Largos supervivientes con Inmunoterapia:

melanoma como prueba de concepto

en metastásico y adyuvancia

Dra. Ainara Soria Rivas

Oncología Médica

Dunn et al, Immunity, 2004

INMUNOVIGILANCIA e INMUNOEDICIÓN

Sharma P, et al. Science. 2015;348:56-61.

DATOS DE SUPERVIVENCIA A LARGO PLAZO…

La inmunoterapia en melanoma metastásico ha conseguido en términos de supervivencia global….

1. Impacta de modo marginal en SG.

2. Sólo ha beneficiado subgrupos específicos de enfermos.

3. Ha conseguido aumentar supervivencia global por encima de los 24 meses.

4. Son tratamientos que precisan su continuidad para mantener el beneficio indefectiblemente.

Estudios antiPD-1 tras progresión a Ipilimumab + iBRAF

CA209-037

Nivolumab

D´Angelo SP.

SMR 2014

KEYNOTE-002

Pembrolizumab

Ribas A.

SMR 2014 N 540

CA209-037

OS in All Treated Patients Censored at Start of Subsequent Anti-

PD-1 Therapy in ICC Group

9

NIVO

ICC

102 94 73 0 48 28 14 11 9 9 5 ICC

Number of Patients at Risk

268 229 207 0 177 157 137 122 112 103 71 NIVO

0

3

0

16

2

44

Time (Months)

OS

(%)

90

80

70

60

50

40

30

20

0

10

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

100

39%

29%

NIVO (n = 268) ICC (n = 102)

Events 172 53

Median OS, months (95% CI)

16.4 (12.9, 20.3)

11.8 (9.9, 14.4)

HR (95% CI) 0.81 (0.59, 1.11)

• In this post-hoc analysis, median OS was 4.6 months longer in NIVO vs ICC

Ribas A, et al. Lancet Oncol 2015

KEYNOTE-002

KEYNOTE 001: Resultados finales

Robert C, et al. N Engl J Med 2015

ACTUALIZACIÓN DE SUPERVIVENCIA

GLOBAL KEYNOTE-006

Unresectable or Metatastic Melanoma

• Previously untreated

• 945 patients

CA209-067: Study Design CheckMate 067

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)

15

Larkin J. NEJM 2015 Larkin J. ESMO 2017

Grob JJ. ESMO 2017

KEYNOTE 006: LARGAS SUPERVIVENCIAS

TRAS TRATAMIENTO

KEYNOTE 006: LARGAS SUPERVIVENCIAS TRAS TRATAMIENTO

Robert C. JCO Dec 2017

DFS de enfermos con CR que discontinuaron Pembrolizumab

DFS 24 meses: 89,9%

KEYNOTE 001

Patients Alive at 3 Years – On and Off Treatment

aNIVO arm was from CheckMate 067 study only

CheckMate 069/067:

Pooled 3-Year Analysis

Still on treatment

Off treatment and never received subsequent systemic therapy

Off treatment and received subsequent systemic therapy

32.2% n = 48

41.6% n = 62

26.2% n = 39

NIVOa (n = 149)

13.4% n = 30

69.2% n = 155

17.4% n = 39

NIVO+IPI (n = 224)

8.8% n = 10

31.6% n = 36

59.6% n = 68

IPI (n = 114)

• In the NIVO+IPI arm, median duration of response was not reached with 69% of patients alive and remaining treatment free

Postow M. STIC 2017

La inmunoterapia en melanoma metastásico ha conseguido en términos de supervivencia global….

1. Impacta de modo marginal en SG.

2. Sólo ha beneficiado subgrupos específicos de enfermos.

3. Ha conseguido aumentar supervivencia global por encima de los 24 meses.

4. Son tratamientos que precisan su continuidad para mantener el beneficio indefectiblemente.

PAPEL EN ADYUVANCIA …

La adyuvancia con inmunoterapia en melanoma ….

