Post on 20-Aug-2020
P. García Alfonso
Sr. Oncología Médica
HGU Gregorio Marañón de Madrid
Tumores RAS nativo: tratamiento 1ª línea
“ A favor del bevacizumab”
Bevacizumab4
Supervivencia global en el Cáncer
Colorrectal metastásico
Median OS
Tim
e (
mo
nth
s)
BSC
5-FU
30
20
10
0
Irinotecan1
Capecitabine2
Oxaliplatin3
Cetuximab5,6
1980s 1990s 2000s 2010
Panitumumab7
Aflibercept8
Regorafenib9*
*Not approved by the EMA or for use in the Czech Republic
1. Cunningham, et al. Lancet 1998; 2. Van Cutsem, et al. BJC 2004; 3. Rothenberg, et al. JCO 2003
4. Hurwitz, et al. NEJM 2004; 5. Cunningham, et al. NEJM 2004; 6. Van Cutsem, et al. NEJM 2009
7. Van Cutsem, et al. JCO 2007; 8. Van Cutsem, et al, JCO 2012; 9. Grothey, Van Cutsem, et al. Lancet 2012
2012 ESMO consensus guidelines
Schmoll HJ et al. Ann Oncol 2012;23:2479–516.
La efficacia depende de la primera línea
1. Maughan TS, et al. Lancet 2011;377:2103–2114; 2. Saltz LB, et al. J Clin Oncol 2008;26:2013–2019; 3. Bokemeyer C, et al. Ann Oncol 2011;22:1535–1546; 4. Hurwitz H, et al. New Engl J Med 2004;350:2335–2342;
5. Langer C, et al. ESMO 2008 (Abstract No. 385P); 6. Peeters M, et al. J Clin OncoI 2010;28:4706–4713;
7. Giantonio BJ, et al. J Clin Oncol 2007;25:1539‒1544; 8. Grothey A, et al. Lancet 2013;38:303–312;
9. Karapetis CS, et al. N Engl J Med 2008;359:1757‒1765
Parameter 1st line 2nd line Later lines
ORR (%)* 38.0–64.01,2 10.3–35.05,6 1.0–12.88,9
Median PFS
(months)* 8.3–10.63,4 4.0–7.35,7 1.9–3.78,9
Conclusion: 1st linea de tratamiento es crítica en la OS
*Range of results for targeted treatment arms of key Phase II and III trials (KRAS 12/13 wt for EGFR inhibitor trials)
¿Con que biológico empezamos?
Antiangiogénicos?
Anti-EGFR?
Cúal es la primera línea de tratamiento
más activa para pacientes con CCRm
1st line
2nd line
3rd line
Biomarcadores
predictivos
Disponibilidad de los
fármacos (costes)
Medicina
basada en la
evidencia.
Eficacia/
Toxicidad
Angiogenesis is mediated through the interaction
between VEGF and its receptors1–5
7
1. Ferrara. Endocr Rev 2004; 2. Hicklin, Ellis. JCO 2005; 3. Baka, et al. Expert Opin Ther Targets 2006; 4. Morabito, et al. Oncologist 2006; 5. de Vries, et al. Science
1992; 6. Bergers, Benjamin. Nat Rev Cancer 2003; 7. Jain. Science 2005; 8. Gerber, Ferrara. Cancer Res 2005; 9. Jain. Nat Med 2001; 10. Inoue, et al. Cancer Cell 2002;
11. Margolin. Curr Oncol Rep 2002; 12. Hu, et al. Am J Pathol 2002
VEGF
VEGF
receptor Facilitates survival of
existing endothelial cells1,2,6–8
Contributes to vascular
abnormalities1,2,6,7,9
The interaction of the VEGF ligand with VEGF receptors is a key mediator of angiogenesis
Stimulates new
vessel growth1,2,6–8,10
Increases vessel
permeability11,12
Eficacia de las combinaciones
de Bevacizumab
Bevacizumab for 1L treatment of mCRC: significant
benefit with different chemotherapy regimens in phase
III trials
1. Hurwitz, et al. NEJM 2004; 2. Saltz, et al. JCO 2008; 3. Tebbutt, et al. JCO 2010 4. Cunningham, et al. ASCO GI 2013;
Regimen
Tx
line N Post-study therapy
ORR
(%)
Median
PFS
(months)
Median
OS
(months)
