INMUNOTERAPIA EN CÁNCER DE CABEZA Y CUELLO · HISTORIA DEL TRATAMIENTO DE LOS TUMORES DE CABEZA Y...

INMUNOTERAPIA EN CÁNCER DE CABEZA Y CUELLO

JULIO LAMBEA SORROSAL Servicio de Oncología Médica

CLÍNICO LOZANO BLESA ZARAGOZA

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HISTORIA DEL TRATAMIENTO DE LOS TUMORES DE CABEZA Y CUELLO

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HISTORIA DEL TRATAMIENTO

DE LOS TUMORES DE CABEZA

Y CUELLO

AÑO 2000: 1º SIMPOSIUM INTERNACIONAL

DE TUMORES DE CABEZA Y CUELLO AÑO 2001:

NACE EL TTCC

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En 1884 se había observado cierta relación entre la infección por erisipela y la

remisión de ciertos tumores y se dice que Anton Chekhov recogió datos

sobre esa relación.

FDA Grants Nivolumab Breakthrough Designation for Head

and Neck Cancer

Published Online: Monday, Apr 25, 2016

The FDA has granted a breakthrough therapy designation to nivolumab (Opdivo)

as a treatment for patients with recurrent or metastatic squamous cell carcinoma

of the head and neck (SCCHN) following a platinum-based therapy, according to

the developer of the PD-1 inhibitor Bristol-Myers Squibb

The FDA is expected to act on the review by Nov. 11, 2016, according to a written

statement from Bristol-Myers Squib, makers of nivolumab.

19 Apr 2016

INMUNOTERAPIA

http://www.onclive.com/printer?url=/web-exclusives/fda-grants-nivolumab-breakthrough-designation-for-head-and-neck-cancer

http://www.onclive.com/printer?url=/web-exclusives/fda-grants-nivolumab-breakthrough-designation-for-head-and-neck-cancer

http://news.bms.com/press-release/bristolmyers/bristol-myers-squibb-announces-regulatory-updates-opdivo-nivolumab-previo

http://news.bms.com/press-release/bristolmyers/bristol-myers-squibb-announces-regulatory-updates-opdivo-nivolumab-previo

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The FDA granted accelerated approval based on early data from 174 patients with HNSCC enrolled in the

nonrandomized KEYNOTE-012 trial. These patients had HNSCC that continued to grow and spread despite

treatment with a platinum-containing chemotherapy; the majority of patients in the trial previously had received at

least two different courses of treatment.

According to the FDA approval summary, 28 patients (16%) experienced a tumor response following treatment with

pembrolizumab. In 23 (82%) of those patients, the tumor response lasted for 6 months or longer, and several have

lasted for more than 2 years.

Several patients in the trial had a complete response, according to data from the trial presented in JuneExit

Disclaimer at the American Society of Clinical Oncology annual meeting by trial investigator Ranee Mehra, M.D.

INMUNOTERAPIA

http://www.fda.gov/forpatients/approvals/fast/ucm405447.htm

http://www.fda.gov/Drugs/InformationOnDrugs/ApprovedDrugs/ucm515627.htm

https://www.cancer.gov/Common/PopUps/popDefinition.aspx?id=CDR0000044085&version=Patient&language=English

https://www.cancer.gov/Common/PopUps/popDefinition.aspx?id=CDR0000045652&version=Patient&language=English

http://meetinglibrary.asco.org/content/168015-176

http://meetinglibrary.asco.org/content/168015-176

https://www.cancer.gov/global/web/policies/exit



http://www.google.es/url?sa=i&rct=j&q=&esrc=s&source=images&cd=&cad=rja&uact=8&ved=0ahUKEwjazIm7vozQAhWGExoKHf1MD7sQjRwIBw&url=http://www.oacancer.com/keytruda-melanoma-cancer-treatment/&bvm=bv.137132246,d.d2s&psig=AFQjCNGvnByFJRm41PrzH6AB6g6TOEkv8A&ust=1478259052386311

¿Por qué nos hemos vuelto locos con la inmunoterapia?

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RETOS Y PROBLEMAS DE LA INMUNOTERAPIA

-Cuando parar, cómo valorar la respuesta?

