Diez años de avances en el tratamiento del cáncer de cabeza y cuello

Incorporación de la inmunoterapia a la estrategia de

tratamiento del cáncer de cabeza y cuello.

Ricard Mesía Instituto Catalán de Oncología - Badalona

SCCHN tiene microambiente “inflamatorio”

Standard of care in R/M disease

• Taxane ± platin

• Cetuximab* ± taxane

• Methotrexate

<10% 2nd line 80%

Cetuximab + platinum-based CT

Erbitax (No P candidates;

PS 2)

Cetuximab maintenance

until PD

1st line

RR: 35-40% Median SV: 10 mo

RR: <10% Median SV: 3-5 mo

3rd line

• Individualise

(slow PROG // previous RR)

• Methotrexate

RR: Anecdotic Median SV: ??

Checkmate 141

Más de 100 hospitales van a indicar tratamientos sin experiencia Existe formación en manejo de afectos adversos, en los resultados del estudio Checkmate 141, pero no en indicación del tratamiento en la práctica clínica

< 15 de los 120 hospitales del TTCC tienen experiencia en ICI - CCC

Conocer el manejo del fármaco

CHECKMATE 141

KEYNOTE 012

KEYNOTE 055

KEYNOTE 048

HAWK ROCHE

Nº patients N=361 N= 192 N=171 N=495 N=112 N=32

Prior treatment lines ≥2

54.5% 57% 75% 29% 100% 100%

AEs G3-4 13.1% vs 35.1%

9% 15% 13.4% vs 36.1%

8% 12%

Efectos de la inmunoterapia? Los conocemos por el uso en otros tumores

CheckMate 141

R 2:1

Nivolumab

3 mg/kg IV Q2W

Investigator’s Choice

• Methotrexate 40 mg/m² IV

weekly

• Docetaxel 30 mg/m² IV

weekly

• Cetuximab 400 mg/m² IV

once, then 250 mg/m²

weekly

Key eligibility criteria

• R/M HNSCC of the oral cavity,

pharynx, or larynx

• Progression on or within 6 months

of last dose of platinum-based

therapy

• Irrespective of no. of prior lines of

therapy

• Documentation of p16 to

determine HPV status

(oropharyngeal)

• Regardless of PD-L1 statusa

Stratification factor

• Prior cetuximab treatment

Randomised, global, Phase III trial of efficacy and safety of nivolumab

versus investigator’s choice

Ferris RL, et al. N Engl J Med 2016;375:1856–1867.

Median OS, mo (95% CI)

HR (97.73% CI)

p-value

7.5 (5.5, 9.1) 0.70 (0.51, 0.96)

0.0101 5.1 (4.0, 6.0)

Main objective:

OS in the overall population

Median OS,

mo (95% CI)

HR

(95% CI)

Nivolumab (n = 240) 7.7 (5.7, 8.8) 0.68 (0.54, 0.86) IC (n = 121) 5.1 (4.0, 6.2)

OS

(%)

10

20

30

40

50

60

70

80

100

90

0

56.5%

43.0%

19.8%

33.6%

22.2%

8.6%

IC

16.9% 11.7%

6.0% 2.3%

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

240 169 132 98 78 57 50 42 37 28

121 88 51 32 23 14 10 8 7 4

Nivo

IC

No. at risk 15

1

10

1

4

0

0

0

Nivo

Symbols represent censored observations

EORTC QLQ - Time To Deterioration CheckMate 141: Nivolumab vs IC in R/M SCCHN After Platinum Therapy

HPV +: 50-70% HPV –: 30-40%

Extraído de: Zandberg DP, Strome SE. The role of the PD-L1:PD-1 pathway in squamous cell carcinoma of the head and neck. Oral Oncol. 2014;50(7):627-32.

