BRAF mutados: terapia diana, largos supervivientes y reversión de resistencia
María González Cao
Hospital Quiron Dexeus
Instituto Oncológico Dr Rosell
Barcelona
Foro Debate Oncología, Formigal 2018
Karachaliou et al. ATM 2015
Molecular alterations in melanoma
Phase I Vemurafenib
Phase I trial:
• Recommended Phase II dosing of 960 mg po BID
• Tumor responses at 960 mg BID (extension cohort):
– Unconfirmed response rate of 81%
– Confirmed response rate of 56%
Flaherty K et al N Engl J Medicine, August 2010
1. Long G et al . Annals Oncol 2017, 28: 1631 3. Dummer.ASCO 20182. ASCO 2018 4. Robert C. New England 2015
COMBI-D1
74,5%
49,0%
38,5% 34,7%
COBRIM2
COLUMBUS3 COMBI-V4
1. Long G et al . Annals Oncol 2017, 28: 1631 3. Dummer.ASCO 20182. Dreno et al. ASCO 2018 4. Robert C. New England 2015
COMBI-D1 COBRIM2
COLUMBUS3 COMBI-V4
100
80
60
40
20
0
PFS
%)
Cotellic + Zelboraf (n=247)Placebo + Zelboraf (n=248)
+9 13 17 21 25
++
+++++++++++++++++++++
+++++++++++++++++++
+++
+
+
+++++
+++
++ +++ ++++ ++++++ ++++ ++++ +++++
AEs associated with BRAFand MEKi
COMBO450 COBRIM COMBI-D COMBI-V VEMU
PFS 14.9 12.6 11 11 7.3
PFS3y 28% NR 22% 25% 13%
OS 33.6 22.5 24 NR 16.9
OS3y 47% 38.5% 44% 45% 32%
OR 76% 70% 69% 64% 49%
DOR 18.6 12.9 12.9 13.8 15
AEs discont 15% 19% 14% 13% 17%
1. Long G et al . Annals Oncol 2017, 28: 1631 3. Dummer.ASCO 20182. Dreno et al. ASCO 2018 4. Robert C. ESMO 2016
% alelo mutado
80%
0% 0,50%
10,48%
0
50
100
11-12-2014 9-01-2015 13-09-2015 23-11-2015
BRAFi+MEKi
Gonzalez-Cao 2015
BRAF mutations in cfDNA: Prognosis stage IV
Gonzalez Cao et al. Mel Res 2015
Gonzalez Cao et al. Mel Res 2018
3.6
8.8
5.3
17
Early prediction of response/survival: GEM1304
Gonzalez-Cao et all. Mel Res , 2018
5.3
16.6
15.1
Patie
nts
Time from 1st dose (mo)
BRAFV600 early-cfDNA positive
BRAFV600 early-cfDNA negative
BRAFi/MEKi: OS
Phase III COBRIM
Vem + Cobi
Daud et al. ASCO 2018; Dréno et al. ASCO 2018
Phase Ib BRIM7
Vem + Cobi
4Y 35%
4Y 29%5Y 39.2%
Five Baseline Factors Influenced OS
ECOG = 0 ECOG ≥ 1
N = 93
1Y = 71%
2Y = 43%
3Y = NE
N = 56
1Y = 42%
2Y = 19%
3Y = 16%
LDH Normal LDH ≥ ULN N = 617
Disease Sites ≥ 3Disease Sites < 3
N = 161
1Y = 76%
2Y = 55%
3Y = 38%
N = 237
1Y = 90%
2Y = 75%
3Y = 70%
LDH >1-≤ 2 × ULN LDH ≥ 2 × ULN
N = 70
1Y = 40%
2Y = 7%
3Y = 7%
N = 149
1Y = 60%
2Y = 33%
3Y = 9%
N = 219
1Y = 54%
2Y = 25%
3Y = 7%
N = 398
1Y = 85%
2Y = 67%
3Y = 57%
a Regression tree analysis.
NE, not estimable.