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PROBLEMAS -Cuando parar, cómo valorar la respuesta?

-Qué diana seleccionar para diseñar tratamiento?

Upadhyay R et al. Lymphoma: Immune Evasion Strategies.

Cancers 2015, 7, 736-762

PROBLEMAS



-Sostenibilidad? Combinaciones? De momento en cabeza y cuello solo en ensayo.

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DESDE EL PUNTO DE VISTA DEL ONCÓLOGO Y DEL PACIENTE MERECE LA PENA

http://www.google.es/url?sa=i&rct=j&q=&esrc=s&source=images&cd=&cad=rja&uact=8&ved=0ahUKEwisivLpiYvQAhXJPRoKHUZCC3MQjRwIBw&url=http://www.laportadacanada.com/noticia/canadienses-pagan-medicamentos-mas-caros-que-en-otros-paises/1998&bvm=bv.137132246,d.cGw&psig=AFQjCNGcLcIp6m8OQbxbXcUGPCigrY6QmQ&ust=1478210564357065

http://www.google.es/url?sa=i&rct=j&q=&esrc=s&source=images&cd=&cad=rja&uact=8&ved=0ahUKEwiWzof-iovQAhXG0hoKHeYYCAIQjRwIBw&url=http://liberesudinero.blogspot.com/&bvm=bv.137132246,d.cGw&psig=AFQjCNHXvI9PzWpDqAvEdIJUDAB7SVYfig&ust=1478210866891279

http://www.google.es/url?sa=i&rct=j&q=&esrc=s&source=images&cd=&cad=rja&uact=8&ved=0ahUKEwiv3vGP5IrQAhWDVxoKHRjHDuUQjRwIBw&url=http://thelancet.com/journals/lanonc/article/PIIS1470-2045(16)30366-7/fulltext&bvm=bv.137132246,d.d24&psig=AFQjCNFxaIS4c_RL_H5AFgFOHshPMv5yPg&ust=1478200492113013

PROBLEMAS




-Selección de pacientes ¿PD-L1?

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PROBLEMAS




-Selección de pacientes ¿PD-L1? ¿PD-L2? ¿HPV? ¿VEB?

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PROBLEMAS




-Selección de pacientes ¿PD-L1? ¿PD-L2? ¿HPV? ¿VEB?

-¿Qué dar a la progresión?

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Study First

Author SCCHN Presentatio

n Type Slide

Range

CheckMate

141 Ferris

Further Evaluations of Nivolumab Versus Investigator’s Choice

Chemotherapy for Recurrent or Metastatic (R/M) Squamous Cell

Carcinoma of the Head and Neck (SCCHN): CheckMate 141

Oral 385-406

Phase 3 CheckMate 141 Study Design Nivolumab in R/M SCCHN After Platinum Therapy

• Randomized, global, phase 3 trial of the efficacy and safety of nivolumab vs investigator’s choice in patients with R/M SCCHN

20

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 SCCHN 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

Primary endpoint

• OS

Other endpoints

• PFS

• ORR

• Safety

• DOR

• Biomarkers

• Quality of life

aTissue required for testing.

DOR = duration of response; IV = intravenous; ORR = objective response rate; PFS = progression-free survival; Q2W = once every 2 weeks; R = randomized. Clinicaltrials.gov NCT02105636.

Nivolumab

(n = 240)

Investigator’s

Choice

(n = 121)

Total

(N = 361)

Median age, years 59.0 61.0 60.0

<65, n (%) 172 (71.7) 76 (62.8) 248 (68.7)

Smoking/tobacco use, n (%)

Current/former 191 (79.6) 85 (70.2) 276 (76.5)

Never 39 (16.3) 31 (25.6) 70 (19.4)

ECOG performance status, n (%)

0 49 (20.4) 23 (19.0) 72 (19.9)

1 189 (78.8) 94 (77.7) 283 (78.4)

≥2 1 (0.4) 3 (2.5) 4 (1.1)

Not reported 1 (0.4) 1 (0.8) 2 (0.6)

Number of prior lines of systemic cancer therapy, n (%)

