CRCTREATMENT BEYOND SECOND LINE DR DLEK ERDEM Limited

CRC-TREATMENT BEYOND SECOND LINE DR DİLEK ERDEM

• Limited stage IV disease is sometimes curable • Biological agents improve outcomes • Molecular predictive factors presented individulized treatment

SURVIVAL ACCORDING TO MOLECULAR SUBTYPE

INDIVIDUALIZED THERAPY

m. OS INCREASES with TREATMENT LINES

TREATMENT DECISION CHARACTERISTICS

THE BEST CHOICE in RAS MUTANT 1 st LINE?

1 st LINE RAS WT-TUMOR LOCATION

EGFR/VEGF? 1 st LINE RAS WT

FACTORS AFFECT SECOND LINE TREATMENT • First line treatment is important, combination with VEGFR/+EGFR inhibitör? ? • Progression after 6 months of Anti-VEGFR? • Progression during 6 months of Anti-VEGFR? • Tumor molecular characteristics (MSI, B-RAF, Her-2…) • Toxicity consideration

VEGF INHIBITION AFTER 1 st LINE BEVACIZUMAB

SECOND LINE

THIRD LINE and BEYOND

REGORAFENİB

CORRECT TRIAL

REGORAFENIB-TOXICITY-TIME INTERVAL

Re. DOS: DOSE OPTIMISATION

TAS-102

B-RAF MUTANT DISEASE

FIRST LINE/B-RAF INHIBITION

m. OS in B-RAF MUTANT DISEASE

B-RAF V 600 E MUTATION

ENCORAFENİB/ALPELİSİB/CETUXİMAB

ANTI-EGFR THERAPY AS A TARGET IN RAS WT/B-RAF MUTANT DISEASE

SWOG 1406

NON-V 600 E MUTATIONS • • Codon 594/596 kinase activity impaired Favourable prognosis L sided Male>Female Low grade K-RAS mutation + MSI – No peritoneal disease Codon 601/597 similar to V 600 E

• 2 % of CRC patients who undergo liver resection have BRAF (V 600 E)

B-RAF RESISTANCE MECHANISM

B-RAF MUTANT CRC • B-RAF mutant-poor prognosis/need intensive therapy (FOLFOXİRİ) • B-RAF (V 600 E)+MSI-H/d. MMR Checkmate 142 • EGFR inhbitors have importance • VEGF inhbitors MAY have importance • EGFR, B-RAF ve MEK inhbitor combination • Randomised trials are on the way: Better MAPK supression (ERK inhb), BRAF +immunotherapy, New agents: HMG-Co. A redüktaz • Firstly think clinical trial • 1 st line FOLFOXİRİ • Anti-PD-1 in MSI-H

HER-2 PATHWAY

HER-2 POSITIVITY IS A NEGATIVE PREDICTIVE FACTOR

HERACLES TRIAL

DUAL INHIBITION

EGFR RESISTANCE SECONDARY TO HER-2 OVEREXPRESSION

MSI-H TUMOR

IMBLAZE TRIAL

TAKE HOME MESSAGES • New data is coming for new biomarkers • To individualize therapy we have to choose the best options • Combination therapies better but what about the toxicity • Worse genomic alterations should be found out like B-RAF, Her-2, MSI

THANK YOU