Tumor PD-L1 – Dako 28-8 Nivolumab

Tumor and inflammatory cells PD-L1 – Dako 22C3 – Tumor cells PD-L1 Pembrolizumab

Tumor PD-L1. VENTANA SP263 Durvalumab

Immune cells PD-L1 – VENTANA SP142 Atezolizumab

Expresión de PD-L1 en SCCHN

Overall survival according to PD-L1 expression

HR (95% CI)

0.55 (0.36, 0.83)

Ove

rall s

urv

iva

l (%

of

pa

tie

nts

)

Nivolumab (n = 88)

IC (n = 61)

Months

0 3 6 9 12 15 18

0

10

20

30

40

50

60

70

80

90

100 PD-L1 ≥1%

Nivolumab

IC

No. at risk

88 67 44 18 6 0

61 42 20 6 2 0

Ove

rall s

urv

iva

l (%

of

pa

tie

nts

)

PD-L1 <1%

Nivolumab (n = 73)

IC (n = 38)

Months

0 3 6 9 12 15 18

0

10

20

30

40

50

60

70

80

90

100

73 52 33 17 3

38 29 14 6

8

2 0

0

0

HR (95% CI)

0.89 (0.54, 1.45)

Ferris RL, et al. N Engl J Med 2016;375:1856–1867. CI, confidence interval; HR, hazard ratio;

IC, investigator’s choice; PD-L1, programmed death-ligand 1.

Deberemos decidir a qué pacientes no lo damos

PD-L1 <1% Median OS, mo (95% CI)

HR (95% CI)

Nivolumab 6.5 (4.4, 11.7) 0.73 (0.49, 1.09) IC 5.5 (3.7, 8.5)

OS in patients with tumor PD-L1 expression <1%

2-year follow-up (September 2017 data cutoff)

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

Months

0

10

20

30

40

50

60

70

80

90

100

OS

(%)

Nivo

IC

76 54 39 32 29 20 19 17 15 11

40 30 19 14 10 7 5 4 4 1

Nivo

IC

No. at risk

5

0

4

0

3

0

0

0

1-year follow-up (September 2016 data cutoff)

0 3 6 9 12 21 15 18 24 27

Nivo

IC

73 52 37 30 27 13 8 3 1

38 29 18 13 10 5 2 2 0

Nivo

IC

No. at risk

0

0

0

10

20

30

40

50

60

70

80

90

100

OS

(%)

Months

PD-L1 <1% Median OS, mo (95% CI)

HR (95% CI)

Nivolumab 6.1 (4.4, 10.3) 0.83 (0.54, 1.29) IC 5.5 (3.7, 8.5)

10 Ferris RL, et al. IJROBP. 2018. En prensa. Presentado en el Multidisciplinary Head and Neck Cancers Symposium. LBA10.

In patients with tumor PD-L1 expression <1%, the HRs for risk of death trended lower as follow-up time increased, with HR (95% CI) of:

0.89 (0.54, 1.45) at 6-month follow-up (December 2015 data cutoff) 0.83 (0.54, 1.29) at 1-year follow-up (September 2016 data cutoff) 0.73 (0.49, 1.09) at 2-year follow-up (September 2017 data cutoff)

Overall Survival by Tumor PD-L1 Expression and PD-L1+ TAIC Abundance

Tumor PD-L1 ≥1% & PD-L1+ TAIC Abundance Tumor PD-L1 <1% & PD-L1+ TAIC Abundance

• Tumor PD-L1 ≥1% and rare PD-L1+ TAICs: mOS increased with NIVO vs IC (6.7 vs 4.9 months, HR 0.89 [0.44, 1.80]) • Tumor PD-L1 <1% and rare PD-L1+ TAICs: no difference mOS with NIVO vs IC (3.7 vs 4.9 months, HR 1.09 [0.50, 2.36])

1.0

0.8

0.2

0.0

0.6

0.4

Surv

ival

pro

bab

ility

5 10 0 20 25 15 Months

29 22 43 2 0 11

15 8 25 1 4

NIVO

IC

Patients at risk

mOS IC: 4.60 (95% CI: 3.81, 6.24)

mOS NIVO: 9.10 (95% CI: 7.03, 11.56)

HR: 0.43 (0.28, 0.67)

mOS NIVO: 11.73 (95% CI: 5.16, 15.57)

mOS IC: 6.51 (95% CI: 4.01, 10.61)

HR: 0.67 (0.38, 1.18)

1.0

0.8

0.2

0.0

0.6

0.4

Surv

ival

pro

bab

ility

5 10 0 20 25 15 Months

41 25 61 6 0 14

21 6 47 0 2

NIVO

IC

Patients at risk

0

[Tumor PD-L1 ≥1% HR: 0.55 (0.37, 0.77)] [Tumor PD-L1 <1% HR: 0.83 (0.54, 1.29)]

