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NOVEDADES EN EL TRATAMIENTO
DEL CÁNCER DE PULMÓN . VISIÓN
DEL ONCÓLOGO
Pilar Mut Sanchis
Hospital Son Llàtzer .
10 Octubre 2015
• CPNM : 80- 85% de todos los cánceres de
pulmón
• 70% : enfermedad localmente avanzada o
metástasica
• CPNM avanzado. SG : 10- 12 meses ( Bonomi 2010 )
Clinical Prognostic Factors Affecting NSCLC
Survival
•
•
•
•
•
•
•
Stage of disease at diagnosis1-6
Performance status1,4-6
Gender1,4-6
Recent weight loss1,4-6
Smoking history5-8
Ethnicity5,6,7,8,10
Emerging evidence for histology9,11
1. Jiroutek et al. ASCO 1998;1774. 2. Brundage et al. Chest 2002;122:1037-57. 3. Mountain Semin Surg Oncol. 2000;18:106-15. 4. Ginsberg et al. Lippincott-Raven 2001;925-81. 5. Syrigos et al. Annals of
Oncology 2010; 21: 556–561. 6. Scagliotti et al. J Clin Oncol 2008;26(21):3543-51 7. Shepherd et al. N Engl
3 J Med 2005;353:123-32. 8. Hung et al. J Thorac Cardiovasc Surg 2007;134:638-43. 9. Scagliotti
et al. Oncologist 2009;14:253-63. 10. Ou et al. Cancer 2007;110:1532-41. 11. Hirsch et al. J Thorac Oncol 2008;3:1468-81.
Primer cambio ….
•
The IASLC Lung Cancer Staging Project: Proposals for the Revisions of the T Descriptors
in the Forthcoming Eighth Edition of the TNM Classification for Lung Cancer. Rami-Porta
R, Bolejack V, Crowley J, Ball D, Kim J, Lyons G, Rice T, Suzuki K, Thomas CF Jr, Travis WD, Wu YL
J Thorac Oncol. 2015 Jul;10(7):990-1003
•
The IASLC Lung Cancer Staging Project: Proposals for the Revisions of the N
Descriptors in the Forth coming Eighth Edition of the TNM Classification for Lung
Cancer. Asamura H, Chansky K, Crowley J, Goldstraw P, Rusch VW, Vansteenkiste JF, Watanabe H, Wu Y,
Zielinski M, Ball D, Rami-Porta R
J Thorac Oncol 2015 Sep 3
•
The IASLC Lung Cancer Staging Project: Proposals for the Revisions of the M
Descriptors in the Forthcoming Eighth Edition of the TNM Classification for Lung
Cancer. Eberhardt WEE, Mitchell A, Crowley J, Kondo H, Kim YT, Turrisi A, Goldstraw P, Rami-Porta R
J Thorac Oncol 2015 Sep 3
Cambios en la T
Results: The 3-cm cutpoint significantly separates T1 from T2. From
1 to 5 cm, each centimeter separates tumors of significantly different
prognosis. Prognosis of tumors greater than 5 cm but less than or
equal to 7 cm is equivalent to T3, and that of those greater than 7 cm
to T4. Bronchial involvement less than 2 cm from carina, but without
involving it, and total atelectasis/pneumonitis have a T2 prognosis.
Involvement of the diaphragm has a T4 prognosis. Invasion of the
mediastinal pleura is a descriptor seldom used.
Conclusions: Recommended changes are as follows: to subclassify
T1 into T1a (≤1 cm), T1b (>1 to ≤2 cm), and T1c (>2 to ≤3 cm);
to subclassify T2 into T2a (>3 to ≤4 cm) and T2b (>4 to ≤5 cm);
to reclassify tumors greater than 5 to less than or equal to 7 cm as
T3; to reclassify tumors greater than 7 cm as T4; to group involvement
of main bronchus as T2 regardless of distance from carina; to
group partial and total atelectasis/pneumonitis as T2; to reclassify
diaphragm invasion as T4; and to delete mediastinal pleura invasion
as a T descriptor.
Cambios en la N
• Conclusions: Current N descriptors adequately
predict the prognosis and therefore should be
maintained in the forthcoming staging system.
Furthermore, we recommend that physicians
record the number of metastatic lymph nodes
(or stations)
Cambios en la M
• Results: No significant differences were found among the M1a
(metastases within the chest cavity) descriptors. However, when
M1b (distant metastases outside the chest cavity) were assessed
according to the number of metastases, tumors with a single
metastasis in a single organ had significantly better prognosis than
those with multiple metastases in one or several organs.
