Post on 11-Feb-2020
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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
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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?
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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
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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
American Society of Clinical Oncology (ASCO) 2016 Congress Presentations
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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
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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
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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
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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
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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
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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
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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
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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
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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)
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
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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
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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)
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.
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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%
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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
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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)
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