IFL
IFL + bevacizumab1 1L 813 2L: ~50%
2L: ~50%
35
45*
6.2
10.6*
15.6
20.3*
XELOX/FOLFOX
XELOX/FOLFOX + bevacizumab2 1L 1,401
2L: 53%
2L: 46%
38
38
8.0
9.4*
19.9
21.3
Capecitabine
Capecitabine + bevacizumab3 1L 313 68%
62%
30
38
5.7
8.5*
18.9
18.9
Capecitabine
Capecitabine + bevacizumab4 1L 280 37%
37%
10
19*
5.1
9.1*
16.8
20.7
*Statistically significant difference vs the control arm
NR = not reported
Amplia experiencia - Datos de eficacia consistentes
en EECC
Supervivenci
a Global
Supervivencia
Libre de
progresión
1. Bevacizumab [package insert]. South San Francisco, CA: Genentech; 2011. 2. Nalluri SR, et al. JAMA.
2008;300;2277-2285. 3. Hurwitz H, et al. J Clin Oncol. 2011;29:1757-1764.
Adverse Event Incidence With Bev Across Indications,[1] %
Comments
Grade ≥ 3 ATE 2.6
Risk of ATE increased in pts 65 yrs of age or older or with ATE history
Grade 3/4 HTN 5-18* Patients should receive otherwise standard CV
prophylaxis and have BP monitored and managed
GI perforations 0.3-2.4
Grade ≥ 3 hemorrhagic event 1.2-4.6†
Bev not recommended for pts with serious hemorrhage or recent hemoptysis
Risk of major bleeding does not appear to be increased in pts receiving full-dose anticoagulation tx without other risk factors
Wound complications
15‡ Discontinue 4-8 wks before surgery; resume 6-8 wks
postsurgery
Potential for increased VTE risk controversial; increased risk noted in 1 study but not in others.[2,3]
*Predominantly grade 3. †May apply more to NSCLC. ‡When surgery conducted during bev therapy.
Bevacizumab-Associated Toxicity
TRIBE: phase III trial comparing bevacizumab +
FOLFOXIRI with bevacizumab + FOLFIRI
OLIVIA study design
Criteria for unresectability
Patients had to meet at least one of the following criteria:
– no upfront R0/R1 resection of all hepatic lesions possible
– less than 30% estimated residual liver after resection
– disease in contact with major vessels of the remnant liver
FDG-PET was performed to exclude extrahepatic metastases
Primary endpoint: overall resection rate (R0/R1/R2)
Previously untreated,
unresectable colorectal
cancer with metastases
confined to the liver
N=80 Bevacizumab + mFOLFOX6 Bevacizumab 5 mg/kg, oxaliplatin
85 mg/m2, folinic acid 400 mg/m2, bolus
5-FU 400 mg/m2 then 5-FU 2400
mg/m2 46-hr infusion on day 1 q2w
Bevacizumab + FOLFOXIRI Bevacizumab 5 mg/kg, oxaliplatin
85 mg/m2, irinotecan 165 mg/m2, folinic
acid 200 mg/m2 and 5-FU 3200 mg/m2
46-hr infusion on day 1 q2w
Stratification factors:
• Centre
• ECOG performance status
• No. of metastatic lesions
Randomization
1:1
OLIVIA: Resection and Response rate and PFS –
ITT population
Variable, n (%)
Bev +
FOLFOXI
RI
(n=41)
Bev +
mFOLFO
X-6
(n=39)
Differ
ence
(%)
P
valu
e
Resection
rate
R0/R1/R2* 25 (61.0) 19 (48.7) 12.3 0.27
1
R0/R1 21 (51.2) 13 (33.3) 17.9 0.10
6
R0 20 (48.8) 9 (23.1) 25.7 0.01
7
Overall
response rate 33 (80.5) 24 (61.5) 18.9
0.06
1
Utilización de Bevacizumab en primera línea de
CCRm
1st
line
3rd
line
FU FU + Bev Optional 1st line
Oxaliplatin-based 1st line Irinotecan-based 1st line Chemo-
triplet
4th
line Regorafenib*
2nd
line
FU/Ox FU/Ox/Iri FU/Ox + Bev FOLFOX +
Pan or Cet
(FOLF)IRI+
Pan/Cet
FU/Iri +
Bev Fu/Iri Pan/Cet ± Iri
or FU/Bev
Pan/Cet ± Iri FU+Bev
FOLFIRI +
Aflibercept
Regorafenib*
FU/Iri +
Cet FU/Iri FU/Iri + Bev
FU/Ox FOLFOX +
Cet (Pan)
Pan/Cet ± Iri FU + Bev
Regorafenib*
Regorafenib* Regorafenib*
FU/Ox+
Bev
Schmoll, et al. Ann Oncol 2012 *Not approved by the EMEA or for use in the Czech Republic
FU/Ox/Iri
+Bev *
*Falcone, et al. ASCO 2013
¿Qué aportan los tratamientos de
mantenimiento con bevacizumab ?