1 106 (44.2) 58 (47.9) 164 (45.4)

2 80 (33.3) 45 (37.2) 125 (34.6)

≥3 54 (22.5) 18 (14.9) 72 (19.9)

p16 statusa,b, n (%)

Positive 63 (26.3) 29 (24.0) 92 (25.5)

Negative 50 (20.8) 36 (29.8) 86 (23.8)

Not tested 127 (52.9) 56 (46.3) 183 (50.7)

Demographics Nivolumab in R/M SCCHN After Platinum Therapy

21 aRequired from patients with oropharyngeal cancer only. bDetermined via p16 immunohistochemistry ECOG = Eastern Cooperative Oncology Group.

Median OS,

mo (95% CI)

HR

(97.73% CI) P-value

Nivolumab (n = 240) 7.5 (5.5, 9.1) 0.70

(0.51, 0.96) 0.0101

Investigator’s Choice (n = 121) 5.1 (4.0, 6.0)

Overall Survival Nivolumab in R/M SCCHN After Platinum Therapy

22

Months Nivolumab 240 167 109 52 24 7 0

Investigator’s

Choice 121 87 42 17 5 1

No. at Risk

0

Overa

ll S

urv

ival

(% o

f p

ati

en

ts)

0 3 6 9 12 15 18 0

10

20

30 40

50 60

70

80 90

100

1-year OS rate (95% CI)

36.0% (28.5, 43.4)

16.6% (8.6, 26.8)

No. of patients Overall Survival

Subgroupsa Nivolumab IC Unstratified Hazard Ratio (95% CI)

Overall 240 121 0.69 (0.53, 0.91)

Age category, years

<65 172 76 0.64 (0.45, 0.89)

≥65 to <75 56 39 0.93 (0.56, 1.54)

≥75 12 6

ECOG performance status

0 49 23 0.60 (0.30, 1.23)

≥1 190 97 0.71 (0.53, 0.96)

Tobacco use

Current/Former 191 85 0.71 (0.52, 0.99)

Never 39 31 0.58 (0.32, 1.06)

Prior lines of systemic therapy, n

1 106 58 0.72 (0.48, 1.07)

2 80 45 0.64 (0.40, 1.00)

≥3 54 18 0.77 (0.38, 1.57)

Intended IC therapy

Methotrexate 119 52 0.64 (0.43, 0.96)

Docetaxel 88 54 0.82 (0.53, 1.28)

Cetuximab 33 15 0.47 (0.22, 1.01)

Favors Nivolumab Favors IC

0.125 0.25 0.5 1 2 aHazard ratios were not calculated for subgroups

with fewer than 20 patients across both arms 23

Progression-Free Survival Nivolumab in R/M SCCHN After Platinum Therapy

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Months Nivolumab 240 79 32 12 4 1 0 Investigator’s

Choice 121 43 9 2 0 0

No. at Risk

0

Pro

gre

ss

ion

-Fre

e S

urv

ival

(% o

f p

ati

en

ts)

0 3 6 9 12 15 18 0

10

20

30 40

50 60

70

80 90

100

6-month PFS rate (95% CI)

19.7% (14.6, 25.4)

9.9% (5.0, 16.9)

Median OS, mo

(95% CI)

HR

(97.73% 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)

Objective Response Rate Nivolumab in R/M SCCHN After Platinum Therapy

25

Nivolumab

(n = 240)


(n = 121)

Objective response rate, n (%) 32 (13.3) 7 (5.8)

95% CI 9.3, 18.3 2.4, 11.6

Best overall response, n (%)

Complete response 6 (2.5) 1 (0.8)

Partial response 26 (10.8) 6 (5.0)

Stable disease 55 (22.9) 43 (35.5)

Progressive disease 100 (41.7) 42 (34.7)

Not determined 53 (22.1) 29 (24.0)

Time to response, mo

Median (range) 2.1 (1.8–7.4) 2.0 (1.9–4.6)

Overall Survival by p16 Status Nivolumab in R/M SCCHN After Platinum Therapy

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Overa

ll S

urv

ival

(% o

f

pati

en

ts)