Ferris et al. AACR 2017

Progression-Free Survival

0 3 6 9 12 15 18 Months

Nivolumab 240 79 32 12 4 1 0

Investigator’s Choice

121 43 9 2 0 0

No. at Risk

0

0

10

20

30

40

50

60

70

80

90

100

Pro

gre

ssio

n-F

ree

Su

rviv

al

(% o

f p

atie

nts

)

Median PFS, mo (95% CI)

HR (95% CI)

P-value

Nivolumab (n = 240) 2.0 (1.9, 2.1) 0.89

(0.70, 1.1) 0.3236 Investigator’s Choice (n =

121) 2.3 (1.9, 3.1)

6-month PFS rate (95% CI) 19.7% (14.6, 25.4)

9.9% (5.0, 16.9)

We need to identify patients who go worse

in the first 4 monts of treatment

Hyperprogression (1)

N=34 10/34 (29%) - 9 LR recurrence // 1 M1 alone

Fast Progression(2)

1. Saada-Bouzid E. Ann Oncol 2017; 28:1605-11 2. Ortega A. SEOM 2017

Both related with shorter PFS

Hiperprogresión

1. Saada-Bouzid E. Ann Oncol 2017; 28:1605-11

Sangrado Ahogo Disfagia Infección

Fast progressors (FP)

• Progression in <2 months + fast clinical deterioration • n=18 (26%) • ECOG PS 0–1 at baseline: 94% → ECOG PS 3 at progression: 72%

Long-term responders (LR)

• Time to treatment failure >6 months • n=9 (13%)

Factor FP n (%)

No FP n (%)

p

PD-L1 positive (n=26) 6 (33) 20 (59) 0.2

IM-CT (n=5) 0 (0) 5 (15) 0.1

“Bulky disease” (n=25) 11 (59) 14 (41) 0.1

Tumoural complication (n=15) 10 (55) 5 (15) 0.03

Platinum resistance (<6 month) (n=28)

12 (81) 16 (47) 0.1

Neutrophil count 60980 (SD

813)

5177 (SD 418)

0.03

Factor n=9 Factor n=9

Tumoral response

CR PR SD

2 4 3

Treatment: Anti-PD-1 / PD-L1 IMD

IM-CT

4 1 4

Line 1st

2nd

3/4th

5 4 0

PD-L1: Positive

Negative Unknown

7 1 1

Survival (95% CI) LR 15 mo (5.9–24) No-LR 4 mo (2.6–5.3)

HR 0.4 (0.8–2); p=0.2

Log-Rank p=0.03

1.0

0.8

0.6

0.4

0.4

0.0

Cu

mu

lati

ve s

urv

ival

0 5 10 15 20 25 30

Time (months)

Median OS (95% CI)

No-FP 14 mo (8.6–20) FP 2 mo (1.2–2.0)

HR 5.6 (2.7–12); p=0.001

Log-rank p=0.02

1.0

0.8

0.6

0.4

0.4

0.0

Cu

mu

lati

ve s

urv

ival

0 5 10 15 20 25 30

Time (months)

Results: long-term survivors versus fast progressors

Ortega A, et al. SEOM 2017

100

Ch

ange

Fro

m B

ase

line

in

Sum

of

Targ

et

Lesi

on

s (%

)

75

50

25

0

-25

-50

-75

-100

Weeks

Responders

0 6 12 18 24 30 36 42 48 54 60 66 72 78 84

100

Ch

ange

Fro

m B

ase

line

in

Sum

of

Targ

et

Lesi

on

s (%

)

75

50

25

0

-25

-50

-75

-100

Weeks

Stable Disease

0 6 12 18 24 30 36 42 48 54 60 66 72 78 84

100

Ch

ange

Fro

m B

ase

line

in

Sum

of

Targ

et

Lesi

on

s (%

)

75

50

25

0

-25

-50

-75

-100

Weeks

Responders

0 6 12 18 24 30 36 42 48 54 60 66 72 78 84

100

Ch

ange

Fro

m B

ase

line

in

Sum

of

Targ

et

Lesi

on

s (%

)