Tratamiento de Mantenimiento con Bevacizumab
Trial 1L 2L SLP1 SLP2 OS
MACRO XELOX - Beva XELOX - Beva NA 10.4 NA 21.1
XELOX - Beva Beva NA 9.6 NA 20.4
CAIRO-3 XELOX - Beva XEL - Beva
XELOX - Beva 8.5 19.8 21.7
XELOX - Beva Observ 4.1 15 18.2
SAKK Quimio- Beva Beva NA 9.5 NA 25.1
Quimio- Beva Observ NA 8.5 NA 22.8
TML Quimio- Beva Quimio- Beva 5.7 NA 9.8
Quimio- Beva Quimio 4.1 NA 11.2
Está indicado el tratamiento de mantenimiento hasta la
progresión. El estándar es bevacizumab más capecitabina
CAIRO3: maintenance Beva + capecitabine versus observation
Koopman, et al. ASCO 2013
• Phase III trial
• Primary endpoint: PFS after re-introduction = PFS2
• Secondary endpoints: PFS1, OS, TTP2, ORR, safety
• PFS2 was considered to be equal to PFS1 for patients in whom Avastin + XELOX was
not reintroduced after PFS1 for any reason
Previously
untreated
mCRC
(n=558)
R Beva +
XELOX
(x6)
CR
PR
SD
Beva +
capecitabine
Observation Beva + XELOX PD2 PD1
PFS2 PFS1
TTP2
Arm A
Arm B
Beva + XELOX PD2 PD1
CAIRO3: resultados eficacia
Presented By Miriam Koopman, at 2014 ASCO Annual Meeting
Presented By Miriam Koopman, at 2014 ASCO Annual Meeting
Presented By Dirk Arnold, at 2014 ASCO Annual Meeting
Presented By Dirk Arnold, at 2014 ASCO Annual Meeting
Presented By Dirk Arnold, at 2014 ASCO Annual Meeting
Presented By Dirk Arnold, at 2014 ASCO Annual Meeting
Selección de Biológicos por biomarcadores
Bevacizumab independiente de RAS
…Hasta ahora los resultados de eficacia de Bevacizumab ha
resultado independiente del estado mutacional de Kras
PRIME study RAS analysis
KRAS, NRAS and BRAF mutation hotspots
Based on Douillard JY, et al. N Engl J Med 2013; 369:1023-34;
Oliner KS, et al. EJC 2013; 49 (suppl 3):abstract 2275 (and poster).
Percentages have been rounded; 7 patients harboured either KRAS or
NRAS codon 59 mutations
EXON 2 EXON 3 EXON 4 EXON 1
12 13 61 117 146
EXON 2 EXON 3 EXON 4 EXON 1
12 13 61 117 146
EXON 15 EXON 16 EXON 1
600
40% 5% 6%
4% 4% 0%
59
59
9%
Among WT KRAS exon 2 patients, an additional 17% of
tumours with RAS mutations were found
12 13 61 117 146 59
12 13 61 117 146 59
600
Overall RAS and BRAF
ascertainment rate: 89%
Overall RAS
ascertainment rate: 90%
NRAS
BRAF
KRAS
What data are available to support selection of
first-line therapy?
