fundamentales

Overall Survival Results From a Phase III Trial of Nivolumab Combined With Ipilimumab in

Treatment-naïve Patients With Advanced Melanoma (CheckMate 067)

James Larkin,1 Vanna Chiarion-Sileni,2 Rene Gonzalez,3 Piotr Rutkowski,4 Jean-Jacques Grob,5

C. Lance Cowey,6 Christopher D. Lao,7 Dirk Schadendorf,8 Pier Francesco Ferrucci,9 Michael Smylie,10

Reinhard Dummer,11 Andrew Hill,12 John Haanen,13 Michele Maio,14 Grant McArthur,15 Dana Walker,16

Linda Rollin,16 Christine Horak,16 F. Stephen Hodi,17,* Jedd D. Wolchok18,*

1Royal Marsden Hospital, London, UK; 2Oncology Institute of Veneto IRCCS, Padua, Italy; 3University of Colorado Cancer Center, Denver, CO,

USA; 4Maria Sklodowska-Curie Memorial Cancer Center & Institute of Oncology, Warsaw, Poland; 5Hospital de la Timone, Marseille, France; 6Texas Oncology-Baylor Charles A. Sammons Cancer Center, Dallas, TX, USA; 7University of Michigan, Ann Arbor, MI, USA; 8Department of

Dermatology, University of Essen, Essen, Germany; 9European Institute of Oncology, Milan, Italy; 10Cross Cancer Institute, Alberta, Canada; 11Universitäts Spital, Zurich, Switzerland; 12Tasman Oncology Research, QLD, Australia; 13Netherlands Cancer Institute, Amsterdam, The

Netherlands; 14University Hospital of Siena, Siena, Italy; 15Peter MacCallum Cancer Centre, Victoria, Australia; 16Bristol-Myers Squibb,

Princeton, NJ, USA; 17Dana-Farber Cancer Institute, Boston, MA, USA; 18Memorial Sloan-Kettering Cancer Center and Weill Cornell Medical College, New York, NY, USA; *Contributed equally to this study.

Abstract Number CT075

Larkin AACR 2017

Unresectable or

Metatastic Melanoma

• Previously untreated

• 945 patients

CA209-067: Study Design CheckMate 067: Study Design

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)

10

¿Cuántos hubiesen sido necesarios para alcanzar ese poder estadístico?

Larkin AACR 2017

Study Endpoints: NIVO+IPI or NIVO vs IPI

• Co-primary endpoints:

– PFS and OS (intent-to-treat population)

• Secondary and exploratory endpoints:

– ORR by RECIST v1.1

– Efficacy by tumor PD-L1 expression level

– Safety profile (in patients who received ≥1 dose of study drug)

• Current analysis:

– Per protocol, a total of 644 deaths were projected to occur at 28 months (99% power to detect a HR of 0.65 for each NIVO-containing arm vs IPI)

• However, the actual number of deaths was 28% lower than anticipated (95% power to detect a HR of 0.65 vs IPI)

– The study was not powered for a comparison between NIVO+IPI and NIVO

11 Larkin AACR 2017

NIVO+IPI (N=314)

NIVO (N=316)

IPI (N=315)

ORR, % (95% CI)* 58.9 (53.3–64.4) 44.6 (39.1–50.3) 19.0 (14.9–23.8)

Best overall response — %

Complete response 17.2 14.9 4.4

Partial response 41.7 29.7 14.6

Stable disease 11.5 9.8 21.3

Progressive disease 23.6 38.6 51.1

Unknown 6.1 7.0 8.6

Median duration of response, months (95% CI)

NR (NR–NR) 31.1 (31.1–NR) 18.2 (8.3–NR)

Updated Response To Treatment

*By RECIST v1.1; NR = not reached.