75

50

25

0

-25

-50

-75

-100

Weeks

Stable Disease

0 6 12 18 24 30 36 42 48 54 60 66 72 78 84

Patrones respuesta Checkmate 141

Nivolumab Investigator’s Choice

1st occurrence of new lesion Off treatment Time of first response

16

*Evaluable Analysis Set (N=111); BICR Assessment using RECIST 1.1

Durvalumab (N=111)

-110

-100

-90

-80

-70

-60

-50

-40

-30

-20

-10

0

10

20

30

40

50

60

70

80

90

100

110

120 B

est

ch

ange

fro

m b

ase

line

in t

arge

t le

sio

n s

ize

(%

)

39.6% of patients had a decrease in target lesions

Hawk trial – Enriched PDL1 patients Best % change from baseline in tumor size*

17

*Evaluable Analysis Set (N=111); BICR Assessment using RECIST 1.1

Hawk trial – Enriched PDL1 patients Best % change from baseline in tumor size*

Durvalumab (N=111)

-110

-100

-90

-80

-70

-60

-50

-40

-30

-20

-10

0

10

20

30

40

50

60

70

80

90

100

110

120 B

est

ch

ange

fro

m b

ase

line

in t

arge

t le

sio

n s

ize

(%

)

61.4% of patients had a increase in target

lesions

18

Siu L. Multidisciplinary Head and Neck Cancer Symposiu. Arizona. Febrero-2018

ESTUDIO CONDOR

Tumor PD-L1< 25% - VENTANA SP263

19

ESTUDIO CONDOR

Siu L. Multidisciplinary Head and Neck Cancer Symposiu. Arizona. Febrero-2018

20

Tumor and inflammatory cells PD-L1 – Dako 22C3 – Tumor cells PD-L1

Keynote 040 Pembrolizumab phase III study

All pts CPS≥1 TPS≥50

RR 14.6% vs 10.1% 17.3% vs 9.9% 26,6% vs 9,2%

RC 4 vs 1 3 1

HR OS 0.81 - ns 0.75 - p.0078 0.54 - p.0017

Indicación

Seguiremos ficha técnica o ampliaremos indicaciones?

- Nasofaringe?

- Senos maxilares, glándulas salivares?

- PS 2?

- Unfit para CDDP?

21

No existe evidencia para ninguna de ellas!!!

Soportar el gasto qué supone

Algunos cánceres Nuevos fármacos Inmunoterapia Combinaciones inmuno

Otras enfermedades

Mama Pertuzumab Inh. Ciclinas Everolimus,...

Neurológicas

Colon Avastin, antiEGFR Cardivasculares

Próstata Abiraterona Reumatológicas

Pulmón AntiEGFR, antiALK, Ros,...

+++ En estudio Infecciosas

Urológicos Sutent,... ++ En estudio

Melanoma Anti BRAF + Utilizadas

Hematológicos Multitud ++ En estudio

Ca CyC Cetuximab + En estudio

Ovario Inh. Ciclinas Avastin

Prevención Asistencia 1aria

22

Sistema sanitario finito y equitativo

• ¿es esta indicación sostenible?

CONCLUSION - UK:

While nivolumab improves overall survival, at its

current cost it would not be considered a cost-effective

treatment option for patients with HNC.

CONCLUSION - USA: Nivolumab is preferred to single-agent cetuximab but requires a willingness-to-pay of at least $150,000/QALY to be considered cost-effective when compared to docetaxel or methotrexate. Selection by PD-L1 does not markedly improve the cost-effectiveness of nivolumab. This informs patient selection and clinical care-path development.

CONCLUCION – CANADA:

We conclude that although nivolumab offers clinical

benefit for the treatment of r/m HNSCC over current

regimens, it is not cost-effective based on its list price.

Nivolumab would be cost-effective if its price was reduced

by 20%. Our subgroup analysis seemed to indicate

that nivolumab might be cost-effective for tumors with expression of programmed death-ligand 1 >5%.

Conclusiones

• Existe una base racional para el desarrollo de inmunoterapia en CCC.

• Nivolumab ha sido el primer IO aprobado en la patología.

• Simplemente estamos empezando, y hemos de tomar conciencia de a qué pacientes beneficiamos, pero también de que podemos perjudicar.

• Precisaremos de una fuerte base traslacional para acertar en el desarrollo clínico.

• El precio del fármaco puede afectar a su incorporación a la clínica.

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