1st
line
3rd
line
FU FU + Bev Optional 1st line
Oxaliplatin-based 1st line Irinotecan-based 1st line Chemo-
triplet
4th
line Regorafenib*
2nd
line
FU/Ox FU/Ox/Iri FU/Ox + Bev FOLFOX +
*Pan or **Cet
(FOLF)IRI+
Pan/Cet
FU/Iri +
Bev Fu/Iri Pan/Cet ± Iri
or FU/Bev
Pan/Cet ± Iri FU+Bev
FOLFIRI +
Aflibercept
Regorafenib*
FU/Iri +
Cet FU/Iri
FU/Iri +
Bev
FU/Ox FOLFOX +
Cet (Pan)
Pan/Cet ± Iri FU + Bev
Regorafenib*
Regorafenib* Regorafenib*
FU/Ox+
Bev
Schmoll, et al. Ann Oncol 2012 *Oliner, et al. ASCO 2013 **Primrose JN, et al. ASCO 2013
WT RAS
Pmab – QT
Oxali
WT RAS
Cetux – QT
Irinotecan
CALGB 80405
(phase III)
FIRE III
(phase III)
Untreated
KRAS WT mCRC
(n=1,100)
Bevacizumab +
FOLFOX or FOLFIRI
Cetuximab +
FOLFOX or FOLFIRI
R
PD
PD Primary endpoint: OS
Untreated,
unresectable
KRAS WT mCRC
(n=285)
Bevacizumab +
mFOLFOX6
Panitumumab +
mFOLFOX6
R
PEAK
(phase II)
Primary endpoint: ORR
Primary endpoint: PFS
PD
PD
Untreated
KRAS WT
mCRC
(n=520)
Bevacizumab +
FOLFIRI
Cetuximab +
FOLFIRI
R
PD
PD
Cross-trial comparisons have
limitations – are head-to-head trials
available?
PEAK study mFOLFOX6 + panitumumab or bevacizumab in 1st-line
treatment of WT KRAS exon 2 mCRC
Karthaus M, et al. EJC 2013; 49 (suppl 3):abstract 2262 (and poster);
Protocol ID: 20070509; ClinicalTrials.gov identifier: NCT00819780. ORR, objective response rate; mFOLFOX6, modified FOLFOX6
Metastatic
CRC
WT KRAS exon 2
(n = 285)
Tumour Assessment Q8W (±7 days);
Treatment administered until
disease progression, death,
or withdrawal from study
1:1
mFOLFOX6 (Q2W) +
panitumumab 6 mg/kg (Q2W)
mFOLFOX6 (Q2W) +
bevacizumab 5 mg/kg (Q2W)
• Study endpoints: PFS (1°); OS, ORR, safety, exploratory biomarker analysis
• No formal hypothesis testing was planned
E
n
d
o
f
t
r
e
a
t
m
e
n
t
S
a
f
e
t y
f
o
l
l
o
w
u
p
P
o
s
t
t
r
e
a
t
m
e
n
t
f
o
l
l
o
w
u
p
E
n
d
o
f
s
t
u
d
y
30 days
(+ 3 days)
Every 3 months (±28 days)
until end of study
R
PEAK study RAS analysis: PFS
PEAK study RAS analysis: OS
FIRE-3 study design
Stintzing S, et al. Journal of clinical oncology 2014 32(suppl 3):abstr 445. Pres. at ASCO GI 2014
FIRE-3 study results
Stintzing S, et al. Journal of clinical oncology 2014 32(suppl 3):abstr 445. Pres. at ASCO GI 2014
RAS: Evaluation of ORR
Stintzing S, et al. Journal of clinical oncology 2014 32(suppl 3):abstr 445. Pres. at ASCO GI 2014
RAS: Evaluation of PFS
Stintzing S, et al. Journal of clinical oncology 2014 32(suppl 3):abstr 445. Pres. at ASCO GI 2014
RAS: Evaluation of OS
Stintzing S, et al. Journal of clinical oncology 2014 32(suppl 3):abstr 445. Pres. at ASCO GI 2014
CALGB/SWOG 80405: <br /> FINAL DESIGN
Presented By Alan Venook at 2014 ASCO Annual Meeting
CALGB/SWOG 80405: Statistics
Presented By Alan Venook at 2014 ASCO Annual Meeting
CALGB/SWOG 80405: Overall Survival <br />
Presented By Alan Venook at 2014 ASCO Annual Meeting
