Targeted Agents: Solid Tumors Part 1

What are the benefits of Molecular Tumor Boards?

a multidisciplinary team that assesses tumors mutation(s)

• reviews and provides recommendations for molecular targeted therapies

• track pt outcomes

Small molecular drugs (TKIs) vs Biologic agents (monoclonal antibodies): Route of administration

TKIs: PO

Monoclonal antibodies: IV, SubQ, IM

Small molecular drugs (TKIs) vs Biologic agents (monoclonal antibodies): Absorption and distribution

TKIs: through passive diffusion/permeability and active transporters

Monoclonal antibodies: through lymphatic system due to large size

Small molecular drugs (TKIs) vs Biologic agents (monoclonal antibodies): Target

TKIs: surface and intracellular targets - receptors + proteins

Monoclonal antibodies: membrane proteins + soluble proteins/signaling molecules

Small molecular drugs (TKIs) vs Biologic agents (monoclonal antibodies): Metabolism/clearance

TKIs: mainly through CYP enzymes, renal excretion, biliary excretion; usually linear

Monoclonal antibodies: through proteolysis, hydrolysis; target mediated clearance

Small molecular drugs (TKIs) vs Biologic agents (monoclonal antibodies): Drug interactions

TKIs: PK and PD

Monoclonal antibodies: PD

Name the K-RAS G12C inhibitors

• sotorasib (Kumakras)

• adagrasib (Krazati)

Class effects of K-RAS inhibitors

• hepatotoxicity

• pulmonary toxicity

• decreased albumin/electrolytes

• lymphocytopenia

• heart failure (rare)

Unique effects of sotorasib (lumakras)

Decreased Hgb

Unique effects of Adagrasib (Krazati)

• GI toxicity

• QTc prolongation

• increased CPK

• AKI

• mental status change (rare)

• hyperpigmentation

are EGFR mutations likely to occur in the same settings as KRAS mutations

NO due to functional redundancy

Name the ALK rearrangement inhibitors

• Alectinib

• Brigatinib

• Ceritinib

• Crizotinib

• Ensartinib

• Lorlatinib

Class effects of ALK rearrangement inhibitors

• bradycardia

• pulmonary toxicity

• hepatotoxicity (not in lorlatnib)

• photosensivitity (not in lorlatnib)

Unique effects of lorlatinib

• CNS effects

• Hyperlipidemia

Dose modification and medical management for lorlatinib: CNS effects

grading

• grade 1: continue at the same sode or withhold until recovery to baseline. Resume at the same or reduced dose

• grade 2-3: withhold dose until Grade 0-1. Resume at a reduced dose

• Grade 4: D/C

medical management

• psych consult

• antipsychotic agents

• antidepressants agents

• agents for sleep

Dose modification and medical management for lorlatinib: Hypercholesterolemia or hypertriglyceridemia

grading

• grade 4: withhold until recovery to less than or equal to grade 2. resume at the dose. If severe or recurraence, resume at reduced dose

medical management

• Statins (DDI with lorlatinib): ROSUVASTATIN PREFERRED

• fibrates (2nd line)

Dose modification and medical management for lorlatinib: HTN

grading

• grade 3: withhold until recovery to grade 0-1,t hen resume at same dose. If adequate control cannot be achieved with medical management, D/C

• grade 4: withhold until recovery to less than or equal to grade 0-1 and resume at a reduced dose. If grade 4 reoccurs, D/C

medical management

• CCB

• ACE-I/ARB

• thiazide diuretics

Dose modification and medical management for lorlatinib: Hyperglycemia

grading

• grade 4: withhold until adequatelly controlled, then resume at the next lower dosage. If controlled cannot be achieved, D/C

medical management

• oral agents

• injectable agents

• insulin

Name the MET exon skipping mutation inhibitors

• capmatinib (tabcrecta)

• crizotinib (Xalkori)

• tepotinib (tepmetko)

Class effects of MET inhibitors

• hepatoxicity

• pulmonary toxicity

• peripheral edema

• decreased hemoglobin/lymphocytopenia

Unique effects of capmatinib (tabcrecta)

edema

• facial, genital

pancreatic toxicity

Unique effects of tepotinib (tepmetko)

pulmonary embolism (RARE)

Name the RET rearrangement inhibitors

• Cabozantinib

• Pralsetinib

• Selpercatinib

Class effects of RET inhibitors

• hemorrhage

• hepatotoxicity

• HTN

• wound healing impairment

• pulmonary toxicity (except carbozantinib)

• tumor lysis syndrome (except in carbozantinib)

• thyroid dysfunction (except in pralsetinib)

Which of the following agents should you monitor for QTc prolongations?

• adagradisb

• selpercatinib

• crizotinib

• ceritinib

Which agents are CYP3A4 inhibitors

• adagrasib

• crizotinib

• ceritinib

• lorlatinib

Which agents are CYP3A4 substrates

All of them

Which of the K-RAS inhibitors is most likely to prolong the QTc interval?

Adagrasib (Krazati)

What questions would you ask of a patient receiving Sotorasib or Adagrasib to probe for the onset of delayed toxicities?

• What lab tests would you follow to monitor for toxicities?

• Does better CNS penetration by Adagrasib mean that Sotorasib is not effective upon CNS metastases of cancers?

Tests

• Imaging can tell us if its malignant-caused or if its true ADR caused by the medication through inflammation

• LFTs

• CBC

CNS pentration

• sotorasib still have good activity within the CNS