aplicaciones de la inmunoterapia · keynote-024: diseño del estudio de pembrolizumab frente a...
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APLICACIONES DE LA INMUNOTERAPIA
CÁNCER DE PULMÓN
Histologic Subtypes
Wahbah M, et al. Ann Diagn Pathol. 2007;11:89-96.American Cancer Society database.
Decreasing Incidence of Squamous Cell Subtype Over Time
85% of lung cancers are NSCLC
Adenocarcinoma
Squamous cell carcinoma
Large cell carcinoma
Other or not otherwise specified
40%20%
10% to 15%
25% to 30%
Adenocarcinoma
Squamous cell
Large cell
45
40
35
30
25
20
15
10
5
0
Ca
nce
r In
cid
en
ce (
%)
Yr of Diagnosis (3-Yr Moving Average)
Localizado16%
LocamenteAanzado22%
Metastásico57%
NoConocido
5%
ESTADIOALDIAGNÓSTICO
4,5%
28,9%
55,6%
7,5%
0 10 20 30 40 50 60
Metastásico
LocalmenteAvanzado
Localizado
Noconocido
Supervivenciaa5años
LOCAL RESECABLECirugía +- QT
LOCAL RESECABLE AVANZADOQT neoadyuvante + tratamiento local
LOCAL NO RESECABLE RT + QT
METASTÁSICOS 1L
QuimioterapiaAntiangiogénicos *
2LQuimioterapia
TRATAMIENTO FUTURO INMUNOTERAPIA
INMUNOTERAPIA ADYUNATE
INMUNOTERAPIA NEOADYUVANTE
2019 INMUNOTERAPIA +- QT
2019 IO MANTENIMIENTORT+QT+IO
2015 INMUNOTERAPIA
1970 1980 1990 2000
Docetaxel2000
2010
Pemetrexed‡
2009
Median OS, months
12+~8–10
~6~2–4
13+
Carboplatin*1989
Gemcitabine1996
Vinorelbine1994
Bevacizumab‡
2006Paclitaxel1998
Cisplatin*1978
Despite advances, only small incrementalOS benefits in overall patient population
*Not approved in NSCLC, but commonly used; †Restricted to patients participating in a clinical trial or continuing to benefit from treatment already initiated; ‡Non-squamous NSCLC only; §ALK-positive NSCLC only; **EGFR exon 19 deletions or exon 21 (L858R) substitution mutations only;#Afatinib is approved for the treatment of patients with activating EGFR mutations but only PFS data have been published (May 2014).
U.S. Food and Drug Administration. Available at www.fda.gov. Accessed September 2014; European Medicines Agency. Available at
http://www.ema.europa.eu. Accessed September 2014; NCCN Guidelines. Non-small cell lung cancer. v3.2014.
Dr. Mark A. Socinski https://bit.ly/2Ld0jng
Mantenimiento
5-Y OS: 13.4% NIVO vs 2.6% DOC
Additional Exploratory Biomarkers Under Investigation for I-O Therapies1−12
Biomarker
investigations
TILs/
immunoscore
(eg, CD4 and
CD8 T cells)Gene expression
signatures
Other tumor immune
marker expression
(eg, CTLA-4, PD-L2)
Mutational load/burden,
neo-antigens
TCR
sequencing Other known oncogenic
driver mutations
(eg, EGFR, KRAS, BRAF)
Tumor
biomarkers Immune monitoring: absolute
lymphocyte count, circulating
T-cell subsets
Gene expression
profiling:
peripheral blood
TCR
sequencing
Serum chemokines/cytokines:
interferons, interferon
inducible factors, serum
soluble factors
sPD-L1
Circulating
miRNAsAntitumor
antibodies
SNPs
(germline)
Peripheral
biomarkers
1. Sosman JA et al. Poster presentation at ASCO 2013. TPS3114. 2. Choueiri TK et al. Oral presentation at ASCO 2015. 4500. 3. Clinical Protocol CA209009. 4. Lawrence MS et al. Nature. 2013;499(7457):214-218.5. Antonia SJ et al. Poster presentation at WCLC 2013. P2.11-035. 6. Weber JS et al. Lancet Oncol. 2015;16(4):375-384. 7. Brown SD et al. Genome Res. 2014;24(5):743-750. 8. Postow MA et al. J TranslMed. 2014;12(suppl 1):O8. 9. Komatsu N et al. Cancer. 2012;118(12):3208-3221. 10. Wang Z et al. Med Hypotheses. 2013;81(1):41-43. 11. Luborsky J et al. Am J Reprod Immunol. 2005;54(2):55-62. 12. Schneider BP et al. Lancet Oncol. 2012;13(10):e427-e436.