CALGB/SWOG 80405: Progression-Free Survival<br />(Investigator Determined)
Presented By Alan Venook at 2014 ASCO Annual Meeting
CALGB/SWOG 80405: Overall Survival<br />FOLFOX Treated
Presented By Alan Venook at 2014 ASCO Annual Meeting
CALGB/SWOG 80405: Overall Survival<br />FOLFIRI Treated
Presented By Alan Venook at 2014 ASCO Annual Meeting
Grade 3-4 Toxicities<br />
Presented By Alan Venook at 2014 ASCO Annual Meeting
Slide 23
Presented By Alan Venook at 2014 ASCO Annual Meeting
Conclusiones
La supervivencia global de la QT/Cetuximab no es diferente
de la de la QT/Bevacizuab en primera línea de tratamiento en
pacientes kras wt.
Ambas combinaciones puedes ser considerados opciones
terapéuticas en kras wt
La SG en ambas ramas es superior a 29 meses,
estableciéndose un nuevo baremo para esta enfermedad
Análisis detallado de subgrupos y de largos supervivientes
pueden ofrecer una valiosa información
Hay que esperar a los resultados del estudio evaluados por
RAS
CALGB 80405
(phase III)
FIRE III
(phase III)
Untreated
KRAS WT mCRC
(n=1,100)
Bevacizumab +
FOLFOX or FOLFIRI
Cetuximab +
FOLFOX or FOLFIRI
R
PD
PD Primary endpoint: OS
Untreated,
unresectable
KRAS WT mCRC
(n=285)
Bevacizumab +
mFOLFOX6
Panitumumab +
mFOLFOX6
R
PEAK
(phase II)
Primary endpoint: ORR
Primary endpoint: PFS
PD
PD
Untreated
KRAS WT
mCRC
(n=520)
Bevacizumab +
FOLFIRI
Cetuximab +
FOLFIRI
R
PD
PD
Evaluación KRAS: Negativos
Estudios fase III: Evaluación por RAS total
PEAK:
– RAS total : aumento de PFS
– Estudio fase II generador de hipótesis
FIRE
– RAS total negativo
– Incremento de OS!!
CALGB
– RAS total ???
Personalización en el Tratamiento del CRCm:
Consideraciones
Extensión de la enfermedad
Intención del tratamiento (paliativo vs potencialmente curativo)
Performance status Edad Comorbilidades Adyuvancia previa en 1
año Marcadores moleculares
Función de órgano: hepatica y renal
Riesgo de toxicidad: Enf coronaria o ACA activo, proteinuria, hemorragia activa, heridas no cicatrizadas, alergia a los mAc, neuropatia, Enfermedad inflamatoria intestinal, Gilberts
Conveniencia Costes/recursos Preferencias del paciente
A favor de los antiangiogénicos
Los estudios fase III/II y los meta-análisis confirman la
eficacia de los antiangiogénicos
Perfil de tolerabilidad adecuado
Bevacizumab incrementa la supervivencia
independientemente del estado de RAS
Los estudios comparativos con anti-EGFR en pacientes
seleccionados por KRAS no encuentran diferencias en
eficacia
Permiten abordajes terapéuticos que priorizan calidad de
vida
Pueden mejorar la tasa de R0 en pacientes con metástasis
hepáticas en esquemas de tripletes
Slide 30
Presented By Alan Venook at 2014 ASCO Annual Meeting
Preferencia del paciente y de los efectos
secundarios
Antiangiogénicos?
Anti-EGFR?
¡ Muchas Gracias!
pgarcaalfonso@gmail.com