1. Debe considerarse experimental, dada la inmadurez de sus datos.

2. Ha demostrado reducir en más de un 10% el riesgo de recaída de los enfermos.

3. No ha demostrado aumentar supervivencia global.

4. El interferon alfa debe seguir considerándose un estándar de tratamiento.

SLR SG

Seguimiento 6,9 años

OS 3.82 vs 2.78 y HR = 0.67 (P = .0237)

RFS 0.72 vs 0.98 y HR = 0.61 (P = .0023)

J Clin Oncol. 1996 Jan;14(1):7-17.

287 pacientes Estadios IIB,IIC,III

NEJM 2016

EORTC 18071/CA184-029: Study Design

•Stratification factors

– Stage (IIIA vs IIIB vs IIIC 1-3 positive lymph nodes vs IIIC ≥4 positive lymph nodes)

– Regions (North America, European countries, and Australia)

•Enrollment Period: June 2008 to July 2011

26

Randomized, double-blind, phase 3 study evaluating the efficacy and safety

of ipilimumab in the adjuvant setting for high-risk melanoma

INDUCTION Ipilimumab 10 mg/kg

Q3W × 4 High-risk, stage

III, completely

resected

melanoma INDUCTION

Placebo

Q3W × 4

R

MAINTENANCE

Ipilimumab 10 mg/kg

Q12W up to 3 years

MAINTENANCE

Placebo

Q12W up to 3 years

Treatment up to a maximum of 3 years, or until disease progression, intolerable

toxicity, or withdrawal

N = 475

N = 476

Week 1 Week 12 Week 24

N = 951

Q3W = every 3 weeks; Q12W = every 12 weeks; R = randomization.

aStratified by stage provided at randomization. CI = confidence interval.

Pat

ien

ts A

live

an

d W

ith

ou

t R

ecu

rren

ce

(%)

Ipilimumab Placebo

Events/patients 264/475 323/476

HR (95% CI)a 0.76 (0.64, 0.89)

Log-rank P valuea 0.0008

Median RFS,

months

(95% CI)

27.6

(19.3, 37.2)

17.1

(13.6, 21.6)

RECURRENCE FREE SURVIVAL (per IRC)

41%

30%

Years 0 1 2 3 4 5 6 7 8

0

10

20

30

40

50

60

70

80

90

100

O N Number of patients at risk 264 475 283 217 184 161 77 13 1

323 476 261 199 154 133 65 17 0

Ipilimumab

Placebo

Pat

ien

ts A

live

(%

)

aStratified by stage provided at randomization.

Ipilimumab Placebo

Deaths/patients 162/475 214/476

HR (95.1% CI)a 0.72 (0.58, 0.88)

Log-rank P valuea 0.001

SUPERVIVIENCIA GLOBAL

65%

54%

Years 0 1 2 3 4 5 6 7 8

0

10

20

30

40

50

60

70

80

90

100

O N Number of patients at risk 162 475 431 369 325 290 199 62 4

214 476 413 348 297 273 178 58 8

Ipilimumab

Placebo

SAFETY SUMMARY

Ipilimumab (n = 471)

Placebo

(n = 474)

Any Grade

Grade 3/4

Any grade

Grade 3/4

Any AE, % 98.7 54.1 91.1 26.2

Treatment-related AE, % 94.1 45.4 59.9 4.0

Treatment-related AE leading to discontinuation, %

48.0 32.9 1.5 0.6

Any immune-related AE, %

90.4 41.6 39.7 2.7

o 5 patients (1.1%) in the ipilimumab group

3 patients with colitis (2 with gastrointestinal perforations)

1 patient with myocarditis

1 patient had multiorgan failure with Guillain-Barré syndrome

o No deaths related to study drug in the placebo group

Adjuvant Therapy With Nivolumab Versus Ipilimumab After

Complete Resection of Stage III/IV Melanoma: A Randomized, Double-blind, Phase 3 Trial (CheckMate 238)

Jeffrey Weber,1 Mario Mandala,2 Michele Del Vecchio,3 Helen Gogas,4 Ana M. Arance,5