Months 0 3 6 9 12 15 18

0

10

20

30

40

50

60

70

80

90

100

Months 0 3 6 9 12 15 18

0

10

20

30

40

50

60

70

80

90

100

Overa

ll S

urv

ival

(% o

f

pati

en

ts)

Nivolumab (n

= 63)


(n = 29)

Nivolumab (n

= 50)


(n = 36)

HR (95% CI)

0.56 (0.32, 0.99)

HR (95% CI)

0.73 (0.42, 1.25)

p16-Negative p16-Positive

Nivolumab

Investigator’s

Choice

No. at Risk 63 49 35 0

29 20 11 0

18

4

10

1

3

0

50 32 25 0

36 26 13 0

12

7

6

3

1

1

Overall Survival by Tumor PD-L1 Expression at 1% Nivolumab in R/M SCCHN After Platinum Therapy

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Investigator’s Choice (n = 61)

Nivolumab (n = 88)

PD-L1 ≥ 1% PD-L1 < 1%

HR (95% CI)

0.55 (0.36, 0.83)

Overa

ll S

urv

ival

(% o

f

pati

en

ts)

Nivolumab (n = 73)


HR (95% CI)

0.89 (0.54, 1.45)

Months 0 3 6 9 12 15 18

0

10

20

30

40

50

60

70

80

90

100

Overa

ll S

urv

ival

(% o

f

pati

en

ts)

Nivolumab

Investigator’s

Choice

No. at Risk 88 67 44

61 42 20

18

6

6

2

0

0

73 52 33 0

38 29 14 0

17

6

8

2

3

0

Months 0 3 6 9 12 15 18

0

10

20

30

40

50

60

70

80

90

100

Overall Survival by Tumor PD-L1 Expression Level Nivolumab in R/M SCCHN After Platinum Therapy

28

PD-L1

Expression

Nivolumab n = 240

Investigator’s Choice n = 121

n Median OS,

mo n Median OS,

mo Unstratified Hazard Ratio (95% CI)

≥ 1% 88 8.7 61 4.6 0.55 (0.36, 0.83)

≥ 5% 54 8.8 43 4.6 0.50 (0.30, 0.83)

≥ 10% 43 8.7 34 5.2 0.56 (0.31, 1.01)

< 1% 73 5.7 38 5.8 0.89 (0.54, 1.45)

< 5% 107 7.0 56 5.1 0.81 (0.55, 1.21)

< 10% 118 7.2 65 4.6 0.73 (0.50, 1.06)

Favors

Nivolumab

Favors

Investigator’s

Choice

0.25 0.5 1 2

Overall Survival by Tumor p16 Status and PD-L1 Expression at 1%

• The hazard ratios for OS favored nivolumab vs investigator’s choice for all subgroups

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Nivolumab Investigator’s Choice

n Median OS, mo n Median OS, mo

Hazard ratio

(95% CI)

PD-L1 ≥ 1%/p16-positive 23 8.8 14 3.9 0.50 (0.21, 1.19)

PD-L1 ≥ 1%/p16-negative 17 8.8 16 5.6 0.44 (0.18, 1.10)

PD-L1 < 1%/p16-positive 24 10.0 10 6.4 0.55 (0.22, 1.39)

PD-L1 < 1%/p16-negative 14 7.1 12 7.4 0.82 (0.31, 2.19)

Objective Response Rate by PD-L1 Expression Nivolumab in R/M SCCHN After Platinum Therapy

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PD-L1

Expression

Level

Objective Response Rate

Nivolumab Investigator’s Choice

n/N % n/N %

≥ 1% 15/88 17.0 1/61 1.6

≥ 5% 12/54 22.2 1/43 2.3

≥ 10% 12/43 27.9 1/34 2.9

< 1% 9/73 12.3 4/38 10.5

< 5% 12/107 11.2 4/56 7.1

< 10% 12/118 10.2 4/65 6.2

Treatment-Related Adverse Events Nivolumab in R/M SCCHN After Platinum Therapy

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Event

Nivolumab (n = 236)


Any grade n (%)

Grade 3–4 n (%)

Any grade n (%)

Grade 3–4 n (%)

