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TUMORES DE CABEZA Y CUELLO RECURRENTES /METASTÁSICOS

A FAVOR DE LA INMUNOTERAPIA

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

AÑO 2001: NACE EL TTCC

3

3

LOGROS DE LA QUIMIOTERAPIA

Brazo control más efectivo de lo esperado

TUMORES DE CABEZA Y CUELLO

ASCO 2017-Bevacizumab en Recurrente Metastásico (Abstract 6000)_ Dr Argiris-

¿Por qué nos hemos vuelto locos con la inmuno?

¿Por qué nos hemos vuelto locos con la inmuno?

5

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

7

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

American Society of Clinical Oncology (ASCO) 2016 Congress Presentations

8

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

9

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.

CARACTERISTICAS DE LOS PACIENTES

10

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)

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

11

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)

Overall Survival Nivolumab in R/M SCCHN After Platinum Therapy

BENEFICIO EN SUBGRUPOS

13

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 13

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

14

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

15

Nivolumab

(n = 240)

Investigator’s Choice

(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

16

Ove

rall S

urv

iva

l (%

of

pa

tie

nts

)

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

Ove

rall S

urv

iva

l (%

of

pa

tie

nts

)

Nivolumab (n = 63)

Investigator’s Choice (n = 29)

Nivolumab (n = 50)

Investigator’s Choice (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

17

Investigator’s Choice (n = 61)

Nivolumab (n = 88)

PD-L1 ≥ 1% PD-L1 < 1%

HR (95% CI)

0.55 (0.36, 0.83)

Ove

rall S

urv

iva

l (%

of

pa

tie

nts

)

Nivolumab (n = 73)

Investigator’s Choice (n = 38)

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

Ove

rall S

urv

iva

l (%

of

pa

tie

nts

)

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

18

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

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

19

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

20

Event

Nivolumab (n = 236)

Investigator’s Choice (n = 111)

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

TUMORES DE CABEZA Y CUELLO Subestudios Checkmate 141: NIVOLUMAB EN RECURRENTE / METASTÁSICO. Poster Discussion.

Abstracts 6019 y 6020.

TUMORES DE CABEZA Y CUELLO Subestudios Checkmate 141: NIVOLUMAB EN RECURRENTE / METASTÁSICO

Exposición previa a cetuximab

Primera línea

TUMORES DE CABEZA Y CUELLO Fase I ECHO-204 Nivolumab + Epacadostat en RECURRENTE/METASTÁSICO. Abstract 3003

Pacientes pretratados. 23% de respuestas. Respuestas duraderas. Toxicidad manejable.

26

Journal of Clinical Oncology - published online before print

September 30, 2016

TUMORES DE CABEZA Y CUELLO Subestudio de biomarcadores genómicos del KEYNOTE 012(pembrolizumab) RECURRENTE/METASTÁSICO

Dr Haddad

Abstract 6009

Carga mutacional (ML) y patrón génico de expresión de inflamación de linfocitos T (GEP) se correlacionan con la respuesta al pembrolizumab

59% 23%

33

ACTUALIZACIÓN ESMO 2016. KEYNOTE 055. HADDAD

TUMORES DE CABEZA Y CUELLO Fase I/II ECHO-202-KEYNOTE-037 Pembrolizumab + Epacadostat en RECURRENTE/METASTÁSICO

Pacientes pretratados. 34% de respuestas. Respuestas duraderas. Toxicidad manejable.

Abstract 6010

36

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)

Do

se

esca

latio

n

10 mg/kg q2w x 1 year

Do

se

exp

an

sio

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

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

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DEBEMOS SEGUIR INVESTIGANDO

TUMORES DE CABEZA Y CUELLO CONCLUSIONES

• La inmunoterapia cobra protagonismo en un escenario de fracaso al platino en enfermedad metastásica/recurrente , incluso en fallo a tratamiento locorregional basado en platino.

• Demuestra eficacia en pacientes pretratados con varias líneas.

• Perfil de toxicidad excelente.

• Empezamos a investigar combinaciones de inmunocheckpoints.

• Los largos respondedores son los responsables del aplanamiento de la curva de supervivencia global

• Necesitamos biomarcadores para identificar el subgrupo de pacientes que se van a beneficiar de la inmunoterapia.

GRACIAS