C. Lance Cowey,6 Stéphane Dalle,7 Michael Schenker,8 Vanna Chiarion-Sileni,9 Ivan Marquez-Rodas,10

Jean-Jacques Grob,11 Marcus Butler,12 Mark R. Middleton,13 Michele Maio,14 Victoria Atkinson,15

Paola Queirolo,16 Veerle de Pril,17 Anila Qureshi,17 James Larkin,18* Paolo A. Ascierto19*

1NYU Perlmutter Cancer Center, New York, New York, USA; 2Papa Giovanni XIII Hospital, Bergamo, Italy; 3Medical Oncology, National Cancer Institute, Milan, Italy; 4University of Athens, Athens, Greece; 5Hospital Clínic de Barcelona, Barcelona, Spain; 6Texas Oncology-Baylor Cancer Center, Dallas, Texas, USA; 7Hospices

Civils de Lyon, Pierre Bénite, France; 8Oncology Center Sf Nectarie Ltd., Craiova, Romania; 9Oncology Institute of Veneto IRCCS, Padua, Italy; 10General University Hospital Gregorio Marañón, Madrid, Spain; 11Hôpital de la Timone, Marseille, France; 12Princess Margaret Cancer Centre, Toronto, Ontario, Canada;

13Churchill Hospital, Oxford, United Kingdom; 14Center for Immuno-Oncology, University Hospital of Siena, Istituto Toscano Tumori, Siena, Italy; 15Gallipoli Medical Research Foundation and Princess Alexandra Hospital, Woolloongabba, and University of Queensland, Greenslopes, Queensland, Australia; 16IRCCS San Martino-IST, Genova, Italy; 17Bristol-Myers Squibb, Princeton, New Jersey, USA; 18Royal Marsden NHS Foundation Trust, London, UK; 19Istituto Nazionale Tumori

Fondazione Pascale, Naples, Italy; *Contributed equally to this study.

30

CA209-238: Study Design

ESMO 2017

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

Primary endpoint: RFS: time from randomization until first recurrence (local, regional, or distant metastasis), new primary melanoma, or death

Secondary endpoints OS, Safety and tolerability, RFS by PD-L1 tumor expression, HRQoL

Current interim analysis: Primary endpoint (RFS), safety, and HRQoL ;DMFS (exploratory)

Duration of follow-up: minimum 18 months; 360 events

Stage IIIB, IIIC, or stage IV melanoma by the American Joint Committee on Cancer 2009 classification, 7th edition Complete regional lymphadenectomy or resection was required within 12 weeks of randomization

Acral or Mucosal Melanomas were allowed

CARACTERÍSTICAS BASALES

• 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)

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

ESMO 2017

Primary Endpoint: RFS R

FS (

%)

Months

0

10

20

30

40

50

60

70

80

90

100

0 6 12 18 24 27 3 9 15 21

453 353 311 249 5 0 399 332 291 71 NIVO

453 314 252 184 2 0 364 269 225 56 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%

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)

Subgroup Analysis of RFS: PD-L1 Expression Level

RFS

(%

)

Months

0

10

20

30

40

50

60

70

80

90

100

0 6 12 18 24 27 3 9 15 21

NIVO

IPI

275 204 171 129 3 0 242 189 159 41 NIVO

286 184 139 100 2 0 219 153 124 31 IPI

Number of patients at risk

RFS

(%

)

Months

152 130 122 105 2 0 135 125 114 26 NIVO

154 120 105 78 0 0 133 108 93 21 IPI

Number of patients at risk

64%

54%

0

10

20

30

40

50

60

70

80

90

100

0 6 12 18 24 27 3 9 15 21

NIVO

IPI

82%

74%

ESMO 2017

Stage III Stage IV

Subgroup Analysis of RFS: Disease Stage

RFS

(%

)

Months

0

10

20

30

40

50

60

70

80

90

100

0 6 12 18 24 27 3 9 15 21

367 290 257 203 3 0 322 272 239 58 NIVO

366 259 208 152 1 0 299 223 186 45 IPI

Number of patients at risk

72%

62%

RFS

(%

)