• Conclusions: In this revision of the TNM classification, cases with
pleural/pericardial effusions, contralateral/bilateral lung nodules,
contralateral/bilateral pleural nodules or a combination of multiple
of these parameters should continue to be grouped as M1a
category. Single metastatic lesions in a single distant organ should
be newly designated to the M1b category. Multiple lesions in a
single organ or multiple lesions in multiple organs should be
reclassified as M1c category.
QXT de 1ª línea en el CPNM
avanzado
• El CNMP estadio IV no tratado tiene una mediana de
supervivencia de unos 4 meses, con apenas un 10% de
supervivientes a 1 año.
• La QXT ha demostrado un beneficio frente a BSC
– Meta-análisis (BMJ 1995)
• Mediana de supervivencia: 4 vs 6 meses
• Supervivencia a 1 año: 5% al 15%
– Meta-análisis (JCO 2008)
• Mediana de supervivencia: 4’5 vs 6 meses
• Supervivencia a 1 año: 20% vs 29%
QXT de 1ª línea en el CPNM
avanzado
• Doblete de QXT basada en platino como “gold
standard”
• Triplete de QXT NO es mejor que doblete
• No hay ningún doblete superior a otro
• Cisplatino es superior a Carboplatino
• Elección de la QXT en función del ECOG y de la
toxicidad a evitar
• Duración del tratamiento : No administrar más de 4
ciclos si como máxima respuesta se consigue
enfermedad estable
QXT de 1ª línea en el CPNM
avanzado
• Doblete de QXT basada en platino como “gold
standard”
• Triplete de QXT NO es mejor que doblete
• No hay ningún doblete superior a otro
• Cisplatino es superior a Carboplatino
• Duración del tratamiento: No administrar mas de 4
ciclos en aquellos pacientes que como máxima
respuesta hayan obtenido enfermedad estable
WCLC 2007 – Boyer M et al., Abstract # PD4-2-1
TRATAMIENTO INDIVIDUALIZADO
• Tratamiento por histología
– CDDP-Pemetrexed
– Bevacizumab
• Mantenimiento
• Tratamiento según EGFR
– Erlotinib, Gefitinib , Afatinib , AZD9291
• Tratamiento según ALK
- Crizotinib , Ceritinib , Alectinib
• Tratamiento según otros marcadores
moleculares : BRAF , Ros 1
TRATAMIENTO INDIVIDUALIZADO
• Tratamiento por histología
– CDDP-Pemetrexed
– Bevacizumab
PEMETREXED
• Estudio fase III, de no inferioridad
• CDDP + Pemetrexed vs CDDP + Gemcitabina
• 1725 pacientes
– 76% estadio IV, 49% adenocarcinoma
• RESULTADOS:
– SG:
• Adenoc.
• Cel. Grande
• Escamosos
– SLP:
– Sv. a 1 año:
– Sv. a 2 años
10’3
12’6
10’4
9’4
4’8
43’5%
19%
vs 10’3 m
p: ns
vs 10’9 m p < 0’05
vs 6’7 m p < 0’05
vs 10’8 m p < 0’05
vs 4’8 m p: ns
vs 42% p: ns
vs 14% p: ns
Scagliotti, JCO 2008; 26:3543-3551
VEGF: Resumen de efectos
ESTIMULA LAS CÉLULAS ENDOTELIALES
PROLIFERACIÓN
MIGRACIÓN
NUEVOS VASOS SANGUÍNEOS
PERMEABILIDAD
AUMENTO DE LA PRESIÓN INTERSTICIAL
TORTUOSOS
POROSOS
DEPENDIENTES DEL VEGF PARA SOBREVIVIR
DIFICULTAD
PARA LA
SALIDA DE
FÁRMACOS Y
OXÍGENO AL
TUMOR
ACCIÓN DEL BEVACIZUMAB EN EL TUMOR
1
Regresión
Reducción del tamaño
tumoral
EFECTOS TEMPRANOS
EFECTOS CONTINUADOS
2
3
Normalización
Incremento de la llegada
de la quimioterapia
Inhibición
Supresión del crecimiento de
nuevos vasos sanguíneos
Supresión del recrecimiento de
vasos sanguíneos
BEVACIZUMAB
AVAIL , Reck JCO 2010
Sandler, NEJM 2006
•
•
•
Taxol-Carbo +/- BVZ 15 mg/Kg
876 pacientes