• At the 18-month DBL, the CR rate for NIVO+IPI, NIVO and IPI was 12.1%, 9.8% and 2.2%, respectively

12

Database lock: Sept 13, 2016, minimum f/u of 28 months

Larkin AACR 2017

Updated Progression-Free Survival

50%

43%

18%

43%

37%

12%

Perc

en

tag

e o

f P

FS

Months

0

10

20

30

40

50

60

70

80

90

100

0 3 6 9 12 15 18 36 30 24 33 27 21

0 IPI

NIVO+IPI (N=314) NIVO (N=316) IPI (N=315)

Median PFS, mo (95% CI) 11.7

(8.9–21.9) 6.9

(4.3–9.5) 2.9

(2.8–3.2)

HR (95% CI) vs. IPI 0.42

(0.34–0.51) 0.54

(0.45–0.66) --

HR (95% CI) vs. NIVO 0.76

(0.62–0.94) -- --

Pro

gre

ss

ion

-fre

e S

urv

iva

l (%

)

5 16 27 30 33 35 43 46 58 77 136 315

Patients at risk:

0 NIVO 16 62 88 97 103 107 112 120 132 151 178 316

0 NIVO+ IPI 16 71 104 110 118 125 132 137 156 176 218 314

NIVO+IPI

NIVO

IPI

8 Database lock: Sept 13, 2016, minimum f/u of 28 months

Larkin AACR 2017

Overall Survival

Months Patients at risk:

73%

74%

67%

64%

59%

45%

Pe

rce

nta

ge

of

PF

S

0

10

20

30

40

50

60

70

80

90

100

0 3 6 9 12 15 18 39 30 24 33 27 21

Ove

rall S

urv

iva

l (%

)

36

0 IPI 34 104 129 136 149 164 182 205 228 254 285 315 4

0 NIVO 55 157 175 181 191 201 213 230 244 265 292 316 3

0 NIVO+IPI 49 170 192 198 200 209 221 226 247 265 292 314 7

*P<0.0001

NIVO+IPI (N=314) NIVO (N=316) IPI (N=315)

Median OS, mo (95% CI) NR NR

(29.1–NR) 20.0

(17.1–24.6)

HR (98% CI) vs. IPI 0.55

(0.42–0.72)* 0.63

(0.48–0.81)* --

HR (95% CI) vs. NIVO 0.88

(0.69–1.12) -- --

NIVO+IPI

NIVO

IPI

14

Database lock: Sept 13, 2016, minimum f/u of 28 months

Igualdad de beneficio al año, 5% más de beneficio a los 2 años, pendientes de 3 años… Larkin AACR 2017

¿QUÉ PASARÁ A LOS TRES AÑOS?

18

12

43

37

50

43

0

10

20

30

40

50

60

70

80

1 AÑO 2 AÑOS

SLP

ipilimumab nivolumab ipi+nivo

15

67

45

74

59

73

64

0

10

20

30

40

50

60

70

80

1 AÑO 2 AÑOS

SG

ipi SG nivo SG ipi+nivo SG

Deconstrucción con mótivos académicos, a partir de Larkin AACR 2017

16

YA SÉ QUE NO TIENE NADA QUE VER…

Von Minckwitz NEJM 2017

NIVO+IPI (N=314)

NIVO (N=316)

IPI (N=315)

Any subsequent therapy, n (%)* 129 (41) 169 (54) 225 (71)

Systemic therapy 100 (32) 140 (44) 196 (62)

Anti-PD-1 agents 30 (10) 32 (10) 132 (42)

Anti-CTLA-4 19 (6) 83 (26) 12 (4)

BRAF inhibitors 40 (13) 57 (18) 68 (22)

MEK inhibitors 30 (10) 38 (12) 39 (12)

Investigational agents** 8 (3) 6 (2) 15 (5)

Median time to subsequent systemic therapy, mo (95% CI)

NR (NR‒NR) 26.8 (18.0‒NR) 8.5 (7.3‒9.7)

2 year % of pts free of subsequent therapies

65.8 53.8 24.7

Subsequent Therapies: All Randomized Patients

17

*Patients may have received more than 1 subsequent therapy (e.g. radiation, surgery and systemic therapies)

**Other than investigational immunotherapy, BRAF inhibitors, and MEK inhibitors

Larkin AACR 2017

18

Los pacientes del CHECK-MATE 067 no podían participar en este ensayo

Pero tenían acceso a pembro…

Schadendorf ASCO 2017

CHECK-MATE 064

19 Weber Lancet 2016

IPI POST NIVO ENSAYO 066

20 Atkinson SMR 2015

Subgroup

Patients Unstratified Hazard Ratio Unstratified Hazard Ratio (95% CI)