Months

0

10

20

30

40

50

60

70

80

90

100

0 6 12 18 24 27 3 9 15 21

82 59 51 43 2 0 73 56 49 12 NIVO

87 55 44 32 1 0 65 46 39 11 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

ESMO 2017

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)

Subgroup Analysis of RFS: BRAF Mutation Status

RFS

(%

)

Months

0

10

20

30

40

50

60

70

80

90

100

0 6 12 18 24 27 3 9 15 21

NIVO

IPI

187 142 126 102 2 0 159 135 118 32 NIVO

194 142 112 78 1 0 155 118 100 26 IPI

Number of patients at risk

RFS

(%

)

Months

0

10

20

30

40

50

60

70

80

90

100

0 6 12 18 24 27 3 9 15 21

197 154 137 108 2 0 175 145 127 26 NIVO

214 140 111 80 1 0 174 122 96 22 IPI

Number of patients at risk

NIVO

IPI

72%

57%

68%

63%

36 ESMO 2017

Exploratory Endpoint: DMFS for Stage III Patients

DM

FS (

%)

Months

0

10

20

30

40

50

60

70

80

90

100

0 6 12 18 24 27 3 9 15 21

369 309 280 214 3 0 335 292 264 62 NIVO

366 284 239 176 1 0 312 254 217 51 IPI

Number of patients at risk

NIVO

IPI

NIVO IPI

Events/patients 93/369 115/366

Median (95% CI) NR NR

HR (95% CI) 0.73 (0.55, 0.95)

Log-rank P value 0.0204

80%

73%

ESMO 2017

Safety Summary

• There were no treatment-related deaths in the NIVO group

• There were 2 (0.4%) treatment-related deaths in the IPI group (marrow aplasia and

colitis), both >100 days after the last dose

AE, n (%)

NIVO (n = 452) IPI (n = 453)

Any grade Grade 3/4 Any grade Grade 3/4

Any AE 438 (97) 115 (25) 446 (98) 250 (55)

Treatment-related AE 385 (85) 65 (14) 434 (96) 208 (46)

Any AE leading to discontinuation

44 (10) 21 (5) 193 (43) 140 (31)

Treatment-related AE leading to discontinuation

35 (8) 16 (4) 189 (42) 136 (30)

ESMO 2017

Treatment-Related Select Adverse Events

AE, n (%)

NIVO (n = 452) IPI (n = 453)

Any grade Grade 3/4 Any grade Grade 3/4

Skin 201 (44.5) 5 (1.1) 271 (59.8) 27 (6.0)

Gastrointestinal 114 (25.2) 9 (2.0) 219 (48.3) 76 (16.8)

Hepatic 41 (9.1) 8 (1.8) 96 (21.2) 49 (10.8)

Pulmonary 6 (1.3) 0 11 (2.4) 4 (0.9)

Renal 6 (1.3) 0 7 (1.5) 0

Hypersensitivity/infusion reaction 11 (2.4) 1 (0.2) 9 (2.0) 0

Endocrine

Adrenal disorder 6 (1.3) 2 (0.4) 13 (2.9) 4 (0.9)

Diabetes 2 (0.4) 1 (0.2) 1 (0.2) 0

Pituitary disorder 8 (1.8) 2 (0.4) 56 (12.4) 13 (2.9)

Thyroid disorder 92 (20.4) 3 (0.7) 57 (12.6) 4 (0.9)

ESMO 2017

NIVOLUMAB + IPILIMUMAB

NIVOLUMAB

Melanomas III-B or III-C or III-D AJCC 8th edition

CHECKMATE-915

Primary endpoint: RFS

La adyuvancia con inmunoterapia en melanoma ….

1. Debe considerarse experimental, dada la inmadurez de sus datos.

2. Ha demostrado reducir en más de un 10% el riesgo de recaída de los enfermos.

3. No ha demostrado aumentar supervivencia global.

4. El interferon alfa debe seguir considerándose un estándar de tratamiento.

¿¿¿ALGUNA PREGUNTA???

MUCHAS GRACIAS