Este documento presenta el caso de una mujer de 68 años diagnosticada con adenocarcinoma de pulmón con mutación EGFR positiva en el exón 19. Se describe su tratamiento inicial con erlotinib, un inhibidor de tirosina quinasa dirigido, que duplicó su supervivencia libre de progresión en comparación con la quimioterapia estándar, con una tasa de respuesta tres veces mayor. El documento resume los beneficios del tratamiento dirigido con inhibidores de EGFR en pacientes con mutación EGFR.
4. Oncología Médica
XXI Vigo
Lung Cancer: Incidence and Mortality
New cases in 2013: 228,190
40% with stage IV disease at
presentation (~ 90,000)
~ 160,000 deaths in 2012,
comparable to prostate,
pancreas, breast, and colon
cancer combined
5-yr relative survival rate: 15.7
% overall; 3.7% for patients
with distant-stage disease
180,000
Estimated Cancer Deaths
by Site, 2012
160,000
140,000
120,000
100,000
80,000
60,000
Prostate
Pancreas
Breast
Lung
cancer
40,000
20,000
Colon
0
Other Cancers
Lung Cancer
NCI. Non-small-cell lung cancer treatment (PDQ ®). ACS. Cancer facts & figures: 2012. CDC. Lung cancer
rates by race and ethnicity. Howlader N, et al. SEER cancer statistics review.
5. Oncología Médica
Lung Cancer: Evaluación
Diagnóstico: biopsia!
Información sobre histología y alteraciones
moleculares, útiles para la selección de
tratamiento
XXI Vigo
6. Oncología Médica
XXI Vigo
Complexities of Lung Cancer
Pathogenesis Result in Diverse Histologic
Subtypes
SCLC
(~ 15%)
Adenocarcinoma
(~ 45%)
Sun S, et al. Nat Rev Cancer. 2007; 7:778-790.
Travis WD, et al. J Clin Oncol. 2013;[Epub ahead of print].
SCC
(~ 25%)
LPA
(formerly BAC)
(~ 5% to 10%)
Large Cell
(~ 5% to 10%)
NOS
(~ 10% to 30%)
7. Oncología Médica
XXI Vigo
Lung Cancer: Histology
Small-cell
carcinoma
Adenocarcinoma
10% to 15%
Large-cell
carcinoma
10% to 15%
40%
25% to 30%
Squamous cell
carcinoma
American Cancer Society. Lung cancer (non-small-cell). 2013.
9. Oncología Médica
XXI Vigo
NSCLC: AJCC Staging
Lung Cancer Staging: Differences Between the AJCC Cancer Staging Manual 6th and 7th Editions
AJCC 6th Edition
AJCC 7th Edition
T1
≤ 3 cm
T1a: ≤ 2 cm
T1b: > 2 cm but ≤ 3 cm
T2
3 cm or
Invades visceral pleura
Atelectasis of less than entire lung
Proximal extent at least 2 cm from carina
T2a: > 3 cm but ≤ 5 cm
T2b: > 5 cm but ≤ 7 cm
Or tumors ≤ 7 cm with invasion of visceral pleura, atelectasis
of less than entire lung, proximal extent at least 2 cm from
carina
T3
Tumors with invasion of chest wall,
diaphragm, mediastinal pleura
Tumors > 7 cm or with:
Direct invasion of chest wall, diaphragm, phrenic nerve,
mediastinal pleura, parietal pericardium, main bronchus
< 2 cm from carina (without involvement of carina)
Tumor nodules in the same lobe as the primary tumor
T4
Tumor of any size with:
Invasion of mediastinum, heart, great vessels, trachea,
esophagus
Malignant pleural or pericardial effusions
Tumor nodules in the same lobe as the primary
Tumor of any size with:
Invasion of mediastinum, heart, great vessels, trachea,
esophagus
Metastatic tumor nodules in different lobe from the primary
tumor
T descriptor
N descriptor
No changes
M descriptor
M1
Distant metastasis: metastatic tumor nodules in a
different lobe from the primary tumor
Subdivided into:
M1a: Malignant pleural or pericardial effusion pleural
nodules, nodules in contralateral lung
M1b: Distant metastasis
Edge SB, et al. AJCC Cancer Staging Manual. 7th ed. New York, NY: Springer; 2010. pp. 253-270.
10. Oncología Médica
NSCLC avanzado: Factores pronóstico
XXI Vigo
En pacientes inoperables, el pronóstico se ve
afectado de forma adversa por:
Mal PS
Pérdida de peso > 10%
Sexo masculino
Edad avanzada: no afecta a pronóstico por sí
misma
NCI. Non-small-cell lung cancer treatment (PDQ ®).
12. Oncología Médica
XXI Vigo
First-line Therapy: 2013
Column A
Cisplatin
Carboplatin
Column B
Vinorelbine
Gemcitabine
Paclitaxel
Docetaxel
Pemetrexed
Nab-paclitaxel
Irinotecan
Column C
Bevacizumab
Cetuximab?
Column D
Erlotinib
Crizotinib
Option 1: choose 1 from column A and 1 from column B
Option 2: choose 2 from column B
Option 3: option 1 + column C (for certain patients)
Option 4: choose 1 from column D (for selected patients)
National Comprehensive Cancer Network clinical practice guidelines in oncology: Non-small-cell lung cancer (v2.2013). www.nccn.org
13. Oncología Médica
Consideraciones para la primera línea
PS
Edad: comorbilidad
Hemoptisis
Histología
Alteraciones moleculares
Otras
Metástasis SNC
Tratº previo en la adyuvancia
XXI Vigo
15. Oncología Médica
Caso 1
XXI Vigo
Mujer de 68; antecedentes:
Alergia a tetraciclinas.
Nunca fumadora. Bebedora: poco
importante.
HTA a tratº con Micardis Plus.
Mastopatía fibroquística.
Artrosis de hombro derecho y rotura del
tendón del supra e infraespinoso de
hombro derecho, con atrofia muscular
asociada.
Presbiacusia.
Apendicectomía.