Any treatment-related AE in ≥ 10% of patientsa 139 (58.9) 31 (13.1) 86 (77.5) 39 (35.1)

Fatigue 33 (14.0) 5 (2.1) 19 (17.1) 3 (2.7)

Nausea 20 (8.5) 0 23 (20.7) 1 (0.9)

Diarrhea 16 (6.8) 0 15 (13.5) 2 (1.8)

Anemia 12 (5.1) 3 (1.3) 18 (16.2) 5 (4.5)

Asthenia 10 (4.2) 1 (0.4) 16 (14.4) 2 (1.8)

Mucosal inflammation 3 (1.3) 0 14 (12.6) 2 (1.8)

Alopecia 0 0 14 (12.6) 3 (2.7)

Treatment-related select AEs

Skin 37 (15.7) 0 14 (12.6) 2 (1.8)

Endocrine 18 (7.6) 1 (0.4) 1 (0.9) 0

Gastrointestinal 16 (6.8) 0 16 (14.4) 2 (1.8)

Hepatic 5 (2.1) 2 (0.8) 4 (3.6) 1 (0.9)

Pulmonary 5 (2.1) 2 (0.8) 1 (0.9) 0

Hypersensitivity/infusion reaction 3 (1.3) 0 2 (1.8) 1 (0.9)

Renal 1 (0.4) 0 2 (1.8) 1 (0.9) aOne Grade 5 event (hypercalcemia) in the nivolumab arm and one Grade 5 event (lung infection) in the investigator’s choice arm were reported.

A second death occurred in the nivolumab arm subsequent to pneumonitis.

Quality of Life and Symptom Burden Actualización ESMO 2016 y NEJM

34

Journal of Clinical Oncology - published

online before print September 30, 2016

ASCO 2016

59% 23%

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FASE I DURVALUMAB. ESMO 2016

Durvalumab

0.1–10 mg/kg q2w

15 mg/kg q3w

x 1 year

Study design

Key inclusion criteria Key exclusion criteria

Confirmed recurrent/metastatic SCCHN incurable with local

therapy Active autoimmune disease

ECOG PS 0–1 Prior severe or persistent irAE

Adequate organ function Prior anti-PD-1 or anti-PD-L1 therapy

Prior anti-CTLA-4 therapy permitted

PD-L1+ and PD-L1– patients

• After one year of treatment, patients enter follow-up

• Treatment beyond progressive disease was permitted in the absence of clinical deterioration and if the investigator considered that the patient continued to receive benefit

• Upon progressive disease during the follow-up period, retreatment was offered for up to an additional 12 months

Hepatocellular carcinoma (hepatitis C and B virus-positive)

Dose e

scala

tion

10 mg/kg q2w x 1 year

Dose e

xpansio

n

Pancreatic adenocarcinoma

Melanoma (uveal + cutaneous)

Gastroesophageal cancer

Triple-negative breast cancer

Eight additional tumour types

NSCLC (squamous + non-squamous)

SCCHN (PD-L1+ and PD-L1–)

Safety and Efficacy of Durvalumab, an Anti-PD-L1 Antibody, in Patients from a

Squamous Cell Carcinoma of the Head and Neck (SCCHN) Expansion Cohort

Segal NH, et al. Poster presented at ASCO 2015. Poster 3011

44 Segal NH, et al. Presented at ESMO 2016.

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DEBEMOS SEGUIR INVESTIGANDO

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CONCLUSIONES

•La inmunoterapia ofrece una oportunidad a pacientes

que no tenían posibilidades, con sólida evidencia

científica.

•Existen multitud de ensayos en marcha que

posicionaran el uso de estos fármacos.

•El beneficio en SG de estos pacientes hoy por hoy se

produce en respondedores. A priori no sabemos

seleccionarlos adecuadamente.

•Es necesario explorar combinaciones con

quimioterapia de estos fármacos para intentar ampliar

el beneficio a más pacientes.

GRACIAS

INMUNOTERAPIA EN CÁNCER DE CABEZA Y CUELLO · HISTORIA DEL TRATAMIENTO DE LOS TUMORES DE CABEZA Y...

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