¿Cuál es la mejor opción y/o secuencia de tratamiento en el … · 2018-11-27 · vs 14,7 meses...
Transcript of ¿Cuál es la mejor opción y/o secuencia de tratamiento en el … · 2018-11-27 · vs 14,7 meses...
Santiago Ponce Aix
Thoracic Tumors Unit
Medical Oncology Department
University Hospital “12 de Octubre”
H12O-CNIO Lung Cancer Clinical Research Unit
Spanish National Cancer Research Centre (CNIO)
Madrid
¿Cuál es la mejor opción y/o secuencia de tratamiento en el cáncer de
pulmón no microcítico ALK positivo?
Disclosure
I have provided consultation, attended advisory boards and/or provided lectures for thefollowing organizations: Merck Sharp and Dohme, Bristol-Myers Squibb, F. Hoffmann-La
Roche, AstraZeneca, Boehringer-Ingelheim, Eli Lilly, Pfizer, Celgene
I declare no conflict of interest.
• The most common rearrangement isbetween EML4 and ALK, which producesthe EML4-ALK-fusion protein
• The breakpoint within ALK occurs at exon20 (A20)
• The breakpoint within EML4 can differ, thusgenerating different variants of the fusionprotein
Soda, et al. Nature 2007; Hallberg, et al. Nat Rev Cancer 2013 ; Rikova, et al. Cell 2007
Discovery of ALK Fusion in NSCLC
Dearden, et al. Ann Oncol 2013; . Barlesi, et al. Lancet 2016 ; Johnson, et al. ASCO 2013; Li, et al. PLoS One 2013
Discovery of ALK Fusion in NSCLC
ESPAÑA ?
• 20-30% patients at diagnosis will have with brain mets
• 60-90% patients will progress at CNS, even after crizotinib (60%)
• Brain MRI should be perform baseline instead CT scan
ALK patients: a distinct disease
Kim DW ASCO 2014; Soria JC Lancet 2017; Solomon BJ NEJM 2014; Camidge DR, Lancet Oncol 2012
Profile 1007
Shaw AT, et al. N Engl J Med 2013;368:2385–94
Crizotinib(n=172a)
Pemetrexed(n=99a)
Docetaxel(n=72a)
Median, mo 7.7 4.2 2.6
HRb (95% CI) 0.59 (0.43 to 0.80) 0.30 (0.21 to 0.43)
P <0.001 <0.001
Pro
bab
ility
of
surv
ival
wit
ho
ut
pro
gre
ssio
n (
%)
100
80
60
40
20
00 5 10 15 20 25
Time (months)
Endpoint
ORR % 65%
Median PFS 7.7 months
Median duration of response 8.0 months
0 5 10 15 20 35
PFS
pro
ba
bil
ity
1.0
0.8
0.6
0.4
0.2
0
HR=0.45 (0.35–0.60)Log-rank p<0.0001
Crizotinib (n=172)
Chemotherapy (n=171)
Time (months)
25 30
10.9 months7.0 months
Endpoint
ORR % 74%
Median PFS 10.9 months
Median duration of response 11.3 months
Profile 1014
Solomon, et al. NEJM 2014
Sub-Optimal CNS disease control with Crizotinib
ITT Treated BM Without BM at baseline
Intracranial Time to Progression Profile 1014
Solomon BJ JCO 2016CNS assessment by CT
ASCEND 4
Soria et al. Lancet 2017
16.6 months8.1 months
PFS in patients without and with BM - Ascend 4
26.3 months8.3 months 10.7 months6.7 months
CNS assessment by CT Soria et al. Lancet 2017
If a TKI is the standard of care in first line, what after?
ASCEND 5
Shaw AT, et al. Lancet Oncol 2017;18:874–86
ALUR: phase III trial of alectinib versus chemotherapy in previously treated ALK+ NSCLC
S.Novello ESMO 2017
Alectinib Arm (N=72)Chemotherapy Arm
(N=35)
PFS (investigator) – ITT Population1
KM estimates of PFS (in months)
Median (95% CI2) 9.6 (6.9, 12.2) 1.4 (1.3, 1.6)
Hazard ratio (alectinib vs. chemotherapy)3 0.15
ALTA
Huber ASCO 2018
ALTA
90180 mg
Median follow-up 18,6m 24,3m
Confirmed ORR 55% 56%
Median PFS* 15.6months 16.7 months
Median DOR* 13.8 months 13.8 months
Median OS 27.6 months 34,1 months
90180 mg
Median follow-up
Confirmed intracranial ORR(measurable brain mets)
67%
Median intracranial PFS(any brain mets)
18.4 months
Median intracranial DOR(measurable brain mets)
16.6 months
Confirmed CRs (non measurable brain mets)
18%
Huber ASCO 2018
Lorlatinib
DOR
One TKI 12.4 m
More One TKI 11.7 m
All 9.3 m
Shaw Lancet Oncology 2017
Addictive effects of multiple ITK s
Tx 1
PFS 1
Tx 2
PFS 2
Tx 3
PFS 3
PFS 1
Tx 1 Tx 2
PFS 2
Can we define a strategy based on molecular biomarkers instead clinical features? or is all about M1 SNC?
Acquired resistance on crizotinib that makes sense to avoid?
OS ?