Neumonía mayo 2011
16. Oncología Médica
Caso 1
Debut en octubre de 2011: bulto
supraclavicular izquierdo, no otros síntomas
TAC t/a
Nódulo que 8 mm en LSI ; 2 lesiones sólidas
de en LII 34.51 mm y 29 . Conglomerado de
adenopatías abrazando a la carina en su
margen inferior. En D11 en el margen
derecho se evidencia una lesión blástica que
sugiere un islote óseo
Biopsia: adenocarcinoma de origen
pulmonar; mutación EGFR positiva
(exón 19)
XXI Vigo
17. Oncología Médica
PET-TAC
XXI Vigo
Masa hipermetabólica de 4,8 cms en LII, en contacto posterior con pleura
visceral, con compromiso lobar inferior izdo.
Adenopatías de localización cervical, supraclavicular y mediastínicas
Múltiples lesiones hipermetabólicas en hígado y bazo. Lesión focal
hipermetabólica en glándula suprarrenal derecha.
Estadio IV
18. Mutación de EGFR: factor predictivo de respuesta a EGFR-TKI
EGF
•
Receptor
L domain
90% de las mutaciones son en los
exones 18–24
– Delecciones exon 19
– Mutación exon 21 (L858R)
•
Consecuencias:
- Activación constitutiva del receptor
- Dimerización con HER3 →
activación vía AKT/STAT
Furin-like
domain
Receptor
L domain
Extracellular domain
Transmembrane region
Intracellular domain
G719C
del E746–A750
del L747–T751insS
del L747–P753insS
L858R
Catalytic
kinase
domain
L861Q
Y1068
STAT3
MAPK
AKT
Sordella et al. Science 2004
19. Oncología Médica
IPASS: PFS by EGFR Mutation Status
XXI Vigo
Randomized phase III trial; previously untreated pts with advanced NSCLC (N = 1217)
PFS: gefitinib superior to carboplatin/paclitaxel in ITT population
EGFR mutations strongly predicted PFS (and tumor response) to first-line gefitinib vs
carboplatin/paclitaxel
1.0
EGFR Mutation Negative
Gefitinib
Pac/carbo
0.8
HR: 0.48
(95% CI: 0.36-0.64; P < .001)
0.6
0.4
0.2
0
0
4
8
12
16 20 24
Mos Since Randomization
Mok TS, et al. N Engl J Med. 2009;361:947-957.
Probability of PFS
Probability of PFS
EGFR Mutation Positive
1.0
Gefitinib
Pac/carbo
0.8
HR: 2.85
(95% CI: 2.05-3.98; P < .001)
0.6
0.4
0.2
0
0
4
8
12
16 20 24
Mos Since Randomization
20. TKI en CNMP con mutación EGFR
Study
EGFR TKI
Sample
size
Response
rate (%)
Median PFS
(months)
HR
IPASS1
Gefitinib
261
71 vs 47
9.8 vs 6.4
0.48
First-SIGNAL2
Gefitinib
NR
85 vs 37
8.4 vs 6.7
NR
WJTOC34053
Gefitinib
177
62 vs 31
9.2 vs 6.3
0.49
NEJ0024
Gefitinib
198
74 vs 31
10.8 vs 5.4
0.30
OPTIMAL5
Erlotinib
154
83 vs 36
13.7 vs 4.6
0.16
EURTAC6
Erlotinib
174
58 vs 15
9.7 vs 5.2
0.37
Afatinib
(vs cis-pem)
345
56 vs 22
11,1 vs 6.9
0,001
LUX-Lung 3[7]
Mok et al NEJM 2009, 2Lee et al WCLC 2009, 3Mitsudomi et al Lancet Oncol 2010, 4Maemondo NEJM
2010, 5Zhou et al ESMO 2010, 6Rosell et al ASCO 2011; 7-Sequist LV, et al. J Clin Oncol. 2013
1
21. Oncología Médica
XXI Vigo
EURTAC
Erlotinib 150 mg/día
Sin quimioterapia previa
CPNM en estadio IIIB/IV
Deleción de exón 19 EGFR
o mutación exón 21 L858R
ECOG PS 0–2
R
Quimioterapia con doblete de
platino cada 3 semanas x 4
ciclos*
(n=174)
Objetivo principal
Supervivencia libre de progresión (SLP)
− análisis intermedio planeado a los 88
eventos
1227 pts screened 224 mut +
(17.6%)
Estratificación
Tipo de mutación
ECOG PS (0 vs. a 1 vs. 2)
Objetivos secundarios
Tasa de repuesta objetiva (%)
Supervivencia global (SG)
Localización de la progresión
Seguridad
Análisis de la mutación del EGFR en suero
Calidad de vida
*Cisplatino 75 mg/m2 d1 / docetaxel 75 mg/m2 d1; cisplatino 75 mg/m2 d1 / gemcitabina 1250 mg/m2 d1,8;
carboplatino AUC6 d1 / docetaxel 75 mg/m2 d1; carboplatino AUC5 d1 / gemcitabina 1000 mg/m2 d1,8
Rosell, et al. Lancet Oncol. 2012
22. Oncología Médica
Erlotinib en1ª línea duplicó la SLP en comparación
con la quimioterapia
XXI Vigo
Erlotinib (n=86)
Chemotherapy
(n=87)
10·
4
5·1
Patients at risk
Rosell et al. ESMO 2012
23. Oncología Médica
XXI Vigo
La tasa de respuesta con erlotinib fue más de tres veces mayor que la de la
quimioterapia
100
Erlotinib (n=69)
Deleción en el exón 19
Mutación en el exón 21
80
60
40
20
0
-20
-40
-60
-80
-100
Mejor cambio desde valores iniciales (%)
Mejor cambio en comparación con la
medida basal (%)
100
Quimioterapia (n=64)
Deleción en el exón 19
Mutación en el exón 21
80
60
40
20
0
-20
-40
-60
-80
-100
0
10
20
30
40
50
60
70
0
10
20
30
40
50
60
70
Tasa de repuesta global: 58% Erlotinib frente a 15% quimioterapia
de Marinis, et al. EMCC 2011
24. Subgroup analyses of PFS in ITT
population (updated analysis 26 Jan 2011)
HR (95% CI)
0.37 (0.25–0.54)
All
n
173
0.44 (0.25–0.75)
0.28 (0.16–0.51)
85
Male
0.38 (0.17–0.84)
47
Female
0.35 (0.22–0.55)
126
PS 0
0.26 (0.12–0.59)
57
PS 1
0.37 (0.22–0.62)
92
PS 2
0.48 (0.15–1.48)
24
Current smoker
0.56 (0.15–2.15)
19
Former smoker
1.05 (0.40–2.74)
34
Never smoker
0.24 (0.15–0.39)
120
Exon 19 deletion
0.30 (0.18–0.50)
115
L858R mutation
0.55 (0.29–1.02)
58
<65 yrs
≥65 yrs
0.1
0.2
0.4
0.6 0.8 1.0
Favors erlotinib
HR
1.5 2.0
4.0
Favors chemotherapy
88
25.
