Otras dianas terapéuticas

Dra Ana Arance Oncología Médica

Hospital Clínic Barcelona

Mechamisms of RAS activation

Clin Cancer Res; 20(16) August 15, 2014

Raf isoform switching in NRAS mutant melanoma

Fedorenko et al. Oncogene 2012

NRAS 10-15%

Exon 12, 13, 61

NRAS-mutant Melanoma : Characteristics

Jakob et al. Cancer 2012

•NRAS mutated in 10-15% melanomas •Majority of congenital melanocytic nevi •Meta-analysis: 31 studies and 1972 patients no association Age-NRAS no association Gender-NRAS •NRAS mutations associated:

thicker primary increased mitotoc rate lower incidence of ulceration •Linked to poorer survival compared to BRAF and WT melanomas

Mandalà et al. Crit Rev Onc/Hematol 92 (2014) 107–122

• NRAS ~ 10-20% Lancet Oncol 2013; 14: 249–56

Mutant

RAS

MEK

ERK

CRAF

RTK

iMEK

(binimetinib)

20% RR

PFS 3.7m

N=30

Lancet Oncol 2013; 14: 249–56

Sosman JA, et al. ASCO 2014. Abstract 9009.

LEE011 (iCDK4/6) + Binimetinib (iMEK) en

Melanoma NRAS mutado: Respuestas

Oncolytic Viruses

T-VEC: Mecanismo de Acción

Liu BL, et al. Gene Therapy. 2003;10:292-303. Hu JCC, et al. Clin Cancer Res. 2006;12:6737-6747. Hawkins LK, et

al. Lancet Oncol. 2002;3:17-26. Ring CJA. J Gen Virol. 2002;83:491-502. Toda M, et al. Mol Ther. 2000;2:324-

329. Eager R, Neumunaitis J. Mol Ther. 2005;12:18-27.

TSAs =Tumor-Specific Antigens

26% RR

12% distant responses

Senzer NN, J Clin Oncol 2009

AE’s: mild flu like symptoms

Phase 3 OPTiM Trial: Study Design

ClinicalTrials.gov. OncoVEXGM-CSF Phase III Trial; Kaufman HL & Bines SD. Future Oncol. 2010;6:941-949;

Amgen® Press Release, March 19, 2013

Unresectable stage

IIIb,

stage IIIc, or stage IV

melanoma

Up to 4 ml

Talimogene

Laherparepvec

intratumorally

GM-CSF 125 μg/m2 SQ ×

14d every 28-day cycle

n = 436

2:1 randomization

Exclusion criteria

• LDH ≥ 1.5 × ULN

• Extensive visceral disease

• Brain/bone metastasis

• ECOG > 1 Endpoints • Primary: DRR

• Secondary: OS

T-VEC is investigational

Spain approval 5 april 2013

TVC-ESP-AMG-213-2013- April-NP - T-

VEC-CORE Slide Deck_Post-Press-

Release KOL

IHQ approval: pTVC-IHQ-AMG-097-2013-

March-NP

* * *

* * *

TVEC in combination with Ipilimumab: Phase 1b/2 study

Puzanov abstr 9029, 2014

N=19

RR 56%

Novel Immunomodulating receptors

Targets of Ab immune modulators

Naidoo et al. British J Cancer (2014) 111, 2214–2219

KIR-ligand modulation for cancer therapy

Benson et al. Cancer Imm Res 2014, 2, 99-104

Targeting LAG 3

Nguyen et al. Nat Rev Immunol 2015, 15:45

Agonists Ab to TNFR molecules

Future

• Identification and validation of new targets or new ways to optimally act on already known targets

• Predictive biomarker identification and increased ability to evaluate the correlates with survival benefit

• Greater knowledge of the effect of combination therapy

Gracias

Dr Ana Arance

amarance@clinic.ub.es