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