Objetivo primario: Supervivencia
•
•
•
Cis-Gem +/- BVZ 7’5 o 15 mg/Kg
1043 pacientes
Objetivo primario: SLP
•
•
•
•
RESULTADOS:
SG: 10’3 vs 12’3 meses, p = 0’003
SLP: 4’5 vs 6’2 meses, p < 0’001
Supervivencia a 12 y 24 meses:
•
•
•
RESULTADOS
SG: 13’1 -13’6-13’4 meses p = ns
SLP: 6’2- 6’8-6’6 meses, p = 0’002
44%-15% vs 51%-23% vs p = 0’003
EFECTOS ADVERSOS
Comunes y leves
Graves e infrecuentes
HTA
Troembolismo arterial ( 3,8 %)
Proteinuria
Perforaciones GI ( 1,4 - 2%)
Sangrado
Problemas cicatrización de heridas
TRATAMIENTO INDIVIDUALIZADO
• Mantenimiento
Quimioterapia “secuencial/mantenimiento”:
Pemetrexed vs placebo
Proc ASCO 2009. Abstract CRA8000
Proc ASCO 2009. Abstract CRA8000
PARAMOUNT Study Design
 Randomized, placebo-controlled, double-blind, Phase III study
 Pemetrexed 500 mg/m2; cisplatin 75 mg/m2
 Folic acid, vitamin B12, and prophylactic dexamethasone administered to both arms
Paz-Ares et al. J Clin Oncol. 2013 Aug 10;31(23):2895-902).
Paz Ares JCO 2013 , Aug 10; 31 (23) :2895-902
PARAMOUNT Final OS from Induction
Paz-Ares
J Clin Oncol.
2013(23)
Aug 10;31(23):2895-902).
Paz Ares JCO
2013et al., Aug
10; 31
:2895-902
Frequency of Driver Mutations in
Adenocarcinoma
HER2 3%
BRAF 2%
PIK3CA 1% MET 1% NRAS 1%
MEK1 <1%
Mutation in 1 gene 3%
EGFR (other) 4%
ALK 8%
No oncogenic driver
detected 36%
EGFR
(sensitizing) 17%
KRAS 25%
Some driver mutations have been identified and 2 are acting: ALK and EGFR
Johnson et al. Poster presented at ASCO 2013. Abstract 8019.
TRATAMIENTO INDIVIDUALIZADO
• Tratamiento según EGFR
– Erlotinib, Gefitinib , Afatinib , AZD9291
EGFR
• Receptor transmembrana
cuyo ligando es el EGF y
TGF-Alpha
• Dimerización
• Fosforilación que activa
varias cascadas
relacionadas con la
proliferación celular y la
apoptosis:
– MAPK
– AKT
– JUNK
EGFR
EGFR
• Mutaciones
sensibilizadoras:
–
–
–
–
Exon 18: 5%
Exon 19: 45%
Exon 20: <1%
Exon 21: 45 %
Phase III studies of first-line EGFR TKIs
in EGFR Mut+ NSCLC
Study
Subgroup
from clinical
selection
Molecular
selection
TKI
Chemotherapy
Population
IPASS
Gefitinib
Carbo/Pac
Asian (E/SE)
First-SIGNAL
Gefitinib
Cis/Gem
Asian (Korea)
EURTAC
Erlotinib
Cis OR Carbo
+ Doc OR Gem
Caucasian
OPTIMAL
Erlotinib
Carbo/Gem
Asian (China)
ENSURE
Erlotinib
Cis/Gem
Asian (China)
WJTOG 3405
Gefitinib
Cis/Doc
Asian (Japan)
NEJSG 002
Gefitinib
Carbo/Pac
Asian (Japan)
LUX-Lung 3
Afatinib
Cis/Pem
Majority Asian
LUX-Lung 6
Afatinib
Cis/Gem
Asian (E/SE)
Mok, et al. N Engl J Med 2009; Han, et al. J Clin Oncol 2012; Rosell, et al. Lancet Oncol 2012
Zhou, et al. Lancet Oncol 2011; Chen, et al. Ann Oncol 2013; Wu, et al. WCLC 2013
Mitsudomi, et al. Lancet Oncol 2010; Maemondo, et al. N Engl J Med 2010
Sequist, et al. J Clin Oncol 2013; Wu, et al. ASCO 2013
Meta-analysis of PFS with EGFR TKIs vs
chemotherapy in 1L EGFR Mut+ NSCLC
0,25
0,44
0,43
Lopes G. et al. WCLC 2013 (Abs P2.11-015)
EURTAC Phase III Study Design
Eligibility (N = 174)
Erlotinib 150 mg/day
Chemonaїve
Stage IIIB/IV NSCLC
EGFR exon 19 deletion or
exon 21 L858R mutation
R
Platinum-based doublet
chemotherapy q3wks
x 4 cycles*
*Cisplatin/docetaxel, cisplatin/gemcitabine, carboplatin/docetaxel or
carboplatin/gemcitabine
Rosell R et al. Proc ASCO 2011;Abstract 7503.