PRESENTED BY GV LONG AT SMR 2015
PFS and OS by Best Response
14
Progression-Free Survival Overall Survival
No. at riskComplete Response (CR)
Partial Response (PR)
Stable Disease (SD)
Progressive Disease (PD)
Not Evaluable (NE)
100 87 33 5
316 151 50 5
150 24 2 0
35 0 0 0
16 0 0 0
0.0
0.2
0.4
0.6
0.8
1.0
0 12 24 36
PFS
Pro
bab
ility
MonthsNo. at riskComplete Response
Partial Response
Stable Disease
Progressive Disease
Not Evaluable
100 94 52 5
316 255 107 11
150 68 24 4
35 13 2 0
16 1 1 00
.00
.20
.40
.60
.81
.0
0 12 24 36
OS
Pro
bab
ility
Months
CR
PR
SD
PD
NE
29%
2-yr1-yr
90%
68%
51%
2-yr1-yr
95%88%
55%
83%
PRESENTED BY GV LONG AT SMR 2015
Ongoing Response in BRAF V600E-Mutant Melanoma After Cessation of Intermittent Vemurafenib Therapy: A Case Report
• Lady 88 y old; subcutaneous+lung (<1 mm)
• Vemurafenib
– 2 Weeks: PR
– 10 months: PR and toxicity/ on-off schedule
– 2 months later: CR and discontinue
– 9 months after stop:CR
Dooley et al. Target Oncol 2016
Long survivors with BRAFi: only BRAF mutations on WES
Wheler. BMC Cancer 2015
Adaptive immune response
Lymphocyte-mediated immunity
NK cell-mediated toxicity
Innate immune response
Keratinization
Peptide cross-linking
Xenobiotic glucuronidation
Neg. regulation of cellular glucuronidation
Negative regulation of GT activity
Flavonoid glucuronidation
Drug metabolic process
Flavonoid biosynthetic process
Neg. regulation of FA metabolic process
Flavone metabolic process
0 5 10 15 20
FDR (–log10)
CR
PD
Gene ontology analysis from http://geneontology.org/.
CR, complete response; FA, fatty acid; FDR, false discovery rate; GT, glucuronosyltransferase;
Neg, negative; NK, natural killer; PD, rapid disease progression; RNA-Seq, RNA sequencing.
Differential Gene Expression by RNA-Seq Distinguishes Patients with Complete Response Versus Progressive Disease
CR
N=32
PD
N=40
◆ The enriched gene expression was associated with:
◆ Immune response processes in patients with CR
◆ Keratinization in patients with PD
Acquired resistance
Shi H. Cancer Discovery 2013 Nov
Arozarena et al. ATM 2017
NRAS treatment: PD-0332991(CDk4/6i)+GSK 1120212(MEKi)
Kwong. Nature 2012
CR in 33% of mice
Huang1 Simvast+Falvop/MEKi
Kwong2 MEKi+CDK4i
Corcoran3 MEKi+abt-263 (bcl-xli)
Posch4 MEKi+PI3Ki
Greger5 MEKi+BRAFi+PI3Ki
Means-Powell6 METi+Sorafenib
Eskioscak7 MEKi+digitoxin
4.PNAS 20135.Mol Cancer T 20126. ASCO 20127. Nature 2016
1.Can Discovery 20132.Nature 20123.Cell 2013
Echevarria Vargas. EMBO 2018
Splicing forms p61BRAFV600
• 6/19 patients: 61kd variant form of BRAF(V600E) that lacks exons 4-8, a region
• It could be sensible to higher dose or combination, unless it is also observed in pts with combined treatment (Hartsoughet al , 2014)
Poulikakos P. Nature 2011
Whole exome sequencing identified B-RAFV600E amplification
In vitro testing: growth inhibition could be achieved with higher dose of BRAFi
4/20 patients
Shi. Nature 2012, Thakur 2013
Ligand
Tyrosine kinase
RASPI3K
AKT RAF
MEK1/2
ERK1/2
STAT3
BIM degradation
PP
P
ARQ-736
MK-8353BVD-523
GDC-0994
MK-2206
BuparlisipPictilisibPX-866
Copanlisib
SRC CCT196969CCT241161
JAK1/2
CDK4 pathway
PalbociclibDinaciclibRibociclibSeliciclib
Abemaciclib
Erbb2-Erbb3dimer
PTEN
MTOR
BEZ-235
No
tch
Ligand
Epithelial-Mesenchimal transition
Hes1NICD
Hey1
NICD
γ-secretase
RO-4929097PF-03084014
TGF-b
TGF-
bR
SMAD
TrabedersenFresolimumab
PF-03446962Tasisulam
Galunisertib
IL6
R
IL-6
ruxolitinib JAK1/2
STAT3
SOX2, OLIG2, NANOG, OCT4
WP1066
Gonzalez Cao M et al. ATM 2015
LGX818, MEK162, BKM120, BGJ398, INC280, LEE011 (LOGIC 2)
