El régimen de la combinación: HITO en el tratamiento del melanoma metastásico

Eva Muñoz Couselo, MD, PhD

Hospital Vall d’Hebrón, Barcelona

¿Qué es un HITO en melanoma metastásico?

‘La IO y la terapia dirigida demuestran una supervivencia a largo plazo en pacientes afectos de melanoma metastásico’

Adapted from Luke, J. J. et al. (2017) Targeted agents and immunotherapies: optimizing outcomes in melanoma. Nat. Rev. Clin. Oncol. doi:10.1038/nrclinonc.2017.43

1 año mOS COMBO terapia dirigida o anti-PD1 monoterapia : 74%

2 años mOS COMBO terapia dirigida o anti-PD1 monoterapia : 55%

2y

(59%)9

Long-term survival

Checkpoint Inhibitors para Melanoma: Datos EC Fase III 1a línea de tratamientoa

Median PFS, mo

2.8b,1

IPI

11.54,9,10

NIVO + IPI

1-year OS 47%b,2 73% 9,10

5y

(18%)b,6,7

2y

(55%)9

2y

(64%)9

NIVO PEMBRO

CheckMate 0663

(3 mg/kg, BRAF

WT)

CheckMate 0674

(3 mg/kg)

KEYNOTE 0065

(10 mg/kg)

not approved dose

Q2W Q3W

5.1 6.9 5.5 4.1

70% 74% 74% 68%

aData from separate, noncomparative trials; a cross-trial comparison is not intended. bIn combination with dacarbazine.

IPI = ipilimumab; Mo = months; NA = not available; NIVO = nivolumab; OS = overall survival; PEMBRO = pembrolizumab; PFS = progression-free survival; Q2W = every 2 weeks; Q3W = every 3 weeks; y = years.

1. Wolchok J, et al. Presented at ASCO 2011. 2. Robert C, et al. N Engl J Med. 2011;364:2517-2526. 3. Robert C, et al. N Engl J Med. 2015;372:320-323. 4. Larkin J, et al. N Engl J Med. 2015;373:23-34. 5. Robert C, et al. N Engl J Med. 2015;372:2521-2532. 6. Schadendorf D, et al. J Clin Oncol. 2015;33:1889-1894. 7. Maio M, et al. J Clin Oncol. 2015;33:1191-1196. 8. Atkinson V, et al. Presented at SMR 2015. 9. Schachter et al. Presented at ASCO 2016, 9. Larkin et al.Presented at AACR 2017. 10. Wolchok et al. N Engl J Med. 2017;377:1345-1356

2y

(58%)8

CheckMate 0674,9 (ipi 3 mg/kg + nivo 1mg/kg)

3y

(58%)10

3y

(52%)10

¿Cuáles son los mayores beneficios demostrados por el RÉGIMEN de combinación?

Study Population Results

Phase 1 study (CA209-004)

Treated and untreated melanoma

BRAF WT/MT

• ORR with NIVO+IPI up to 53% • CR with NIVO+IPI of 18% • 2-year OS rate of 79% • 3 year OS rate of 68%

Phase 2 study (CheckMate 069)

Untreated melanoma BRAF WT/MT

• Compared with IPI alone, NIVO+IPI significantly improved ORR and PFS • ORR of 59% with NIVO+IPI vs 11% with IPI alone • Higher OS rate at 2 years: 69% for NIVO+IPI vs. 53% for IPI alone • Treatment-related grade 3-4 Aes: 54% with NIVO+IPI vs 24% with IPI alone

Phase 3 study (CheckMate 067)

Untreated melanoma BRAF WT/MT

• Nivo alone and NIVO+IPI significantly improves OS, PFS and ORR vs IPI alone

• ORR of 59% with NIVO+IPI vs 19% with IPI alone • Higher OS rate at 2 and 3 years: 2y ->64% for NIVO+IPI vs. 45% for IPI

alone, 3y ->58% for for NIVO+IPI vs. 34% for IPI alone • OS, PFS and ORR are numerically greater with NIVO+IPI vs NIVO • Treatment-related grade 3-4 AEs: 58% with NIVO+IPI vs 27% with IPI alone • Most AES managed and resolved in 3-4 weeks (85-100%) • ORR 70% for those patients who discontinued NIVO+IPI for toxicity

Sznol et al. ASCO 2014Larkin Let al. N Engl .J Med 2015; Postow et al. N Engl. J Med 2015; Postow et al. AACR 2016; Larkin et al. AACR 2017; Wolchock et al. NEJM 2017

Ensayos clínicos con NIVO 1mg/kg + IPI 3mg/kg

1. Atkinson V, et al. Presented at SMR 2015. 2. Postow et al. Presented at AACR 2016. 3. Schachter et al. Presented at ASCO 2016.4. Wolchok JD, et al. Presented at ASCO 2015.