26. Protocolo 049/11
Gefitinib 250 mg/24 h
46 pacientes mut + (36 m, 10 h)
20 exon 19
4 exon 20
20 exón 21
Mediana edad: 67 años
93%: PS 0-1
RR
SLP
SG
57%
6 meses
17 meses
29. Oncología Médica
Timeline: ALK-Fusion in NSCLC
EML4-ALK chromosomal
rearrangements reported
in NSCLC[1]
Crizotinib antitumor activity in
advanced cancers with
EML4-ALK rearrangement[4]
FDA approves
crizotinib for
treatment of
ALK+ NSCLC[6]
2007
2009
XXI Vigo
2011
2008
2010
Preclinical studies document
Crizotinib produces a
antitumor activity of ALK inhibitors response in 47/82 ALK+
in lung cancer cell lines and
patients and a 6-mo PFS
[2,3]
xenografts
of 72%[5]
1. Soda M, et al. Nature. 2007;448:561-566. 2. McDermott U, et al. Cancer Res. 2008;68:3389-3395. 3. Koivunen JP, et al.
Clin Cancer Res. 2008;14:4275-4283. 4. Kwak EL, et al. ASCO 2009. Abstract 3509. 5. Kwak EL, et al. N Engl J Med.
2010;363:1693-1703. 6. US Food and Drug Administration.
30. Oncología Médica
XXI Vigo
Los reordenamientos del oncogén ALK están presentes en el
4-5% de pacientes con CNMP.
El oncogén ALK se activa por una ruptura (separación) y
posterior refusión de los 2 genes en la dirección opuesta.
La traslocación ALK se determina mediante FISH.
31. Oncología Médica
XXI Vigo
EML4/ALK Translocations
Typical phenotype
Young, male or female, never/scant smokers
Adenocarcinoma ± signet ring morphology
Poor response to EGFR TKI; conventional response to standard chemotherapy
No overlap with EGFR mutation genotype
Change From Baseline (%)
100
PD
SD
PR
CR
80
60
40
20
Crizotinib in ALK-Positive NSCLC (N = 143)
0
-20
-40
-60
-80
-100
Camidge DR, et al. Lancet Oncol. 2012;13:1011-1019.
32. Overall survival 2nd/3rd line Crizotinib
ALK
ALK Control
Crizotinib
(n=23)
(n=30)
100%
Median Survival, mo
6
1-yr Survival, %
70
44
2-yr Survival, %
80%
NR
55
12
HR=0.36, p=0.004
60%
From 2nd/3rd line crizotinib
40%
20%
From 2nd line therapy
0%
0
1
2
Years
3
4
34. Oncología Médica
Caso 2
Paciente varón de 56 años
Tabaquismo desde los 16 años; enolismo moderado
EPOC
Cólico nefrítico 2009 (litotricia)
Marzo-2012:
Bulto en axila derecha de 1 mes de evolución. No sde
general
TAC t/a: masa mediastínica de 5 cm; adenopatías axilares
derechas; adenopatías subcarinal e hiliares derechas
Biopsia ganglio linfático: adenocarcinoma, TTF1 +, wtEGFR
XXI Vigo
36. Trial
N
Schema
Results
Johnson et al
phase II; random
JCO 2004
99
Carboplatin/paclitaxel
Carbo/paclitaxel/beva 15/7.5
PFS: 7.4 m (15 arm)
PFS: 4.2 m
Niho et al
phase II; random
Lung ca. 2012
180
Carbo/paclitaxel
PFS : 5.9 m
OS: 22.8 m
PFS: 6.9 m
OS: 23.4 m
ECOG 4599
878
Carbo/pacl/beva 15
AVAiL
phase III,
randomized
JCO 2009
1043
PFS: 4.5 m
OS: 10.3 m
Carbo/paclitaxel/beva 15 mg/kg
phase III;
randomized
NEJM 2006
Carboplatin/paclitaxel
PFS: 6.2 m
OS: 12.3 m
Cisplatin/gemcitabine
PFS: 6 m
OS: 13 m
Cisplatin/gemc/bevacizumab 7.5
PFS: 6.7 m
OS: 13.6 m
Cisplatin/gemc/bevacizumab 15
PFS: 6.5 m
OS: 13.4 m
37. Bevacizumab: E4599 y AVAIL Diseño
E45991
Previously untreated
stage IIIB/IV
non-squamous NSCLC
(n=878)
Squamous excluded as
higher risk (20%) severe
hemoptysis
AVAiL2
Previously untreated,
stage IIIB, IV or recurrent
non-squamous NSCLC
(n=1,043)
*No crossover permitted
CP x 6 (n=444)
Bevacizumab
(15mg/kg) every 3
weeks + CP x 6
(n=434)
PD*
Bev
PD
Placebo + CG x 6
(n=347)
Bevacizumab
(15mg/kg) every 3
weeks +
CG x 6 (n=351)
Bevacizumab
(7.5mg/kg) every 3
weeks +
CG x 6 (n=345)
PD*
Bev
PD
Bev
PD
1
Sandler, et al. NEJM 2006
2
Reck, et al. JCO 2009
38. Bevacizumab: PFS No-escamosos
PFS in E45991
PFS in AVAiL2
Probability of PFS
1.0
Placebo + CG
bevacizumab 7.5mg/kg + CG
bevacizumab 15mg/kg + CG
0.8
0.6
0.4
0.2
0
0
6
12
18
24
Duration of PFS (months)
PFS bevacizumab
15mg/kg
PFS bevacizumab
7.5mg/kg
PFS bevacizumab
15mg/kg
6.2 months
6.8 months
6.6 months
HR=0.66
p<0.001
HR=0.75
p=0.0003
HR=0.85
p=0.0456
1
Sandler, et al. NEJM 2006; 2Reck et al JCO 2009
30
39. Bevacizumab: OS No-escamosos
OS in E45991
OS in AVAiL2
CP + bevacizumab
CP
Probability of OS
1.0
Placebo + CG
bevacizumab 7.5mg/kg + CG
bevacizumab 15mg/kg + CG
0.8
0.6
0.4
0.2
0
0
6
12
18
24
30
36
Duration of OS (months)
OS bevacizumab
15mg/kg
OS bevacizumab
7.5mg/kg
OS bevacizumab
15mg/kg
12.3 months
13.6 months
13.4 months
HR=0.93
p=NS
p=0.4203
HR=1.03
p=NS
p=0.7613
HR=0.79
p=0.003
1
Sandler, et al. NEJM 2006; 2Reck, et al. JCO 2009; 3Reck, et al. Ann Oncol 2010
40. Oncología Médica
XXI Vigo
Bevacizumab in Nonsquamous NSCLC:
Key Results
E4599[1]
(N = 878)
AVAiL[2,3]
(N = 1043)
JO19907[4]
(N = 180)
Outcome
PCB
PC
CGB
(7.5 mg/kg)
CGB
(15 mg/kg)
Placebo
PCB
Placebo
ORR, %
35
15
37.8
34.6
21.6
60.7
31.0
P < .001
P < .0001
P = .0002
P = .001
0.66
(P < .001)
0.75
(P = .
