inmunoterapia en cÁncer de cabeza y cuello · historia del tratamiento de los tumores de cabeza y...
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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
3
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
5
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.
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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
8
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
¿Por qué nos hemos vuelto locos con la inmunoterapia?
9
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¿Por qué nos hemos vuelto locos con la inmunoterapia?
¿Por qué nos hemos vuelto locos con la inmunoterapia?
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¿Por qué nos hemos vuelto locos con la inmunoterapia?
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
-Cuando parar, cómo valorar la respuesta?
-Qué diana seleccionar para diseñar tratamiento?
-Sostenibilidad? Combinaciones? De momento en cabeza y cuello solo en ensayo.
15
DESDE EL PUNTO DE VISTA DEL ONCÓLOGO Y DEL PACIENTE MERECE LA PENA
PROBLEMAS
-Cuando parar, cómo valorar la respuesta?
-Qué diana seleccionar para diseñar tratamiento?
-Sostenibilidad? Combinaciones? De momento en cabeza y cuello solo en ensayo.
-Selección de pacientes ¿PD-L1?
16
PROBLEMAS
-Cuando parar, cómo valorar la respuesta?
-Qué diana seleccionar para diseñar tratamiento?
-Sostenibilidad? Combinaciones? De momento en cabeza y cuello solo en ensayo.
-Selección de pacientes ¿PD-L1? ¿PD-L2? ¿HPV? ¿VEB?
17
PROBLEMAS
-Cuando parar, cómo valorar la respuesta?
-Qué diana seleccionar para diseñar tratamiento?
-Sostenibilidad? Combinaciones? De momento en cabeza y cuello solo en ensayo.
-Selección de pacientes ¿PD-L1? ¿PD-L2? ¿HPV? ¿VEB?
-¿Qué dar a la progresión?
18
19
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
24
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)
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
26
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)
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
27
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)
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
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
29
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
30
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
31
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
34
Journal of Clinical Oncology - published
online before print September 30, 2016
ASCO 2016
59% 23%
43
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.
45
DEBEMOS SEGUIR INVESTIGANDO
46
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