5. Larkin et al. AACR 2017, 6. Wolchok et al. NEJM 2017

Anti-PD1: tiempo medio de respuesta 2’8 meses

1. Tasas de respuesta más consistentes, elevadas y más

duraderas que anti-PD1 en monoterapia

2. Doble PFS comparado con anti-PD1 en monoterapia

Larkin et a 2017 AACR Anual Meeting

Updated Progression-Free Survival

50%

43%

18%

43%

37%

12%

Pe

rcen

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 363024 332721

0IPI

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. IPI0.42

(0.34–0.51)0.54

(0.45–0.66)--

HR (95% CI) vs. NIVO0.76

(0.62–0.94)-- --

Pro

gre

ss

ion

-fre

e S

urv

iva

l (%

)

5162730333543465877136315

Patients at risk:

0NIVO 16628897103107112120132151178316

0NIVO+ IPI 1671104110118125132137156176218314

NIVO+IPI

NIVO

IPI

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

Wolchok et al. NEJM 2017

4. OS a 2 y 3 años nunca vistas en melanoma, incluso en aquellos

pacientes que discontinúan por toxicidad

Adapted from Wolchok et al. NEJM 2017

64% Nivolumab plus ipilimumab

59% Nivolumab

45% Ipilimumab

4. Menor necesidad de tratamientos de 2ª línea y mayor

intervalo de tiempo hasta llegar a ellos

Robert et al. ESMO 2017

OS (INTENT-TO-TREAT)

8

Subsequent therapy

32%

46%

63%

5. Claro beneficio en todos los subgrupos de pacientes

Larkin et al presented at 2017 AACR Annual Meeting

6. Beneficio incluso en aquellos pacientes PD-L1 bajo expresores

Larkin et al presented at 2017 AACR Annual Meeting

While a greater PFS benefit for NIVO+IPI relative to NIVO was observed in low PD-L1 expressers, NIVO+IPI resulted in clinically meaningful improvements in ORR regardless of PD-L1 expression level

Wolchok et al. NEJM 2017

7. Beneficio también en aquellos pacientes

BRAF mutados y/o en aquellos con LDH elevada

OS

(%

)

Months

0

10

20

30

40

50

60

70

80

90

100

0 39363330272421181512963

NIVO+IPI NIVO IPI

0IPI 215 32167828796106118134147166194

0NIVO 218 238105119124127134144155163179199

0NIVO+IPI 212 531108120126127133142144157170194

61%

57%

42%

BRAF Wild-type

OS

(%

)

Months

0

10

20

30

40

50

60

70

80

90

100

0 39363330272421181512963

NIVO+IPI NIVO IPI

0IPI 100 11337474953586471818891

0NIVO 98 11752565764676975818693

0NIVO+IPI 102 21862727273767982909598

71%

62%

OS in Patients with BRAF Wild-type and Mutant Tumors

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:

10

Larkin et al presented at 2017 AACR Annual Meeting Larkin et al presented at 2016 SMR Annual Meeting

8. Claro beneficio en pacientes con M1 SNC

¿Qué pasa con la toxicidad?

¿Desmontando el MHITO?

Larkin et al presented at 2017 AACR Annual Meeting

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

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. 13

Most Common Treatment-related Select AEs

Jedd Wolchok presented at 2016 ASCO Annual Meeting

Champiat et al. Ann. Oncol. 2016

Skin (n=18)

Skin (n=5)

Gastrointestinal (n=46)

Gastrointestinal (n=7)

Endocrine (n=15)

Endocrine (n=2)

Hepatic (n=60)

Hepatic (n=8)

Pulmonary (n=3)

Pulmonary (n=1)

Renal (n=6)

Renal (n=1)

0 10 20 30 40 50 60Weeks

5.6 (0.1 – 55.0)

19.4 (1.3 – 50.9)

7.4 (1.0 – 48.9)

26.3 (13.1 – 57.0)

12.1 (2.9 – 17.0)

28.6 (19.1 – 38.1)

7.4 (2.1 – 48.0)

14.1 (1.9 – 25.1)

3.7 (3.7 – 9.4)

6.7 (6.7 – 6.7)

11.3 (3.3 – 23.7)

50.9 (50.9 – 50.9)

Larkin J et al. presented at ECC 2015

NIVO+IPI

NIVO

Time to Onset of Grade 3–4 Treatment-Related Select AEs

Circles represent medians; bars signify ranges

9. Novedosa manera de controlar, tratar y seguir al paciente

Pacientes y familiares

Oncólogos

Enfermería

Otros médicos

especialistas

10. Beneficio incluso mayor en aquellos pacientes

que discontinúan por toxicidad

Schadendorf, D et al. EADO 2016

EVOLUCIÓN DEL TRATAMIENTO DEL MELANOMA METASTÁSICO

Previo a 2011:

- Mantener la calidad de vida de los pacientes

- Paliar los síntomas

- Minimizar los efectos adversos relacionados con

el tratamiento

HITO: Acontecimiento puntual y significativo que marca un momento importante en el desarrollo de un proceso o en la vida de una persona.

Previo a 2018:

- Aumentar la SUPERVIVENCIA de los pacientes

- Selección de pacientes: M1 SNC, mucosas/ocular,

estatus BRAF, carga tumoral, ECOG, nivel LDH, …

- Optimizar las diferentes opciones de tratamiento:

combinaciones, secuencias, biomarcadores,…

- Incorporación del tratamiento adyuvante como

estándar de tratamiento (pacientes alto riesgo)

- Posibilidad de flat dose, de poder parar los

tratamientos y de treatment beyond progression

- Mantener la calidad de vida de los pacientes

- Paliar los síntomas

- Minimizar los efectos adversos relacionados con el

tratamiento

emunoz@vhio.net