0003)
0.85
(P = .
046)
0.61
(P = .009)
6.7
6.5
0.93
(P = NS)
1.03
(P = NS)
13.6
13.4
HR for PFS
Median PFS,
months
6.2
HR for OS
0.79 (P = .
003)
Median OS,
months
12.3
4.5
10.3
6.1
6.9
5.9
0.99
(P = .95)
13.1
22.8
23.4
1. Sandler A, et al. N Engl J Med. 2006;355:2542-2550. 2. Reck M, et al. J Clin Oncol. 2009;27:1227-1234.
3. Reck M, et al. Ann Oncol. 2010;21:1804-1809. 4. Niho S, et al. Lung Cancer. 2012;362-367.
41. Oncología Médica
XXI Vigo
Bevacizumab Safety Profile: 5000+ NSCLC
Patients Treated in Clinical Trials
Patients (%)
30
Grade ≥ 3 Adverse Events of Special Interest
E4599[1] (15 mg/kg)
AVAiL[2] (7.5 mg/kg)
AVAiL[2] (15 mg/kg)
SAiL[3]
ARIES[4,5]
20
10
7.0
4.4 4.0 4.0 4.0
3.6
9.0
6.0
6.0
< 5.0
3.0
1.9 1.5
0.9 1.0 0.9
0
Bleeding
(All Types)
Pulmonary
Hemorrhage/
Hemoptysis
3.0
< 1.0
Hypertension
1.0
NR
Proteinuria
1. Sandler A, et al. N Engl J Med. 2006;355:2542-2550. 2. Reck M, et al. J Clin Oncol. 2009;27:1227-1234. 3. Crinò L, et al.
Lancet Oncol. 2010;11:733-740. 4. Jahanzeb M, et al. ECCO-ESMO 2009. Abstract O-9006. 5. Wozniak AJ, et al. ASCO
2010. Abstract 7618.
42. Oncología Médica
XXI Vigo
18-75 años
CNMP no-escamoso
Estadios IIIB-IV
PS=0-1
1ª línea
Cisplatino 80 mg/m2 d 1
Vinorelbina 25 mg/m2 d 1+8
Bevacizumab 15 mg/kg d 1
Cada 21 d hasta 6 ciclos
Si no PD: mant con beva
León L, et al. Expert Opin Pharmacother. 2012 Jul;13(10):1389–96.
N= 50
OP: PFS
43. Oncología Médica
Eficacia
Outcome
Objective response rate
Complete response, n (%)
PR, n (%)
SD, n (%)
Progressive disease, n (%)
XXI Vigo
N=45
%
0
13
20
12
0
29
44
27
Median PFS, months (95% CI)
6.0 (4.5-7.5)
Median OS, months (95% CI)
14.7 m (8.4-21)
Median duration of response, months
(95% CI)
1-year survival
León L, et al. Expert Opin Pharmacother. 2012 Jul;13(10):1389–96.
4.6 (2.9-6.4)
57%
45. Oncología Médica
XXI Vigo
Bevacizumab en combinación con cisplatino y
docetaxel quincenal en primera línea en CNMP no
epidermoide avanzado (047/10)
Edad > 18 años
CNMP no-escamoso
Estadios IIIB-IV
PS=0-1
1ª línea
Cisplatino 50 mg/m2 d 1+15
Docetaxel 50 mg/m2 d 1+15
Bevacizumab 5 mg/kg d 1+15
Cada 28 d hasta 4 ciclos
Si no PD: mant con beva
Lázaro M, et al. ECCO 2013, WCLC 2013
N= 22 (50) pac
analizados
OP: PFS
46. Oncología Médica
Características de los pacientes
XXI Vigo
Characteristics
N=24
Median age, years
> 65 years
60
28%
Gender, n (%)
Female
Male
6 (19)
26 (81)
ECOG PS, n (%)
0
1
2
9 (28%)
20 (62%)
3 (9)
Histological type, n (%)
adenocarcinoma
large cell
27 (84%)
4 (12.5%)
47. Oncología Médica
XXI Vigo
Eficacia
Outcome
Objective response rate
Complete response, n (%)
PR, n (%)
SD, n (%)
Progressive disease, n (%)
Median PFS, months (95% CI)
En pacientes con mantenimiento
En pacientes sin mantenimiento
N=22
%
0
14
7
1
0
63
32
4.6
6.4 (4.1-8.6)
9.5 (5.9-13)
4.6 (2.6-6.5)
54. Oncología Médica
Caso 3
Paciente mujer de 68 años
Fumadora < 5 cig/d
TBP 2000
HISTORIA
Diciembre de 2012: Febrícula de
20 días de evolución
Hemoptisis leve
Rx tórax
aumento de densidad
paramediastínico derecho con
pérdida de volumen
XXI Vigo
55. Oncología Médica
XXI Vigo
TAC t/a (12/2/12): masa en
LSD; adenopatías
mediastínicas y axilares.