Importancia de la selección de pacientes porla expresión de PD-L1
ESTADIOS METATÁSICOSSEGUNDA LÍNEA TRAS DOBLETE DE PLATINO
ESTADIOS METATÁSICOSPRIMERA LÍNEA
KEYNOTE-024: diseño del estudio de pembrolizumab frente a quimioterapia
Reck M et al. N Engl J Med. 2016;375(14):1–11. TPS = puntuación de proporción tumoral
SLP superior con PEMBROLIZUMAB 200 mg Q3W frente a quimioterapia(HR 0,50, IC del 95%, 0,37–0,68; P<0,001) en pacientes con PD-L1 ≥50%
–Reducción del 50% del riesgo de progresión de la enfermedad o muerte con PEMBROLIZUMAB frente a quimioterapia
a Patients with a sensitizing EGFR mutation or ALK translocation must have disease progression or intolerance of treatment with one or more approved targeted therapies. b Atezolizumab: 1200 mg IV q3w. c Carboplatin: AUC 6 IV q3w. d Paclitaxel: 200 mg/m2 IV q3w. e Bevacizumab: 15 mg/kg IV q3w.
IMpower150 Study Design
Arm A
Atezolizumabb + Carboplatinc + Paclitaxeld
4 or 6 cycles
Atezolizumabb
Arm C (control)
Carboplatinc + Paclitaxeld
+ Bevacizumabe
4 or 6 cycles
Bevacizumabe
Surv
ival
fo
llow
-up
Stage IV or recurrent metastatic nonsquamous NSCLCChemotherapy-naivea
Tumor tissue available for biomarker testing
Any PD-L1 IHC status
Stratification factors:• Sex• PD-L1 IHC expression• Liver metastases
N = 1202
R1:1:1
Arm B
Atezolizumabb + Carboplatinc + Paclitaxeld
+ Bevacizumabe
4 or 6 cycles
Atezolizumabb
+ Bevacizumabe
Maintenance therapy(no crossover permitted)
Treated with atezolizumab until PD per RECIST v1.1
or loss of clinical benefit
AND/OR
Treated with bevacizumab until PD per RECIST v1.1
HRa, 0.78 (95% CI: 0.64, 0.96)
P = 0.0164Median follow-up: ~20 mo
a Stratified HR.Data cutoff: January 22, 2018
25
OS in the ITT-WT (Arm B vs Arm C)
• Statistically significant and clinically meaningful OS benefit with atezolizumab + bevacizumab + chemotherapy vs bevacizumab + chemotherapy was observed
Ove
rall
Surv
ival
(%
)
Time (months)
Median, 19.2 mo(95% CI: 17.0, 23.8)
Median, 14.7 mo(95% CI: 13.3, 16.9)
Landmark OS, %
Arm B:
atezo + bev +
CP
Arm C:
bev + CP
12-month 67% 61%
18-month 53% 41%
24-month 43% 34%
Dr. Mark A. Socinski https://bit.ly/2Ld0jng
ESTADIOS LOCALMENTE AVANZADODESPUÉS DE RADIOTERAPIA-QUIMIOTERAPIACONCOMITANTE
ESTADIO PRECOZNEOADYUVANCIA
CÁNCER MICROCÍTICO DE PULMÓN