Rosell R et al. Lancet Oncol 2012; 13: 239–46
Primary Endpoint: PFS in ITT Population
(Updated Analysis January 26, 2011)
Erlotinib (n = 86)
Chemotherapy (n = 87)
HR = 0.37
Log-rank p < 0.0001
Rosell R et al. Proc ASCO 2011;Abstract 7503.
Rosell R et al. Lancet Oncol 2012; 13: 239–46
EFECTOS SECUNDARIOS INHIBORES TK
• Diarrea
• Rash acneiforme ( dentro de 2- 3 primeras
semanas)
According to NCCN Guidelines, EGFR-TKIs are the recommended first-line
treatment for advanced EGFRm NSCLC1
Advanced NSCLC
Establish histology
Adenocarcinoma
Large cell
NSCLC not otherwise specified
Squamous
EGFR- and ALKmutation testing
Consider EGFR- and
ALK-mutation testing
EGFRm
ALK
positive
EGFR-TKI*
Crizotinib
Doublet chemotherapy
(or bevacizumab +
chemotherapy)†
Chemotherapy
Best supportive care
†if
EGFR/ALK negative
or unknown
Refer to NCCN
guidelines
EGFRm
First line
EGFR -TKI*
ALK
positive
EGFR/ALK negative
or unknown
Crizotinib
Refer to NCCN
guidelines
Second line
PS 0–1
PS 2
PS 3–4
PS 0–1
PS 2
PS 3–4
Doublet chemotherapy
chemotherapy
Best supportive care
criteria met.
NCCN Treatment Guidelines. NSCLC Version 6.2015. Available at:
http://www.nccn.org/professionals/physician_gls/pdf/nscl.pdf
33
MUTACIONES SENSIBILIZANTES DEL EGFR
• Tasas de respuesta 50- 80% con ITK de 1ª línea frente a
menos de 30% QTA convencional 1ª línea
• Progresión de enfermedad 9- 13 meses por resistencia
adquirida a los ITK
Engelman et al 2008, Pao et al 2005, Nguyen et al 2009 , Mok et al 2009, Rosell et al
2012
• Mediana de tasa de SG de un máximo de 2 años a la
progresión de ITK
Wang et al. 2012 , Wu et al 2010, Fukuoka et al 2012
•No existe ningún tratamiento estandar global establecido
tras el fracaso de ITK ( quimioterapia , ensayos clinicos )
Molecular mechanisms of acquired resistance in lung cancers
resistant to approved EGFR-TKIs
Activation of alternative growth and survival pathways
•
•
•
•
The most studied example is c-MET amplification1
c-MET amplification was detected in 5–22% of tumour samples
from patients with progressive disease following EGFR-TKI1
HER2 amplification may also play a key role in
EGFRm cells
A HER2 amplification frequency of 12–13% has been observed in
patients with progressive disease following EGFR-TKI treatment1
Phenotypic transformation
•
Reproduced with permission of the European Respiratory Society:
Eur Respir Rev September 2014;23:356-366;
doi:10.1183/09059180.00004614
– Transformation to SCLC
– Epithelial to mesenchymal transition (EMT)
The main mechanisms of acquired resistance to
EGFR-TKIs that have been identified can be
classified as follows1:
•
1. T790M mutation (most common)
•
2. Alternative pathway activation
3. Phenotypic transformation
1. Cortot AB, Jänne PA. Eur Respir Rev 2014;23:356–366.
Phenotypic transformation includes two mechanisms of resistance
to EGFR-TKI:
•
Transformation of EGFRm NSCLC to SCLC has been reported in 2–
14% of patients following acquired resistance to EGFR-TKI1
During EMT, cells switch from an epithelial phenotype to a
mesenchymal phenotype1
The mechanisms leading to EMT in patients progressing on EGFRTKI are not fully understood1
35
MECANISMO DE ACCIÓN AZD9291
AZD9291 has been designed to address
significant unmet clinical needs:
• AZD9291 is an oral, once-daily, potent,
irreversible EGFR-TKI selective for:
Low activity
WT receptor
– EGFR-sensitising mutations (EGFRm)
– T790M-resistance mutation1
• AZD9291 has a higher selectivity for EGFR
mutations than EGFR WT2
– Potential to reduce the propensity for EGFR WT side
effects, such as rash and diarrhoea2,3
Low activity
vs. IR and
IGF-1R
AZD9291
Target
EGFRsensitising
mutations
• Like the T790M double-mutant EGFR, the IR
and IGF-1R have a methionine gatekeeper in
their kinase domains2
– AZD9291 was designed to exert minimal activity vs.
