cÁncer colorrectal nuevos fÁrmacos y … · phase iii, famitinib • famitinib is a...
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Oncología Médica
CÁNCER COLORRECTAL
NUEVOS FÁRMACOS Y ALTERNATIVAS
• Consultant or Advisory Role: Merck-Serono, Amgen, Roche, Sanofi-Aventis, Bayer, Celgene
• Travel Grants: Roche, Amgen, Merck-Serono
• IP Ensayos Clínicos: Amgen, Abbott, Behringer, Sanofi-Aventis, Bayer, Pfizer
• Mejor comprensión de mecanismos moleculares
– Heterogeneidad del CCR, Subgrupos moleculares
• Cambio de modelos
– Útil en St. IV, no en adyuvancia
– Útil en 2ª línea, no en primera
– CTC, Perfiles moleculares en sangre…
• Nuevos “nichos”
– Mantenimiento
– “Quimiorefractario”
Nuevos Escenarios
Consensus CCR subtypes
Dienstmann, R, Salazar R, Tabernero J. Am Soc Clin Oncol Educ Book. 2014;91-99.
asco.org/edbook
How to improve
• New chemotherapy agents
• Targeted therapy
• Immunotherapy
• Genetics/genomics for individualization of drug
regimens
How to improve
• New chemotherapy agents
• Targeted therapy
• Immunotherapy
• Genetics/genomics for individualization of drug
regimens
• Topoisomerase I Inhibitors
– etirinotecan pegol (NKTR-102) and EZN-2208, are pegylated versions of
irinotecan which delay clearance and prolong the half-life of SN-38
– MM-398: Irinotecan Liposomal. Resultados (+) PC.
• Lurbinectedin
• Platinum compounds
• S-1
• TAS-102, TRIFLURIDINA + TIPIRACIL
• α,α,α-trifluorothymidine (FTD), the active agent, and 5-chloro-6-(2-
iminopyrrolidin- 1-yl) methyl-2,4 (1H,3H)-pyrimidinedione hydrochloride utilized
to prevent first-pass metabolism (INHIBE TP) and maintain therapeutic FTD
concentrations with oral administration. FTD exerts its activity by inhibiting
thymidylate synthase and inhibiting DNA
Chemotherapy
TAS-102, Phase II
TAS 102 EN CCR m REFRACTARIO, FASE III
• Mayer & Van Cutsem et al.
TAS-102.
TOXICIDAD
How to improve
• New chemotherapy agents
• Targeted therapy
– Angiogenesis
– Targeting Membrane Receptors &
Growth factors pathways
• Immunotherapy
• Genetics/genomics for individualization of drug
regimens
ANTIANGIOGÉNICOS, ESTUDIOS FASE III
“refractario”
“sin selección con biomarcadores”
Phase III, Fruquintinib
• Fruquintinib (HMPL-013) is a novel oral small molecule that selectively inhibits
vascular endothelial growth factor receptors (VEGFR) 1, 2, and 3 and has
demonstrated potent inhibitory effects on multiple human tumor xenografts
Phase III, Famitinib
• Famitinib is a tyrosin-inhibitor agent targeting at c-Kit, VEGFR2, PDGFR,
VEGFR3, Flt1 and Flt3, and it's anti-angiogenesis effect has been viewed in
preclinical tests. Phase I study has shown that the toxicity is manageable.
• neutropenia, thrombocytopenia, proteinuria, hypertension, hand–foot syndrome
A Multicenter，Randomized, Double-blind, Placebo-controlled Trial of Famitinib in
Patients With Advanced Colorectal Adenocarcinoma, 1º End Point: OS
Nintedanib
• Eur Respir J. 2015 May; 45(5): 1434–1445.
Nintedanib
How to improve
• New chemotherapy agents
• Targeted therapy
– Angiogenesis
– Targeting Membrane Receptors &
Growth factors pathways
• Immunotherapy
• Genetics/genomics for individualization of drug
regimens
Monoclonal antibodies SYM 004
Small molecules HER1+HER2: NERATINIB
HER1, HER2, HER 4: DACOMITINIB, AFATINIb
HER Inhibition: Rationale
SYM-004
• two-antibody mixture (mAb992 and mAb1024) targeting nonoverlapping EGFR
epitopes.
• Sym004 causes significant EGFR internalization and degradation,
• phase I trial, grade 3 skin toxicity and hypomagnesemia
• 42 patients with metastatic colorectal cancer resistant to EGFR treatment enrolled
in the dose-expansion cohorts, 17 patients (44%) had some degree of tumor
shrinkage during Sym004 therapy
Dienstmann R, Cancer Discovery Published OnlineFirst May 11, 2015;
DOI: 10.1158/2159-8290.CD-14-1432
Mutations in mCRC
Dienstmann, R, Salazar R, Tabernero J. Am Soc Clin Oncol Educ Book. 2014;91-99.
asco.org/edbook
Dienstmann, R, Salazar R, Tabernero J. Am Soc Clin
Oncol Educ Book. 2014;91-99. asco.org/edbook
Dienstmann, R, Salazar R, Tabernero J. Am Soc Clin
Oncol Educ Book. 2014;91-99. asco.org/edbook
PROMISING THERAPY
• New chemotherapy agents
• Targeted therapy
• Immunotherapy
Phase III, Xilonix
• monoclonal antibody (MABp1) cloned from a human being to target interleukin-1α
• proteinuria (n=11; 21%), nausea (7; 13%), and fatigue (7; 13%).
• Xiloni vs Placebo en CCRm, refractario, sintomático- ORR
• Double-blinded, Placebo Controlled Study of Xilonix™ for Improving Survival in
Metastatic Colorectal Cancer - OS
• Lancet Oncol. 2014 May;15(6):656-66.
Phase III: Imprime pgg
• PGG beta-glucan binds to an alternate site on the neutrophil complement
receptor 3 (CR3), priming the neutrophil to become cytotoxic when binding to
complement on tumor cells via CR3. This agent has been reported to selectively
activate immune cells
• Phase II: Increased ORR
MGN1703
• Toll-like receptor 9-immunomodulator. Fever, fatigue, local
• Phase II, Increased PFS after induction chemot
• Schmoll HJ, et al. J Cancer Res Clin Oncol 2014.
Ribas A. N Engl J Med. 2012;366:2517-2519.
CTLA-4 and PD-1/L1 Checkpoint Blockade for Cancer
Treatment
Pembrolizumab
A modo de Conclusiones
• Identificación de nuevas dianas con potencial terapéutico
• Necesidad de profundizar en la caracterización molecular de la enfermedad para la selección del tratamiento
• Nuevos conceptos en el diseño de modelos preclínicos y de los ensayos clínicos
• Atención a la toxicidad
• Definir combinaciones con quimioterapia
• “Si puede pensarse, es fácil que ocurra”. Paul Auster