Nódulos pulmonares
PET-TAC (12/2/12)
Biopsia (FBC):
adenocarcinoma pulmonar; no
mutaciones
T4N3M1
56. 1
Pemetrexed: JMDB Diseño
Randomization factors
• ECOG PS
• Stage
• History of brain metastases
• Gender
• Pathological Dx (histological
vs cytological)
R
R
A
A
N
N
D
D
O
O
M
M
II
Z
Z
E
E
ALIMTA (N=862)
500 mg/m2 IV q21d
+ Cisplatin
75 mg/m2 Day 1
GEMCITABINA (N=863)
1250 mg/m2 on D1 and D8
+ Cisplatin
75 mg/m2 Day 1
Patients in both arms received folic acid, vitamin B 12, and dexamethasone
1. Scagliotti GV, et al. J Clin Oncol. 2008;26:3543-3551.
57. JMDB : Resultados OS No-escamosos1*
ALIMTA/Cisplatin GEMZAR/Cisplatin
(n=618)
(n=634)
Median OS
(95% CI)
Adjusted HR
(95% CI)
p-value
11.0 mo
(10-12.5)
10.1 mo
(9.3-10.9)
0.84 (0.74-0.96)
0.011*
†
* Nonsquamous=adenocarcinoma, large cell carcinoma, and other/indeterminate NSCLC histology
† Superiority p-value.
1. Scagliotti GV, et al. Oncologist. 2009;14:253-263.
59. JMDB: conclusiones
Se cumplió el objetivo primario del estudio: Cisplatino/Pemetrexed no es inferior
a Cisplatino/Gemcitabina (HR=0.94)
Ambos regímenes fueron generalmente bien tolerados pero las toxicidades
hematológicas y no-hematológicas, a excepción de la náusea, fueron
significativamente favorables a Cisplatino/Pemetrexed
Un análisis pre-planificado mostró:
• En los histotipos no escamosos la combinación de cis/pemetrexed se
asoció con una OS estadísticamente superior (p=0.03)
•
En histología escamosa, Cisplatino/Gemcitabina mostró una SG
marginalmente mayor (P=0.05)
60. Oncología Médica
XXI Vigo
PARAMOUNT
Estudio de fase III doble ciego, aleatorizado, controlado con placebo
Pemetrexed 500 mg/m2; cisplatino 75 mg/m2
Ácido fólico y vitamina B12 administrados en ambos brazos
Tratamiento de inducción Tratamiento de mantenimiento de continuación
4 ciclos, cada 21 días
cada 21 días hasta progresión
• No tratados
previamente
• PS 0/1
• CPNM-NS
estadio IIIB-IV
Pemetrexed
+ Cisplatino
CR/PR/SD
según
RECIST
Pemetrexed ++BSC
Pemetrexed BSC
R
2:1
Placebo ++
Placebo
BSC
BSC
Estratificados según:
•PS (0 vs 1)
•Estadio de la enfermedad (IIIB vs IV) previo a la inducción
•Respuesta a la inducción (CR/PR vs SD)
1. Paz-Ares et al. Lancet Oncol 2012;13:247.
2. Paz-Ares et al. J Clin Oncol 2012;30 (suppl; abstr LBA7507).
61. Oncología Médica
XXI Vigo
Pemetrexed en mantenimiento de continuación demostró un beneficio
significativo en la SLP
SLP: revaluada en el momento del análisis de la SG
Probabilidad de
Supervivencia
1.0
Pemetrexed + BSC (n=359)
Placebo + BSC (n=180)
0.8
HR no ajustada: 0.60 (0.50–0.73); p<0.0001
0.6
HR=0.6
HR=0.6
0.4
0.2
0.0
0
3
6
9
12
359 215 139
180 75 33
18
21
24 27
30
33
16
2
5
0
0
0
Tiempo (meses)
Patients at risk
Pem + BSC
Plac + BSC
15
97
16
67
9
47
7
32
6
22
4
10
0
1. Paz-Ares et al. J Clin Oncol 2012;30 (suppl; abstr LBA7507).
62. Oncología Médica
XXI Vigo
Pemetrexed/cisplatino seguido de Pemetrexed demostró un beneficio
significativo en la SG
Pemetrexed + BSC (n=359)
Placebo + BSC (n=180)
SG desde la aleatorización
1.0
Log-rank P=0.0195
HR no ajustada: 0.78 (95% CI: 0.64–0.96)
0.9
Probabilidad de
Supervivencia
0.8
HR=0.78
0.7
13.9
0.6
0.5
11.0
0.4
0.3
0.2
0.1
0.0
0
Patients at risk
Pem + BSC
359
43
Placebo + BSC 180
12
3
6
9
12
15
18
21
24
27
30
33
36
Tiempo desde la aleatorización (meses)
333
15
169
8
272
2
131
3
235
0
103
0
200
166
138
105
79
78
65
49
35
23
1. Paz-Ares et al. J Clin Oncol 30, 2012 (suppl; abstr LBA7507).
63. Tasa de Supervivencia a 2 años1
Placebo + BSC 21% 32%
Pemetrexed + BSC
Tras 2 años desde el fin de la inducción, 1 de cada 3 pacientes permanecía vivo en el
brazo de pemetrexed mientras que sólo 1 de cada 5 sobrevivía en el brazo de
placebo
1. Paz-Ares et al. J Clin Oncol 30, 2012 (suppl; abstr LBA7507)
64. Oncología Médica
XXI Vigo
Paramount: SG desde el inicio de la inducción1
Los pacientes en tratamiento de mantenimiento con
Pemetrexed se beneficiaron de aprox.