Addictive effects of multiple ITK s
Tx 1
PFS 1
Tx 2
PFS 2
Tx 3
PFS 3
PFS 1
Tx 1 Tx 2
PFS 2
Can we define a strategy based on molecular biomarkers instead clinical features? or is all about M1 SNC?
Acquired resistance on crizotinib that makes sense to avoid?
OS ?
ALEX
Cadmige ASCO 2018
ALEX
S. Peters N Engl J Med 2017
Pacientes CON metástasis en SNC al inicio†
100
80
60
40
20
0
PF
S (
%)
Duration of PFS (months)9 15 21 276 12 18 24 303Day 1
7.4
(95% CI: 6.6–9.6)
NR
(95% CI: 9.2–NR)
Pacientes SIN metástasis en SNC al inicio
PF
S (
%)
Duration of PFS (months)9 15 21 276 12 18 24 303Day 1
14.8
(95% CI: 10.8–20.3)
NR
100
80
60
40
20
0
Mediana SLP fue de 27,7 meses (95% CI: 9,2–NE) para
alectinib vs 7,4 meses (95% CI: 6,6–9,6) para crizotinib
HR=0,35 (95% CI: 0,22–0,56)
HR 0.40 (95% CI 0.25–0.64)
p<0.0001
HR=0.51 (95% CI 0.33–0.80)
p=0.0024
Alectinib (n=64)
Crizotinib (n=58)
Alectinib (n=88)
Crizotinib (n=93)
Mediana SLP fue de 34,8 meses (95% CI: 22,4–NE) para alectinib
vs 14,7 meses (95% CI: 10,8–20,3) para crizotinib
HR=0,47 (95% CI: 0,32–0,71)
ASCO 2018
Alecensa logró un beneficio de SLP consistente frente a crizotinib,
independientemente de las metástasis de SNC en el momento basal
Beneficio de SLP en pacientes con y sin metástasis en el SNC
S. Peters N Engl J Med 2017
ALEX
ALTA-1
Camidge WCLC 2018
ALTA-1Intracranial PFS
Camidge WCLC 2018
Camidge WCLC 2018
ALTA-1Whole Body BIRC PFS by BM at Baseline
S. Peters N Engl J Med 2017
ALEX
Est
ima
ció
n S
G (
%)
100
80
60
40
20
0
0 2418126 30
Tiempo (meses)
Alectinib (n=152)
Crizotinib (n=151)
Crizotinib
(n=151)
Alectinib
(n=152)
Pacientes con eventos,
n (%)
48 (31,8) 43 (28,3)
SG mediana,
meses (IC 95%)
NR
(NR)
NR
(NR)
HR 0,76
(IC 95%: 0,5–1,15)
No estadísticamente significativo
Cadmige WCLC 2018
ALTA-1Intracranial PFS
Isozaki, et al. Cancers 2015
Rational Biomarker Driven Approach to Best Treatment
Sai-Hong Ignatius Ou ASCO 2018
Rational Biomarker Driven Approach to Best Treatment
Gainor JF, et al. Cancer Discov 2016;6:1118-33
Rational Biomarker Driven Approach to Best Treatment
Gainor JF, et al. Cancer Discov 2016;6:1118-33
Rational Biomarker Driven Approach to Best Treatment
Cellular ALK phosphorylation mean IC50 (nM)Mutation status Crizotinib Ceritinib Alectinib Brigatinib LorlatinibParental BA/F3 763.9 885.7 890.1 2,774.0 11,293.8
V1 38.6 4.9 11.4 10.7 2.3
C1156Y 61.9 5.3 11.6 4.5 4.6
I1171N 130.1 8.2 397.7 26.1 49.0
I1171S 94.1 3.8 177.0 17.8 30.4
I1171T 51.4 1.7 33.6 6.1 11.5
F1174C 115.0 38.0 27.0 18.0 8.0
L1196M 339.0 9.3 117.6 26.5 34.0
L1198F 0.4 196.2 42.3 13.9 14.8
G1202R 381.6 124.4 706.6 129.5 49.9
G1202del 58.4 50.1 58.8 95.8 5.2
D1203N 116.3 35.3 27.9 34.6 11.1
E1210K 42.8 5.8 31.6 24.0 1.7
G1269A 117.0 0.4 25.0 ND 10.0
Gainor JF JCO 2018
Rational Biomarker Driven Approach to Best Treatment
Tracking the evolution of resistance to ALK through longitudinal analysis of circulating tumor DNA
Gainor JF JCO 2018
Rational Biomarker Driven Approach to Best Treatment
Strengths:
- NGS is feasible and can be used with a good
concordance in tissue
Weakness:
-22 patients
-Single center experience
- Inconsistent intervals of blood samples
-Data at PD, no data available at initial TKI
Odegaard J CCR 2018
Rational Biomarker Driven Approach to Best Treatment
High concordance with orthogonal clinical plasma- and tissue-based genotyping methods supports the clinical
accuracy of Digital Sequencing across all four types of targetable genomic alterations. Digital Sequencing’s clinical
applicability is further supported by high rates of technical success and biomarker target discovery.
Validation of a plasma-based comprehensive cancer genotyping assay utilizing orthogonal tissue- and plasma-
based methodologies.
GRACIAS