Incorporación de la inmunoterapia a la estrategia de tratamiento del cáncer de cabeza y cuello.

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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

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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

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Conocer el manejo del fármaco

CHECKMAT

E 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

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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:

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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) O S (%) 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

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EORTC QLQ - Time To Deterioration

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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

(9)

Overall survival according to PD-L1 expression

HR (95% CI)

0.55 (0.36, 0.83)

O v eral l su rv iv al ( % of pa ti en ts) 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 O v eral l su rv iv al ( % of pa ti en ts) 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. IC, investigator’s choice; PD-L1, programmed death-CI, confidence interval; HR, hazard ratio; ligand 1.

Deberemos decidir a qué pacientes no lo damos

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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 15 18 21 24 27 30 33 36 39 Months 0 10 20 30 40 50 60 70 80 90 100 O S (% ) 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 15 18 21 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 O S (% ) 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)

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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 Su rv iv al p ro b ab ili ty 5 10 0 15 20 25 Months 29 22 43 11 2 0 15 8 25 4 1 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 Su rv iv al p ro b ab ili ty 5 10 0 15 20 25 Months 41 25 61 14 6 0 21 6 47 2 0 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)]

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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 Pr og res si on -Fr ee Sur viv al (% of pa tie n ts)

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

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Hiperprogresión

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

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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 Cumu lat iv e su rv iv al 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 Cumu lat iv e su rv iv al 0 5 10 15 20 25 30 Time (months)

Results: long-term survivors versus fast progressors

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100 C hange F rom B ase line in Sum of Ta rg e t Le si ons (% ) 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 C hange F rom B ase line in Sum of Ta rg e t Le si ons (% ) 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 C hange F rom B ase line in Sum of Ta rg e t Le si ons (% ) 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 C hange F rom B ase line in Sum of Ta rg e t Le si ons (% ) 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

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*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 e st ch an ge fr o m b asel in e in t ar ge t le si o n si ze (% )

39.6% of patients had a decrease in target lesions

Hawk trial – Enriched PDL1 patients

(17)

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*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 e st ch an ge fr o m b asel in e in t ar ge t le si o n si ze (% )

61.4% of patients had a increase in target

lesions

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

ESTUDIO

CONDOR

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ESTUDIO CONDOR

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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

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Indicación

Seguiremos ficha técnica o ampliaremos

indicaciones?

- Nasofaringe?

- Senos maxilares, glándulas salivares?

- PS 2?

- Unfit para CDDP?

21

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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

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• ¿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%.

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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.

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