mediana de SG comparado con placebo
SG desde inicio de la inducción:
en la
Pemetrexed
Mediana SG=16.9 meses (95% CI: 15.8–19.0)
Placebo
Mediana SG=14.0 meses (95% CI: 12.9–15.5)
Log-rank P=0.0191
HR=0.78 (95% CI: 0.64–0.96)
1.0
0.9
0.8
Probabilidad de
Supervivencia
3 meses
0.7
16.9
0.6
0.5
0.4
14.0
0.3
0.2
0.1
0.0
0
3
6
9
12
15
18
21
24
27
30
33
36
Tiempo desde la inducción (meses)
1. Paz-Ares et al. J Clin Oncol 30, 2012 (suppl; abstr LBA7507).
66. Oncología Médica
PRONOUNCE: Phase III Superiority Trial of
Pem/Carbo → Pem vs Pac/Carbo → Bev
XXI Vigo
Induction (q21d, 4 cycles)
Pemetrexed
(folic acid & vitamin B12)
+ Carboplatin
Bev-Eligible Population
Inclusion:
Chemo-naive patients
PS 0/1
Stage IV, nonsquamous
Stable treated CNS mets
Exclusion:
Uncontrolled effusions
R
1:1
Maintenance (q21d until
PD)
Pemetrexed
(folic acid & vitamin B12)
180 patients each
Paclitaxel
+ Carboplatin
+ Bevacizumab
Primary objective: PFS without grade 4 AE
Bevacizumab
Composite endpoint considers the first occurrence of either:
–
Grade 4 AE (lower grade AEs are not considered) or disease progression or death (PFS)
Zinner R, et al. ASCO 2013. Abstract LBA8003. Used with permission.
67. Oncología Médica
XXI Vigo
PRONOUNCE: Primary Endpoint
(G4PFS)
100
Pts (%)
80
Pem + Cb, median G4PFS: 3.9 mos
Pac + Cb + Bev, median G4PFS: 2.9 mos
60
Log-rank P = 0.176
HR: 0.85 (95% CI: 0.70-1.04)
40
20
0
0
3
6
9
12
15
18
21
24
27
5
0
3
0
1
0
0
0
Mos
Pts at Risk, n
Pem + Cb
182
87
44
26
14
7
Pac + Cb + 179
75
33
17
9
3
Bev
Zinner R, et al. ASCO 2013. Abstract LBA8003. Used with permission.
68. Oncología Médica
XXI Vigo
PRONOUNCE: OS (ITT)
100
Pem + Cb, median OS: 10.5 mos
Pac + Cb + Bev, median OS: 11.7 mos
HR: 1.07 (95% CI: 0.83-1.36;
log-rank P = .615)
Patients, %
80
Pem + Cb,
%
(n = 182)
Pac + Cb + Bev,
%
(n = 179)
1 yr
43.7
48.8
2 yrs
18.0
17.6
60
40
20
0
0
3
6
9
12
15
18
21
Mos
24
27
Pts at Risk, n
Pem + Cb
182 156 125 102 72
48
33
20
11
11
Pac + Cb + 179 151 121 96
73
59
38
28
10
3
Bev
Zinner R, et al. ASCO 2013. Abstract LBA8003. Used with permission.
30
33
36
39
42
5
1
5
1
5
0
5
0
5
0
69. Oncología Médica
XXI Vigo
Possibly Drug-Related Grade 3/4 CTCAE
Event
Pem + Cb, %
(n = 171)
Pac + Cb +
Bev, %
(n = 166)
P Value
Anemia
19
5
< .001
Thrombocytopenia
24
10
< .001
Neutropenia
25
49
< .001
Febrile neutropenia
0
2
.118
Hypertension
0
2
.058
Thrombosis/embolism
0
2
.058
Any hemorrhagic events
1
0
.499
Zinner R, et al. ASCO 2013. Abstract LBA8003. Used with permission.
70. Oncología Médica
Conclusiones
Falló en demostrar que pemetrexed/carboplatin fuese
superior a la combinación
paclitaxel/carboplatino/bevacizumab para PFS
PFS, OS, y ORR fueron similares
Diferentes perfiles de toxicidad, aunque manejables:
Pem + Cb: más anemia/trombocitopenia
Pac + Cb + Bev: más neutropenia
Zinner R, et al. ASCO 2013. Abstract LBA8003.
XXI Vigo
71. Oncología Médica
XXI Vigo
Switch vs Continuation Maintenance Therapy
Switch
Register
4 courses of platinum
+ Drug A
SD, or R
PS 0-1
Drug B
Randomize
Observation
PD
Off study
Continuation
Register
Drug A
4 courses of platinum
+ Drug A
SD, or R
PS 0-1
Randomize
Observation
PD
Off study
72. Oncología Médica
XXI Vigo
Switch Maintenance Trials
Study
Switch Agent
Median PFS, Mos
Median OS,
Mos
Immediate docetaxel
Delayed docetaxel
5.7
2.7
12.3
9.7
Pemetrexed
Placebo
4.3
2.6
13.4
10.6
SATURN[3]
Erlotinib
Placebo
2.8
2.6
12.0
11.0
ATLAS[4,5]
Erlotinib + bevacizumab
Placebo + bevacizumab
4.8
3.8
15.9
13.9
INFORM[6]
Gefitinib
Placebo
4.8
2.6
18.7
16.9
Fidias et al[1]
JMEN[2]
1. Fidias PM, et al. J Clin Oncol. 2009;27:591-598. 2. Ciuleanu T, et al. Lancet. 2009;374:1432-1440.
3. Cappuzzo F, et al. Lancet Oncol. 2010;11:521-529. 4. Miller VA , et al. 2009 ASCO. Abstract LBA8002.
5. Kabbinavar J, et al. 2010 ASCO. Abstract 7526. 6. Zhang L, et al. 2011 ASCO. Abstract LBA7511.
73. Oncología Médica
XXI Vigo
Continuation Maintenance Trials
Study
Continuation Agent
Median PFS,
Mos
Median OS,
Mos
Belani et al[1]
Gemcitabine
Best supportive care
7.4
7.7
8.0
9.3
IFCT[2]
Gemcitabine
Erlotinib
Best supportive care
3.8
2.9
1.9
12.1
11.4
10.8
Pemetrexed
Placebo
4.1
2.8
13.9
11.0
PARAMOUNT[3]