IR and IGF-1R2
Target T790M
resistance
mutation
o Minimise the potential for hyperglycaemia3
1. Jänne PA, et al. New Engl J Med 2015;372:1689–1699;
2. Cross DA, et al. Cancer Discov 2014;4:1046–1061;
3. Jänne PA, et al. Ann Oncol 2015;26:(suppl 1 abstract LBA3).
36
AZD9291 demonstrates promising efficacy, with high rates of objective
response in patients with progressing, advanced EGFRm T790M NSCLC who
have received prior EGFR-TKI therapy
AURA Phase I component:
•
Across all doses, investigator-assessed ORR = 59% (95% Cl 51–66%) in patients with T790M NSCLC
–
•
50
40
30
20
10
0
-10
-20
-30
-40
-50
-60
-70
-80
-90
-100
At the 80 mg dose, the ORR in patients with T790M tumours was 66% by investigator assessment (n=61) and 54% by independent
assessment (n=59)
Across all doses, investigator-assessed DCR (CR+PR+SD) = 90% (141/157; 95% CI 84–94%)
– At the 80 mg dose, the DCR in patients with T790M tumours was 92% by investigator assessment (n=61) and
92% by independent assessment (n=59)
Best percentage change from baseline in target lesion
D
D*D*
D
DDD
D
D DD
D
DD
D
DD
D
20 mg
40 mg
80 mg
160 mg
240 mg
D
D
DD DD
DD D
D
D
DD
Selected dose
for Phase II/III
studies
DD
D D D DDD
DDDD
D
DD
D
D
DD D
D
D
D
20 mg
40 mg
80 mg
160 mg
240 mg
Total
n (157)
10
32
61
41
13
157
ORR
(95% CI)
50%
(19–81)
59%
(41–76)
66%
(52–77)
51%
(35–67)
54%
(25–81)
59%
(51–66)
D
D
D
D
*Imputed values for patients who died within 14 weeks (98 days) of start of treatment and had no evaluable target lesion assessments
Nine patients (seven in the 160 mg cohort) currently have a best overall response of not evaluable, as they have not yet had a 6-week follow-up RECIST assessment
Patients are evaluable for response if they were dosed and had a baseline RECIST assessment. Data cut-off 2 Dec 2014
Jänne PA, et al. Ann Oncol 2015;26:(suppl 1 abstract LBA3).
37
TRATAMIENTO INDIVIDUALIZADO
• Tratamiento según ALK
- Crizotinib , Ceritinib , Alectinib
Frequency of Driver Mutations in
Adenocarcinoma
HER2 3%
BRAF 2%
PIK3CA 1% MET 1% NRAS 1%
MEK1 <1%
Mutation in 1 gene 3%
EGFR (other) 4%
ALK 8%
No oncogenic driver
detected 36%
EGFR
(sensitizing) 17%
KRAS 25%
Some driver mutations have been identified and 2 are acting: ALK and EGFR
Johnson et al. Poster presented at ASCO 2013. Abstract 8019.
A Phase I expansion cohort evaluating crizotinib 250 mg BID (MTD) in 82 patients with
advanced, ALK-positive NSCLC reported a 61% response rate and was well tolerated5
Consistent Tumor Response to Crizotinib
Across Studies
100
80
80
60
60
% Decrease or Increase From Baseline
% Decrease or Increase From Baseline
100
Current Study - ORR 51%, n=133
Study 1001 - ORR 61%, n=1161
40
20
0
–20
–40
–60
40
20
0
–20
–40
–60
–80
–80
–100
–100
PD
SD
PR
CR
1Camidge
DR et al. ASCO 2011
 Una mayoria de pacientes que reciben crizotinib desarrollan
resistencia en 12 meses , siendo la localización de progresión más
frecuente a nivel cerebral
 Ceritinib es un inhibidor de ALK oral de segunda generación que
ha sido aprobado para el tratamiento de pacientes con CPCNP ALK
translocado previamente tratados con crizotinib por varias
autoridades sanitarias , incluida una reciente aprobación por la
EMA
– In vitro , los estudios han demostrado una capacidad de inhibir ALK un 20%
mayor que la de crizotinib y una potencia contra lineas celulares derivadas
de pacientes con resistencia a crizotinib
Otterson et al. GA et al. J Clin Oncol 2014;30:abst 7600; 4Weickhardt AJ et al. J Thorac Oncol 2012;7(12):1807–1814; 5Costa DB et al. J Clin Oncol 2015
[Epub ahead of print]; 6Doebele RC et al. Clin Cancer Res. 2012;18:1472–1482; 7FDA Pharmacology Review accessed online 12 Feb 2015 at
http://www.accessdata.fda.gov/drugsatfda_docs/nda/2014/205755Orig1s000PharmR.pdf; 8Novartis lung cancer drug Zykadia® gains EU approval.