NIVO+IPI NIVO PFS OS PFS OS

Overall 314 316 0.77 0.89

<65 years 185 198 0.74 0.81

≥65 years 129 118 0.82 0.99

BRAF Mutant 102 98 0.60 0.71

BRAF Wild-type 212 218 0.86 0.97

ECOG PS = 0 230 237 0.79 0.91

ECOG PS = 1 83 78 0.72 0.82

M0/M1a/M1b 129 132 0.67 0.84

M1c 185 184 0.83 0.90

LDH ≤ ULN 199 197 0.72 0.89

LDH > ULN 114 112 0.79 0.86

LDH > 2 x ULN 37 37 0.70 0.71

PD-L1 ≥5% 68 80 0.87 1.05

PD-L1 <5% 210 208 0.73 0.84

PFS and OS Subgroup Analyses (All Randomized Patients) Descriptive comparison between NIVO+IPI and NIVO

21

NIVO+IPI NIVO

2 0 1

NIVO+IPI NIVO

2 0 1

Larkin AACR 2017

OS

(%

)

Months

0

10

20

30

40

50

60

70

80

90

100

0 39 36 33 30 27 24 21 18 15 12 9 6 3

NIVO+IPI NIVO IPI

0 IPI 215 3 21 67 82 87 96 106 118 134 147 166 194

0 NIVO 218 2 38 105 119 124 127 134 144 155 163 179 199

0 NIVO+IPI 212 5 31 108 120 126 127 133 142 144 157 170 194

61%

57%

42%

BRAF Wild-type

OS

(%

)

Months

0

10

20

30

40

50

60

70

80

90

100

0 39 36 33 30 27 24 21 18 15 12 9 6 3

NIVO+IPI NIVO IPI

0 IPI 100 1 13 37 47 49 53 58 64 71 81 88 91

0 NIVO 98 1 17 52 56 57 64 67 69 75 81 86 93

0 NIVO+IPI 102 2 18 62 72 72 73 76 79 82 90 95 98

71%

62%

OS in Patients with BRAF Wild-type and Mutant Tumors

22

51%

NIVO+IPI NIVO IPI

Median, mo

(95% CI)

NR

NR

(26.4‒NR)

24.6

(17.9‒31.0)

HR (95% CI)

vs NIVO

0.71

(0.45‒1.13) -- --

NIVO+IPI NIVO IPI

Median, mo

(95% CI)

NR

(27.6‒NA)

NR

(25.8‒NR)

18.5

(14.8‒23.0)

HR (95% CI) vs

NIVO

0.97

(0.74‒1.28) -- --

BRAF Mutant

Patients at risk: Patients at risk:

Larkin AACR 2017

NIVO+IPI (N=314)

NIVO (N=316)

IPI (N=315)

Any subsequent therapy, n (%)* 129 (41) 169 (54) 225 (71)

Systemic therapy 100 (32) 140 (44) 196 (62)

Anti-PD-1 agents 30 (10) 32 (10) 132 (42)

Anti-CTLA-4 19 (6) 83 (26) 12 (4)

BRAF inhibitors 40 (13) 57 (18) 68 (22)

MEK inhibitors 30 (10) 38 (12) 39 (12)

Investigational agents** 8 (3) 6 (2) 15 (5)

Median time to subsequent systemic therapy, mo (95% CI)

NR (NR‒NR) 26.8 (18.0‒NR) 8.5 (7.3‒9.7)

2 year % of pts free of subsequent therapies

65.8 53.8 24.7

Subsequent Therapies: All Randomized Patients

23

*Patients may have received more than 1 subsequent therapy (e.g. radiation, surgery and systemic therapies)

**Other than investigational immunotherapy, BRAF inhibitors, and MEK inhibitors

Larkin AACR 2017

OS by Tumor PD-L1 Expression, 5% Cutoff

24

NIVO+IPI NIVO IPI

Median OS, mo

(95% CI)

NR

(31.8–NR)

NR

(23.1–NR)

18.5

(13.7–22.5)

HR (95% CI)

vs NIVO

0.84

(0.63–1.12) ─ ─

PD-L1 Expression Level <5%

OS

(%

)

Months

0

10

20

30

40

50

60

70

80

90

100

0 39 36 33 30 27 24 21 18 15 12 9 6 3

Patients at risk:

202 0 IPI 2 18 63 78 81 90 100 108 125 140 158 179

208 0 NIVO 2 34 99 110 112 118 123 133 144 151 169 189

210 0 NIVO+IPI 7 34 116 127 130 131 139 144 146 163 178 194

NIVO+IPI NIVO IPI

Median OS, mo

(95% CI) NR NR

28.9

(18.1–NR)