1. Belani CP, et al. 2010 ASCO. Abstract 7506. 2. Perol M, et al. 2010 ASCO. Abstract 7507.
3. Paz-Ares L, et al. Lancet Oncol. 2012;13:247-255.
74. 2013: First-line Treatment of Advanced/
Metastatic NSCLC
75%
25%
Non-SCCa
Other
mutations
5% to 10%
Mutational analysis
EGFR mutation
+15%
KRAS or no other “actionable” mutation: 80%
SCCa
EGFR-TKI
10%
EML4/ALK
ROS1
Crizotinib
RET
90%
Any hemoptysis
No hemoptysis
Platinum + pemetrexed
Carboplatin + paclitaxel
+ bevacizumab or
platinum + pemetrexed
? Vandetanib
Platinum +
paclitaxel, docetaxel
gemcitabine or
vinorelbine
nab-paclitaxel
(? cetuximab)
Hinweis der Redaktion
NCI. Non-small-cell lung cancer treatment (PDQ®). http://www.cancer.gov/cancertopics/pdq/treatment/non-small-cell-lung/healthprofessional/page1. Accessed May 15, 2013.
ACS. Cancer facts & figures: 2012. CDC. Lung cancer rates by race and ethnicity. Available at http://www.cancer.org/acs/groups/content/@epidemiologysurveilance/documents/document/acspc-031941.pdf. Accessed May 15, 2013.
Howlader N, et al. SEER cancer statistics review. Available at: http://seer.cancer.gov/csr/1975_2009_pops09. Accessed May 15, 2013.
BAC, bronchioloalveolar carcinoma; LPA, lepidic predominant adenocarcinoma; NOS; not otherwise specified; SCC, squamous cell carcinoma; SCLC, small cell lung cancer;
CI, confidence interval; HR, hazard ratio; PFS, progression-free survival.
Median OS: no significant difference between arms overall, and in patients with or without EGFR mutations
ALK, anaplastic lymphoma kinase; EGFR, epidermal growth factor receptor; OS, overall survival; TTP, time to progression
La viabilidad de la administración de la combinación de bevacizumab con quimioterapia fue probada por Johnson (JCO 2004); quien la probó en un fase II aleatorizado con carbo/paclitaxel y a dosis de 7,5 vs 15 vs placebo, y sin excluir subtipos histológicos. Las dosis altas de beva tuvieron una mejor SLP y lRR.
In the E4599 trial (Sandler et al. 2006), 878 patients with recurrent or advanced NSCLC (stage IIIB or IV) were randomised to 15mg/kg bevacizumab with carboplatin/paclitaxel (CP) (n=434) or CP alone (n=444) every 3 weeks for six cycles until disease progression or unacceptable toxicity. The 15mg/kg dose was chosen based on its activity in an earlier phase II trial (Johnson et al. 2004). The primary endpoint for E4599 was OS.
In the bevacizumab in Lung cancer (AVAiL [BO17704]) trial (Manegold et al. 2007), 1,043 patients with advanced or recurrent non-squamous NSCLC were randomised to cisplatin/gemcitabine (CG) for up to six cycles plus 7.5 mg/kg bevacizumab (n=345), 15 mg/kg bevacizumab (n=351) or placebo (n=347) every 3 weeks until disease progression or unacceptable toxicity. Following the positive survival results of the E4599 trial for bevacizumab-based therapy versus chemotherapy alone, the primary endpoint of AVAiL was amended from OS to PFS.
Both E4599 and AVAIL excluded predominantly squamous cell disease.
The primary objective for the pivotal phase III 1st line ALIMTA trial was noninferior overall survival. This Kaplan-Meier curve clearly shows that the primary objective of this study was met: ALIMTA/cisplatin was demonstrated to be noninferior to GEMZAR/cisplatin for median OS.
As illustrated by the Kaplan-Meier curve here, median OS was 10.3 months in each treatment group (adjusted HR, 0.94; 95% CI, 0.84 to 1.05; noninferiority p<0.001). The confidence intervals for the HR were well below the 1.176 margin set for noninferiority, meaning that superiority studies based on histology could be conducted.
The 1-year survival rate for ALIMTA/cisplatin was 43.5% vs 41.9% for GEMZAR/cisplatin.
Complete Reference for Citation:
1.Scagliotti GV, Parikh P, von Pawel J, et al. Phase III study comparing cisplatin/gemcitabine with cisplatin/ALIMTA in chemonaïve patients with advanced-stage non-small cell lung cancer. J Clin Oncol. 2008;26:3543-3551.
OS was significantly longer with ALIMTA/cisplatin vs GEMZAR/cisplatin when limiting the analysis to patientswith nonsquamous histologies (11.0 vs 10.1 months; HR, 0.84; 95% CI, 0.74, 0.96; superiority p=0.011).
Complete Reference for Citation:
1.Scagliotti GV, et al. Oncologist. 2009;14:253-263.
AE, adverse event; Bev, bevacizumab; Carbo, carboplatin; CNS, central nervous system; Pac, paclitaxel; PD, progressive disease; Pem, pemetrexed; PFS, progression-free survival; PS, performance status; q21d, every 21 days.
David R. Gandara, MD:
PRONOUNCE was designed as a phase III superiority trial evaluating a regimen of pemetrexed/carboplatin followed by maintenance pemetrexed vs the ECOG regimen of paclitaxel/carboplatin plus bevacizumab followed by maintenance bevacizumab. The study was performed in patients with advanced-stage NSCLC of the nonsquamous type and represents an attempt to sort out the histology-related benefit of pemetrexed.
The primary study endpoint was PFS in those patients who did not have grade 4 toxicity. This composite endpoint is a bit unconventional and, to my knowledge, has never been used in another clinical trial in lung cancer. I think this endpoint was used in an attempt to find a less toxic therapy that could also prolong PFS.
Pem, pemetrexed; Cb, carboplatin; Bev, bevacizumab; G4PFS, progression-free survival without grade 4 adverse events.
David R. Gandara, MD:
Unfortunately, similar to the POINTBREAK trial[1] last year, PRONOUNCE did not meet its primary endpoint.
