TKIs and EGFR Inhibitors

Question 1

Imatinib (Gleevec)

Answer 1

TKI

• CML tx- binds to the catalytic cleft of ABL
• single agent treatment gives high rate of molecular CML remission
• Resistance caused by mutation in the binding cleft of ABL that prevents drug binding
• Also inhibits PDGF rec + C-Kit

Question 2

Dasatinib

Answer 2

TKI

• Newer TKI designed to overcome imatinib resistance
• Imatinib/Dasatinib also treat GI stromal tumors and systemic mastocytosis b/c they inhibit C-Kit which is the mutation in those cancers

Question 3

Trastuzamab (Herceptin)

Answer 3

HER2 Inhibitor

• Interferes with Her2 dependent signalling
• Response to herceptin in up to 50% of Her2+ BC
• Cardiotoxic!

Question 4

Trastuzumab DM1

Answer 4

• Toxin conjugated trastuzumab– no cardiotoxicity so far
• Thrombocytopenia
• Increased transaminase levels

Question 5

Lapatinib

Answer 5

Her1/Her2 competitive Inhibitor

• Use in combo w/ chemo (Capecitabine) for heceptin refractory Her2+ BC
• Rash, Diarrhea

Question 6

Neratinib

Answer 6

Irreversible Her1/Her2 Inhibitor

Question 7

Pertuzumab

Answer 7

Blocks Her2 dimerization

Question 8

Erlotinib + Gefitinib

Answer 8

• Small Molecule, TKI specific for EGFR

- Target HER1 EGFR active in Lung, breast and CRC

Question 9

Crisotinib

Answer 9

• Inhibits ALK1, ROS1, HGFR and other TKS
• ~4% of NSCL have EML4-ALK1 translocation w/ constitutive kinase activity
• Tend to be younger, non-smokers who are WT for EGFR and RAS

Question 10

Cetuximab (Erbitux)

Answer 10

• Engineered chimeric mAB to EGFR
• Modest activity in advanced CRC and Head/Neck cancers w/ chemo combo
• Very modest activity in NSCLC
• pt. w/ K-Ras and BRAF mut. lack Cetuximab response