HR (95% CI)

vs NIVO

1.05

(0.61–1.83) ─ ─

PD-L1 Expression Level ≥5%

OS

(%

)

Months

0

10

20

30

40

50

60

70

80

90

100

0 39 36 33 30 27 24 21 18 15 12 9 6 3

Patients at risk:

75 0 IPI 1 13 33 39 40 43 46 55 61 65 67 72

80 0 NIVO 1 18 49 54 57 58 61 63 68 73 75 79

68 0 NIVO+IPI 0 11 35 44 45 45 45 50 52 55 56 63

55%

63%

41%

72%

68%

54%

• ORR of 73.5% for NIVO+IPI and 58.8% for NIVO • ORR of 56.2% for NIVO+IPI and 42.3% for NIVO

Larkin AACR 2017

De 5% a 8% De 5% a -4%

<1% PD-L1 NIVO+IPI NIVO IPI

Median OS, mo

(95% CI)

NR

(26.5–NR)

23.5

(13.0–NR)

18.6

(13.7–23.2)

HR (95% CI)

vs NIVO

0.74

(0.52–1.06) ─ ─

≥1% PD-L1 NIVO+IPI NIVO IPI

Median OS, mo

(95% CI) NR NR

22.1

(17.1–29.7)

HR (95% CI)

vs NIVO

1.03

(0.72–1.48) ─ ─

OS

(%

)

Months

0

10

20

30

40

50

60

70

80

90

100

0 39 36 33 30 27 24 21 18 15 12 9 6 3

60%

49%

41%

OS

(%

)

Months

0

10

20

30

40

50

60

70

80

90

100

0 39 36 33 30 27 24 21 18 15 12 9 6 3

113 0 IPI 1 10 32 43 44 50 57 61 71 79 87 96

117 0 NIVO 2 16 50 55 57 59 62 65 73 76 86 103

123 0 NIVO+IPI 4 18 66 72 74 74 79 82 82 91 102 113

164 0 IPI 2 21 64 74 77 83 89 102 115 126 138 155

171 0 NIVO 1 36 98 109 112 117 122 131 139 148 158 165

155 0 NIVO+IPI 3 27 85 99 101 102 105 112 116 127 132 144

67%

67%

48%

Similar Outcomes Were Observed at a 1% Cutoff

25

PD-L1 Expression Level <1% PD-L1 Expression Level ≥1%

Patients at risk: Patients at risk:

• ORR of 65.2% for NIVO+IPI and 55.0% for NIVO • ORR of 54.5% for NIVO+IPI and 35.0% for NIVO

Larkin AACR 2017

Safety Summary • With an additional 19 months of follow-up, safety was consistent with the initial report1

• Most select AEs were managed and resolved within 3-4 weeks (85–100% across organ categories)

• ORR was 70.7% for pts who discontinued NIVO+IPI due to AEs, with median OS not reached

26

NIVO+IPI (N=313)

NIVO

(N=313) IPI

(N=311)

Patients reporting event, % Any Grade Grade 3-4 Any Grade Grade 3-4 Any Grade Grade 3-4

Treatment-related adverse event (AE)

95.8 58.5 86.3 20.8 86.2 27.7

Treatment-related AE leading to discontinuation

39.6 31.0 11.5 7.7 16.1 14.1

Treatment-related death, n (%) 2 (0.6)a 1 (0.3)b 1 (0.3)b

aCardiomyopathy (NIVO+IPI, n=1); Liver necrosis (NIVO+IPI, n=1). Both deaths occurred >100 days after the last treatment.

bNeutropenia (NIVO, n=1); colon perforation (IPI, n=1).1

1. Larkin J, et al. NEJM 2015;373:23‒34.

27 Presented By MS Carlino at 2017 ASCO Annual Meeting

61% ORR, 15% CR

PEMBRO 2 MG/KG + IPI 1 MG/KG

CHECK-MATE 511: fase III IPI 1 NIVO 3 VS IPI 3 NIVO 1

COMBINACIÓN EN SITUACIONES ESPECIALES

MTS SNC

28

A Randomized Phase 2 Study of Nivolumab

or Nivolumab plus Ipilimumab in Patients

with Melanoma Brain Metastases:

The Anti-PD1 Brain Collaboration (ABC)

Georgina V. Long, Victoria Atkinson, Alexander M. Menzies, Serigne Lo,

Alexander Guminski, Michael P. Brown, Maria Gonzalez, Katrina Diamante,

Shahneen Sandhu, Richard A. Scolyer, Louise Emmett, Grant A. McArthur.