Reference
Patel JD, Socinski M, Garon EB, et al. A randomized, open-label, phase III, superiority study of pemetrexed (Pem) + carboplatin (Cb) + bevacizumab (Bev) followed by maintenance Pem + Bev versus paclitaxel (Pac)+ Cb + Bev followed by maintenance Bev in patients with stage IIIB or IV non-squamous non-small cell lung cancer (NS-NSCLC). Program and abstracts of the 2012 Multidisciplinary Symposium in Thoracic Oncology; September 6-8, 2012; Chicago, Illinois. Abstract LBA8003; Abstract LBPL1.
Pac, paclitaxel; Pem, pemetrexed; Cb, carboplatin; Bev, bevacizumab.
David R. Gandara, MD:
Secondary endpoints also did not differ markedly between the 2 arms. In fact, OS favored the paclitaxel arm numerically.
Bev, bevacizumab; Cb, carboplatin; CTCAE, Common Terminology Criteria for Adverse Events; Pac, paclitaxel; Pem, pemetrexed.
David R. Gandara, MD:
The investigators did not present the grade 4 toxicity data, only grade 3/4 data. The toxicity profile was consistent with what has been seen with these regimens in other trials.
AE, adverse event; Bev, bevacizumab; Cb, carboplatin; Pac, paclitaxel; Pem, pemetrexed; PFS, progression-free survival; ORR, overall response rate; OS, overall survival.
David R. Gandara, MD:
This study leaves the field with many questions about the role of pemetrexed in nonsquamous NSCLC compared to other agents. A few years ago, Dr. Scagliotti and I published the results of a phase III trial comparing pemetrexed/cisplatin to gemcitabine/cisplatin,[1] which suggested that pemetrexed is the best drug for nonsquamous histology. However, this has not been the case in many studies. For example, a large Norwegian phase III trial of over 430 patients comparing pemetrexed-carboplatin to gemcitabine-carboplatin showed equivalent results regardless of histology, with no specificity for pemetrexed.[2] ECOG just published their analysis of various chemotherapy regimens that included pemetrexed and showed that there was no difference in efficacy based on histologic subtype. I think the cumulative data suggest that pemetrexed is a more efficacious drug in nonsquamous NSCLC, but it is not necessarily in comparison with other agents such as taxanes, as we saw in PRONOUNCE and POINTBREAK.
.
Heather Wakelee, MD:
I have a slightly different interpretation of this study. I take issue with the primary endpoint of PFS without grade 4 adverse events (AEs). The trial did not meet the endpoint. However, even if it did, I would question the meaning of the result. It is not an endpoint that will likely be used in other trials; OS and PFS are still the preferred clinical endpoints of interest. Quality of life measures can play a role, but I do not think that was captured by only analyzing grade 4 toxicity as part of the primary endpoint.
I think the findings showed that the carboplatin/pemetrexed regimen is active, but it is not more active than carboplatin/paclitaxel plus bevacizumab. Carboplatin/pemetrexed yields different toxicities compared with carboplatin/paclitaxel plus bevacizumab, including more anemia and thrombocytopenia but less neutropenia. Carboplatin/pemetrexed also showed a better toxicity profile with a lower incidence of grade 1/2 alopecia and sensory neuropathy, which are very relevant toxicities for patients. As clinicians try to determine the optimal regimen for their patients, those types of lower-grade AEs need to be included in the discussion.
It is also confusing to interpret the results of this trial in light of the POINTBREAK trial,[3] considering that both studies included a carboplatin/paclitaxel/bevacizumab arm with bevacizumab maintenance. Overall survival in the 2 trials was actually a little different. Median OS with carboplatin/paclitaxel/bevacizumab in POINTBREAK was 13.4 months, whereas in PRONOUNCE, it was 11.7 months. Although it is not appropriate to make cross-study comparisons, these differences make it difficult to ascertain the benefit of adding bevacizumab to carboplatin/pemetrexed. Median OS reached 10.5 months with carboplatin/pemetrexed in PRONOUNCE and 12.6 months with carboplatin/pemetrexed/bevacizumab in POINTBREAK. These 2 trials leave us with a lot of questions. Should we be using pemetrexed instead of paclitaxel? Should we be adding bevacizumab to chemotherapy?
In sum, PRONOUNCE does not lead to any practice changes for me. I still think that pemetrexed is a reasonable first-line choice. PRONOUNCE did not really answer the question as to whether bevacizumab should be added to chemotherapy, and the POINTBREAK data leave this question unanswered as well. My take-home from this is that carboplatin/paclitaxel/bevacizumab is still a good first-line option. Carboplatin/pemetrexed is no better than the triple-therapy regimen, but it is a viable choice with a different toxicity profile. Whether bevacizumab should be added to carboplatin/pemetrexed is something that can be considered, but it may not offer a substantial clinical benefit based on the POINTBREAK data.
David R. Gandara, MD:
POINTBREAK and PRONOUNCE reflect the fact that sometimes performing additional clinical trials does not clarify the issue; instead, it sometimes makes the issue less clear and makes clinical decisions more complex. I think the key message to take away from these studies is that clinicians have multiple options for first-line therapy, including carboplatin/pemetrexed and carboplatin/paclitaxel/bevacizumab.
References
Scagliotti GV, Parikh P, von Pawel J, et al. Phase III study comparing cisplatin plus gemcitabine with cisplatin plus pemetrexed in chemotherapy-naive patients with advanced-stage non-small-cell lung cancer. J Clin Oncol. 2008;26:3543-3551.
Grønberg BH, Bremnes RM, Fløtten O, et al. Phase III study by the Norwegian lung cancer study group: pemetrexed plus carboplatin compared with gemcitabine plus carboplatin as first-line chemotherapy in advanced non-small-cell lung cancer. J Clin Oncol. 2009;27:3217-3224.
Patel JD, Socinski M, Garon EB, et al. A randomized, open-label, phase III, superiority study of pemetrexed (Pem) + carboplatin (Cb) + bevacizumab (Bev) followed by maintenance Pem + Bev versus paclitaxel (Pac)+ Cb + Bev followed by maintenance Bev in patients with stage IIIB or IV non-squamous non-small cell lung cancer (NS-NSCLC). Program and abstracts of the 2012 Multidisciplinary Symposium in Thoracic Oncology; September 6-8, 2012; Chicago, Illinois. Abstract LBA8003; Abstract LBPL1.