BKM120 , BGJ398, INC280 or LEE011 ***
LGX818MEK162
Part II
BRAF and MEK naive
LGX818/MEK162 combination
Optional
LGX818/MEK162 combination
)
Biopsy
Any BRAF/MEK combination or single agents*
Run-in**LGX818/MEK162 (first scan after
3 weeks)
Genetic Assessment
(Biopsy Analysis)
Biopsyat PD
Columbus, LOGIC1,
CMEK162X2110: LGX818/MEK162
arm
Optional LGX818/MEK162
combination
Genetic Assessment
(Biopsy Analysis)
Biopsyat PD
Part I
Group A
Group B
Group C
Genetic Assessment
(Biopsy Analysis)
Biopsyat PD
Gen. Ass. and/or Run-in
BKM120 , BGJ398, INC280 or LEE011 ***
LGX818MEK162
BKM120 , BGJ398, INC280 or LEE011 ***
LGX818MEK162
Shi H et al. Cancer Discovery 2014; Wilmott 2012; Van Allen 2014; Romano 2014; Turajlic 2014
Heterogenity intratumoral/intrapatient
Das Thakur et al. Nature 2013
Discontinuous dosing strategy attenuates continued dependency on BRAF (V600E)-MEK-ERKsignaling in resistant tumors , akin to reintroducing EGFR TKIs in EGFR mutant NSCLCs following chemotherapy (Sequist et al. Science Trans Med 2011) (Chmielecki 2011)
Back up information Chong Sun, Liqin Wang et Sidong Huang et al Nature. 2014
BRAF/MEK adaptative resistance: on/off schedule
Intermittent Vemurafenib (iBRAF) + Cobimetinib (iMEK): GEM-01-15
Objetivo principal: • SLP
Objetivos secundarios • Tasa de respuesta• SLP 1 año, SLP 2 años• SG, SG 1 año, SG 2 años• Seguridad• cfDNA BRAF V600 subestudio biomarcadores
Vemurafenib (960mg BID oral 1-28d) (ROCHE)Cobimetinib (60mg QD oral 1-21d) (ROCHE)
Melanoma avanzadoBRAFV600 mutado(n=116)
ECOG PS 0–1No tto previo≥ 18 yearsAdecuadas funciones orgánicas
Progresión
Segruidad
RetiradaconsentimientoOF
F2s
OFF2s
CONTINUO (n=58)
INTERMITENTE (n=58)
Justificación
• Optimizar esquema de tratamiento V-C• Retrasar resistencias
• Reducir perfil de seguridad• Reducir coste tratamiento/mes
V+C4sem
V+C4sem
V+C4sem
V+C4sem
V+C4sem
V+C4sem
V+C4sem
V+C4sem
V+C4sem
V+C4sem 4sem
V+C4sem
GEM: Grupo Español de Melanoma
ERK2 (MAPK1 gene) and JUNB: swithing to a metastativ phenotype (MIFT low)
Kong X et al. Nature 2017
Rechallenge with BRAF-directed treatment in metastatic melanoma: A multi-institutional retrospective study
• After progression in 83 patients
• Median time from first BRAFi regimen cessation to rechallenge was 7.7 months (range 0.9–34.9). Immunotherapy was the most commonly administered treatment between first and rechallenge BRAFi treatment (71.5%)
• OR 36% (30 PR and1 CR)
Valpioni et al. EJC 2018
Vemurafenib continuation after PD
Puzanov. Eur J Cancer 2015
Median OS beyond initial progression was 6.1 months (range, 0–41.0) in all 44 patients with PD, 3.4 months (range, 0–26.9) in those who discontinued 30 days after progression (n = 20) and 26 months in those who continued
Survival After Progression by Site of Progression
No. at risk
BL lesions at PD only
New lesions at PD only - Non-CNS
New lesions at PD only - CNS
New and BL lesions PD
Median, mo
Baseline only 10.1
New non-CNS 9.5
New CNS 3.8
New + baseline 4.0
0.0
0.2
0.4
0.6
0.8
1.0
0 12 24 36
114 31 4 1
91 24 4 0
103 11 0 0
68 9 1 1
Pro
po
rtio
n S
urv
iva
l A
fte
r P
rog
ressio
n
Months
40%
Long et al. Lancet Oncol 2016
Increased PD-L2 expression in responding residual tumors
Song, Ribas et al. Cancer Discov 2017
Is anti-PD-1 therapy less effective after failure of BRAFi?
Puzanov et al. SMR 2015
Conclusions
• BRAF-MEK combination rapid responses,also in thosepatients with any other option as high LDH or bad PS
• BRAF-MEK long survivval in low LDH,few met sites
• Combination with immunotherapy
• Several forms of resistance intrapatient