Accessed online May 11 2015 at http://www.novartis.com/newsroom/media-releases/en/2015/1919978.shtml. 9Friboulet L et al. Cancer Discov
2014;4(6):662-673.
ASCEND 1 : Progression-free Survival for ALK+
NSCLC Treated with Ceritinib 750 mg/day
For distribution in response to an unsolicited request for medical information local NP4 approval.
LDK378 Clinical Development Program
X2101: LDK378 in in ALK+ tumors; Dose-finding
study (N=59) escalation to MTD. Expansion: CRZpre-treated and -naïve NSCLC
X1101: LDK378 in
Japanese ALK+ pts with
tumors; MTD and/or
RP2D
Completed
Completed
A2201: LDK378 750 mg QD in
ALK+ NSCLC pts previously
treated with CT and CRZ
A2203: LDK378 750 mg QD in
ALK+ NSCLC CRZ-naïve pts
previously treated with CT
Completed
Completed
A2205: LDK378 750 mg QD
in ALK+ NSCLC pts with
brain metastasis
Planned
A2301: LDK378 vs. CT in pts with
CRZ-naive and CT-naïve ALK+
NSCLC
A2303: LDK378 vs. CT in pts with
ALK+ NSCLC with prior CT and
CRZ
Ongoing
Ongoing
ALCL, Anaplastic Large Cell Lymphoma; CRZ, crizotinib; CT, chemotherapy; IMT, Inflammatory Myofibroblastic Tumors;
MTD, maximum tolerated dose; NB, Neuroblastoma; QD, once daily; RP2D, recommended Phase II dose.
ClinicalTrials.gov. From: http://www.clinicaltrials.gov. Accessed January 2014.
TRATAMIENTO INDIVIDUALIZADO
• Tratamiento según otros marcadores
moleculares : BRAF , Ros 1
1506036248
Dabrafenib Inhibits BRAF V600 Kinase and Trametinib
Inhibits Downstream MEK Signaling
• Patients with BRAF V600E
mutation demonstrate less
favorable outcomes with
platinum based
chemotherapy
RTKs
• NSCLC with BRAF V600E
mutations have histologic
features suggestive of an
aggressive tumor
Dabrafenib
P P
SOS
P P
Grb2
SHC
P P
RAS
PI3K/AKT/mTOR
pathway
BRAF
V600
BRAF
CRAF
MEK
Trametinib
ERK1/2
p90RSK
MSK1
Proliferation, Growth, Survival
Davies H, et al. Nature. 2002;417:949-954; Platz A, et al. Mol Oncol.
2008;1:395-405; Karasarides M, et al. Oncogene. 2004;23:6292-6298; Long, et
al. N Engl J Med. 2014;371:1877; Gilmartin et al Clin Cancer Res 2011;17:989.
48
1506036248
BRF113928: Study Design
Cohort A (monotherapy) n = 60
Stage IV NSCLC
BRAF V600E
ECOG 0-2
At least 1 platinum-based
chemotherapy
Dabrafenib
150mg BID
Stage 1
N = 20
Stage 2
N = 20
Expansion
N = 20
COMPLETE
Reported at
ESMO 2014*
ORR = 32%, and DCR = 56%. Median DoR = 9.6 months . Median PFS = 5.5 months
Interim futility
analyses
Cohort B (combination D+T) n = 40
Stage IV NSCLC
BRAF V600E
ECOG 0-2
1-3 tx lines only
(at least 1 platinum-based
chemotherapy)
Dabrafenib
150mg BID
Trametinib
2mg once daily
Stage 1
N = 20
Stage 2
N = 20
Recruitment stopped if fewer than 6
out of the first 20 subjects responded
*Planchard D, et al. Ann Oncol 2014;25(suppl 4):abstract LBA38_PR.