Presented by Georgina V Long

Intracranial Response C

ha

nge

fro

m B

ase

line (

%)

All Patients

Drug

Treatment

Naive

Cohort A: Nivo+Ipi Cohort B: Nivo alone

-50

-100

50

100

0

150

200

* * * * * * * * * * * *

* * * *

IC RR = 42%

IC RR = 50%

IC RR = 20%

IC RR = 21%

* Deceased prior to week 12 assessment

200

-50

-100

50

100

0

150

* * * * *

Presented by Georgina V. Long

Efficacy and Safety of Nivolumab Plus Ipilimumab in Patients with Melanoma Metastatic to the Brain:

Results of the Phase II Study CheckMate 204

Hussein Tawbi,1 Peter Forsyth,2 Alain Algazi,3 Omid Hamid,4 F. Stephen Hodi,5 Stergios Moschos,6 Nikhil Khushalani,2 Rene Gonzalez,7 Christopher Lao,8 Michael Postow,9 Michael B. Atkins,10 Marc Ernstoff,11 Igor Puzanov,11 Ragini Kudchadkar,12 Reena Thomas,13 Ahmad Tarhini,14 Joel Jiang,15

Alexandre Avila,15 Sheena Demelo,15 Kim Margolin16

1University of Texas, MD Anderson Cancer Center, Houston, TX, USA; 2Moffitt Cancer Center and Research Institute, Tampa, FL, USA; 3University of California-San Francisco, San Francisco, CA, USA; 4The Angeles Clinic and Research Institute, Los Angeles, CA, USA;

5Dana-Farber Cancer Institute, Boston, MA, USA; 6University of North Carolina Lineberger Comprehensive Cancer Center, Chapel Hill, NC, USA; 7University of Colorado Comprehensive Cancer Center, Aurora, CO, USA; 8University of Michigan, Ann Arbor, MI, USA;

9Memorial Sloan Kettering Cancer Center and Weill Cornell Medical College, New York, NY, USA; 10Georgetown-Lombardi Comprehensive Cancer Center, Washington DC, USA; 11Roswell Park Cancer Institute, Buffalo, NY, USA; 12Winship Cancer Institute of

Emory University, Atlanta, GA, USA; 13Stanford University Hospital, Palo Alto, CA, USA; 14University of Pittsburgh Medical Center, Pittsburgh, PA, USA; 15Bristol-Myers Squibb, Princeton, NJ, USA; 16Department of Medical Oncology, City of Hope, Duarte, CA, USA.

Abstract Number 9507

Response to Treatment – All Patients (N = 75)

32

Global Intracranial Extracranial

Best overall response, n (%)

Complete response 4 (5) 16 (21) 5 (7)

Partial response 36 (48) 25 (33) 32 (43)

Stable disease 4 (5) 4 (5) 2 (3)

Progressive diseasea 18 (24) 18 (24) 16 (21)

Not evaluableb 13 (17) 12 (16) 20 (27)

Objective response rate, % (95% CI) 53 (41−65) 55 (43−66) 49 (38−61)

Clinical benefit ratec, % (95% CI) 59 (47−70) 60 (48−71) 52 (40−64) aConfirmed and unconfirmed progressive disease

bIncludes unconfirmed responses

cClinical benefit rate = complete response + partial response + stable disease ≥ 6 months

COMBINACIÓN EN SITUACIONES ESPECIALES

LDH ELEVADA

33

PFS in Patients With LDH > 2x ULN

34

NIVO+IPI

(n = 43)

NIVO

(n = 58)

IPI

(n = 31)

Median PFS, months (95% CI) 2.6 (1.7, 2.9) 2.1 (1.9, 2.6) 2.3 (1.7, 2.6)

HR (95% CI) NIVO+IPI over

NIVO or IPI – 0.7 (0.5, 1.1) 0.5 (0.3, 0.9)

43 14 12 0 11 8 8 6 1 0 NIVO+IPI

Time (Months)