49
1506036248
Overview of Best Confirmed Response for
 2nd Line Patients
Best response
PR, n (%)
SDb, n (%)
PD, n (%)
Non-CR, non-PD, n (%)
Not evaluable
Response rate (confirmed CR + PR)
95% CI
Disease control rate (CR + PR + SD + non-CR,
non-PD)
95% CI
aThe
Investigator
Assessed
N = 24
15 (63)
6 (25)
2 (8)
0 (0)
1 (4)
63%
(40.6–81.2)
88%
(67.6–97.3)
independent review sample size was 22 rather than 24 because the scans for 2 subjects were not available for independent
review at the time of the
data cut.
bSD is defined as meeting SD  12 weeks.
cTwo patients did not have measurable disease at baseline, per independent review.
50
Segundas Líneas con QTA
convencional…
Segundas Líneas
• A QUIEN TRATAR
– Adecuada selección de los pacientes
– ECOG
– Pocas respuestas, alta toxicidad. Superv : 6 – 8 m
• QUE FÁRMACOS
– Docetaxel ( Shepherd JCO 2000 )
– Pemetrexed ( Hanna JCO 2004)
– Erlotinib ( Shepherd NEJM 2005)
INMUNOTERAPIA ……
The History of Cancer Immunotherapy
BCG
approved for
Sipuleucel-T approved
bladder
for prostate cancer (2010)
cancer
IFN-α as
adjuvant therapy
Adoptive
for melanoma
immunotherapy
Immune
component to
spontaneous
regressions in
melanoma
1890s
1970s
1980s
Cancer immunotherapy first
documented:
Virchow described tumor immune infiltrates
Coley observed that injection of bacterial
products could stimulate host immunity and
tumor regression
1990s
2000s
2011
First tumorassociated
antigen cloned
(MAGE-1)
Ipilimumab approved for
advanced melanoma
IL-2 approved for RCC
and melanoma (US)
BCG = Bacillus Calmette-Guérin; MAGE = melanoma-associated antigen.
1. Adapted from Kirkwood JM, et al. Ca J Clin. 2012;62:309–335; 2. George S, et al. JNCCN. 2011;9:1011–1018; 3. Garbe C, et al. The Oncologist. 2011;16:2–24;
4. Cheever MA, et al. Clin Cancer Res. 2011;17:3520–3526; 5. Kantoff PW, et al. N Engl J Med. 2010;363:411–422; 6. Mansh M. Yale J Biol Med. 2011;84:381–
389; 7. Hodi FS, et al. N Engl J Med. 2010;363:711–723; 8. Aldousari S, et al. CUAJ. 2010;4:56–64.
Pan-Tumor Potential
•
I-O therapiesa are being studied for the potential for activity in many different types of
cancer, irrespective of mutated genes or tumor histology
aSelected
therapies and tumor types are shown.
www.clinicaltrials.gov. accessed 19 August 2013.
Selected Immunotherapeutic Approaches
for Cancera
Immunotherapy
Passive (Adoptive)
Active
Acts on the tumor, might utilize
immune-based mechanisms
Acts on the immune system itself
Enhance
Immune
Cell Function
Cytokines
(IL-2, IFN-α,
IL-21, IL-15)
Anti-KIRs
IDO inhibition
Therapeutic
Vaccines
Modulate T-cell
Function
Antitumor
mAbs
Adoptive
Sipuleucel-T
GSK1572932A
TG4010
Belagenpumatucel-L
Tergenpumatucel-L
Racotumomab
CTLA-4 inhibition
PD-1 inhibition
PD-L1 inhibition
PD-L2 inhibition
LAG-3 inhibition
CD137 agonism
CD40 agonism
OX-40 agonism
Rituximab
Trastuzumab
Cetuximab
Adoptive
Cell Transfer
(including CARs)
• Presence of immune cells are associated with prognosis and outcomes
in lung cancer
Regulating the T-cell immune response
Activating
receptors
Inhibitory
receptors
CTLA-4
CD28
• T cell responses are regulated
through a complex balance of
inhibitory (‘checkpoint’) and
activating signals
PD-1
OX40
TIM-3
CD137
• Tumors can dysregulate
checkpoint and activating
pathways, and consequently
the immune response
LAG-3
Agonistic
antibodies
Antagonistic
(blocking)
antibodies
T-cell stimulation
• Targeting checkpoint and
activating pathways is an evolving
approach to cancer therapy,
designed to promote an immune
response
Adapted from Mellman I, et al. Nature. 2011:480;481–489; Pardoll DM. Nat Rev Cancer. 2012;12:252–264.
Immune checkpoint inhibitors are associated with
specific immune-related adverse events (irAE)
Pooled analysis of patients with melanoma
and treated with ipilimumab
Toxicity grade
Rash, pruritis
Liver toxicity
Diarrhoea, colitis
Hypophysitis
0
2
Weber JS, et al. J Clin Oncol. 2012;30:2691–2697.
4
6
8
10
Time (weeks)
12
14
Nivolumab ongoing monotherapy trials
in patients with NSCLC (2L and beyond)
Setting
Population
Study
Up to 5
prior
lines
Selected advanced or
recurrent malignancies,
including NSCLC
NCT00730639
2L
Prior platinum, stage IIIb/IV or
recurrent squamous NSCLC
NCT01642004
Prior platinum, stage IIIb/IV
non-squamous NSCLC
NCT01673867
2L/3L
>2L
Advanced or metastatic
squamous cell NSCLC following
>2 prior systemic regimens
CA209-003/
(Phase 1b)
CA209-017/
Design
Primary
Endpoint
Status/
expected
completion
Active, not
recruiting/
June 2015
Active, not
recruiting/
January 2017
Active, not
recruiting/
May 2016
Nivolumab monotherapy
multi-dose escalation
Safety, tolerability
Nivolumab vs docetaxel
OS
Nivolumab vs docetaxel
OS
Nivolumab monotherapy
Safety
TBC
Safety
Recruiting/
March 2019
ORR
Active, not
recruiting/
February 2015
(Phase 3)
CA209-057/
(Phase 3)
CA209-171/
TBC
(Phase 3)
National Institutes of Health. ClinicalTrials.gov. http://www.clinicaltrials.gov/
Last accessed September 2014
2L/3L
>3L
Advanced/metastatic,
stage IIIb/IV
non-squamous and squamous
NSCLC (US only study)
≥2 prior regimens, stage IIIb/IV
squamous NSCLC
CA209-153
NCT02066636
(Phase 3b/4)
Cohort A: Nivolumab until
disease progression
Cohort B: Nivolumab for
up to 1y; discontinue
treatment; at progression,
retreatment allowed
CA209-063/
NCT01721759
(Phase 2)
Nivolumab monotherapy
Overall Survival. Squamous Lung Carcinoma
100
Nivolumab
n = 135
Docetaxel
n = 137
mOS mo,
(95% CI)
9.2
(7.3, 13.3)
6.0
(5.1, 7.3)
# events
86
113
90
80
70
OS (%)
60
HR = 0.59 (95% CI: 0.44, 0.79), P = 0.00025
1-yr OS rate = 42%
50
40
Nivolumab
30
20
Docetaxel
10
1-yr OS rate = 24%
0
0
3
6
9
12
15
18
21
24
Time (months)
Number of Patients at Risk
Nivolumab
135
113
86
69
52
31
15
7
0
Docetaxel
137
103
68
45
30
14
7
2
0
Symbols represent censored observations
NEJM . May 31st 2015
CheckMate 057 : Non –SC NSCLC Overall survival
100
90
mOS, mo
80
Nivolumab
(n = 292)
Docetaxel
(n = 290)
12.2
9.4
HR = 0.73 (96% CI: 0.59, 0.89); P = 0.0015
70
OS (%)
60
1-yr OS rate = 51%
50
40
1-yr OS rate = 39%
30
Nivolumab
20
10
Docetaxel
0
0
3
6
9
12
15
18
21
24
27
Time (months)
Number of Patients at Risk
Nivolumab
292
232
194
169
146
123
62
32
9
0
Docetaxel
290
244
194
150
111
88
34
10
5
0
Symbols represent censored observations.
CONCLUSIONES
• Introducción de pemetrexed en
mantenimiento en ADC y Carcinoma de célula
grande tras tratamiento de primera línea con
Platino – pemetrexed supone una mejoría en
la supervivencia global en los pacientes que se
benefician de una primera línea
• Adición de antiangiogénicos en pacientes con
ADC sin contraindicaciones también supone
un beneficio en supervivencia
CONCLUSIONES
• Las terapias antidiana están suponiendo una
revolución en la modificación de la
supervivencia , aunque en una proporción
baja de pacientes
• La inmunoterapia está cambiando la
perspectiva de TODOS los tumores
GRACIAS