PF

S (

%)

100

90

80

70

60

50

40

30

20

0

10

3 6 27 9 12 15 18 21 24 0

Number of Patients at Risk

58 13 9 0 5 5 5 5 4 2 NIVO

31 2 0 0 0 0 0 0 0 0 IPI

10%

17%

10%

20%

18%

29%

NIVO+IPI

NIVO

IPI

Larkin SMR 2016

PFS in Patients With BRAF Mutations and LDH > ULN

35

NIVO+IPI

(n = 23)

NIVO

(n = 25)

IPI

(n = 23)

Median PFS, months (95% CI) NR (4.2, NR) 2.8 (2.6, 6.7) 2.8 (2.6, 5.8)

HR (95% CI) NIVO+IPI over

NIVO or IPI – 0.4 (0.2, 0.9) 0.3 (0.1, 0.6)

Time (Months)

100

90

80

70

60

50

40

30

20

0

10

3 6 27 9 12 15 18 21 24 0

NIVO+IPI

NIVO

IPI

Number of Patients at Risk

23 19 15 0 13 12 12 9 3 2 NIVO+IPI

25 10 8 0 7 7 7 6 2 0 NIVO

23 8 5 0 4 2 2 2 1 1 IPI

PF

S (

%)

Larkin SMR 2016

IPI+NIVO LDH >1x… NR, aprox 57% en 1 año

NIVO LDH >1x… 2,8, aprox 30% en 1 año

36

No. at risk

Normal LDH, Disease Sites < 3

Normal LDH, Disease Sites ≥ 3

LDH > 1 x ULN

LDH > 2 x ULN

PFS by LDH and Number of Disease Sitesa

a Factors identified by the regression tree analysis.

0.0

0

.2

0.4

0

.6

0.8

1

.0

0 12 24 36

237 149 53 8

161 69 23 2

149 40 9 0

70 4 0 0

PF

S P

rob

ab

ility

Months

Normal LDH, Disease Sites < 3

Normal LDH, Disease Sites ≥ 3

LDH >1-≤ 2 x ULN

LDH > 2 x ULN

PRESENTED BY GV LONG AT SMR 2015

LDH>2 x, 5,5 meses, 8% al año

LDH >1x, <2x, 7,4 meses, 32% al año

OTRA FORMA DE VERLO, BRAF Y LDH ELEVADA

PFS MEDIANA (mo) PFS % AÑO PFS % 2 AÑOS

IPI+NIVO NR ?? 57 ?? ?? ??

NIVO 2,8 ?? 30 ?? ?? ??

BRAF+MEK 7,4 5,5*

32 8*

18 2*

37 *Valores para LDH>2, no disponibles inmuno

LONG SMR 2015

Long Lancet Oncol 2016

Larkin SMR 2016

COMBINACIÓN EN SITUACIONES ESPECIALES

MELANOMA MUCOSAS

38

D`Angelo 2016 JCO

AGREGACIÓN DE DATOS DE PACIENTES CON MELANOMA DE MUCOSAS N=136 (86 NIVO, 35 IPI+NIVO, 36 IPI) Ensayos 066, 067, 069, 038, 037

D`Angelo 2016 JCO

6 meses combo PFS vs 3 meses monoterapias 37% ORR para combo vs 23% nivo y 8 ipi%

COMBINACIÓN EN SITUACIONES ESPECIALES

MELANOMA UVEAL

41

MELANOMA UVEAL

42 Piulats ASCO 2017

16% respuestas

CONCLUSIONES • La combinación de ipilimumab y nivolumab es superior en PFS y OS a

ipilimumab

• Pero no es superior (en este momento) en OS a nivolumab – En estudio no diseñado para ello

• Un 5% más probabilidad de OS frente a nivolumab a los dos años; mediana de duración respuesta no alcanzada

• Más del doble de discontinuaciones (39,6 vs 16,1%)

• Falta de tamaño muestral podría compensarse con seguimiento más largo y estudios agregados

– Permitirán análisis de subgrupos para decision de tratamiento

• Mucosas

• BRAF+ y LDH elevada

• LDH elevada

• PD-L1 ?

• Ocular?

• No se puede definir como estándar (si nos acogemos a la RAE), pero es una opción más a considerar, teniendo en cuenta los pros y los contras

MUCHAS GRACIAS

I´ll see you again in 25 years…