EGFR Inhibitors
What is the MOA of eGFR inhibitors?
Activation of EGFR results in a range of effects, including cell proliferation, differentiation, migration, adhesion, and inhibition of apoptosis. It also enhances processes crucial to tumor growth and progression, such as angiogenesis, tumor invasiveness, and metastatic spread; eGFR inhibitors inhibit kinase activity of epidermal growth factor receptor by preventing autophosphorylation of tyrosine residues associated with the EGFR receptor, which blocks downstream signaling and EGFR-dependent proliferation.
What is the MOA of VEGF Inhibitors?
VEGF plays a vital role in angiogenesis; VEGF inhibitors are TKI inhibitors that decrease the activity of VEGF, leading to decrease in tumor growth/proliferation and angiogenesis
What is the MOA of BRAF inhibitors? What is the MOA of MEK inhibitors?
BRAF Inhibitors: inhibition of the MAPK pathway and tumor cell growth
MEK Inhibitors: Reversible inhibition of MEK1 and MEK2, which are upstream regulators of the ERK pathway (ERK pathway promotes cellular proliferation)
What is the MOA of ALK Inhibitors?
Tyrosine kinase receptor inhibitors that inhibit anaplastic lymphoma kinase (ALK)
- ALK gene abnormalities result in increased cellular proliferation and survival in tumors which express these fusion proteins.
- Inhibition of ALK phosphorylation and ALK-mediated activation of downstream signaling results in decreased tumor cell viability
What is the MOA for CDK Inhibitors?
Small molecule cyclin-dependent kinase (CDK) inhibitor which is selective for CDK 4 and 6
- Blocks retinoblastoma protein phosphorylation and prevents progression through the cell cycle, resulting in arrest at the G1 phase
What is the most common class-wide adverse effect of EGFR inhibitors?
Skin toxicity!
Hypertension!
What counseling points regarding storage should you share with a patient starting trametinib?
Store refrigerated at 2°C to 8°C (36°F to 46°F). Dispense in original bottle; do not remove desiccant. Protect from light and moisture. Do not transfer to pill boxes.
Which ALK inhibitor can be dosed per BSA and as a flat dose?
Crizotinib
What is the MOA of PARP Inhibitors?
Inhibits poly (ADP-ribose) polymerase (PARP) enzyme (involved in DNA transcription and repair), leading to formation of double-stranded DNA breaks in BRCA1/2-deficient tumor cells and subsequent cell death
What is the hallmark adverse effect of neratinib? What are two methods for us to increase the tolerability of this adverse effect?
(1) Antidiarrheal prophylaxis with loperamide
(2) Dose escalation strategy
(3) Budesonide or colestipol
What renal and/or hepatic dose adjustments are required for axitinib?
No renal adjustments recommended
Hepatic impairment prior to initiation:
- Mod impairment (Child-Pugh B): Reduce starting dose by 50%; adjust subsequent doses based on tolerance
Hepatotoxicity during treatment
- Withhold if AST/ALT >3x ULN
Match the BRAF inhibitor with the MEK inhibitor
- Binimetinib, Vemurafenib, Dabrafenib
- Trametinib, Encorafenib, Cobimetinib
Vemurafenib + Cobimetinib
Binimetinib + Encorafenib
Dabrafenib + Trametinib
What is an important administration education point for ceritinib?
Must take WITH food
What is the dose limiting toxicity of olaparib?
Myelosuppression
Which EGFR inhibitor is indicated in EGFR exon 21 L858R or T790M EGFR mutation?
Osimertinib
A patient is taking pazopanib for metastatic renal cell carcinoma. He is scheduled for a gastric bypass on November 15, 2021. What medication adjustment should be made and why?
Hold pazopanib for at least 1 week prior to elective surgery and for at least 2 weeks after major surgery due to the risk of poor/inadequate wound healing
What adverse effect of vemurafenib sets it apart from other BRAF inhibitors?
Photosensitivity (33-49%; dose and exposure-dependent)
What is one unique adverse effect of crizotinib?
Visual disturbances (blurred vision, decreased visual acuity, diplopia, vision loss, etc)
- Onset: < 1 week
Which CDK4/6 inhibitor dose not require a break in dosing?
Abemaciclib
Match the following eGFR inhibitors to their appropriate generation and share one indication for each agent
1) Afatinib
2) Gefitinib
3) Osimertinib
A) First Generation
B) Second Generation
C) Third Generation
1) Afatinib --- B) Second Generation (NSCLC)
2) Gefitinib -- A) First Generation (NSCLC, pancreatic)
3) Osimertinib -- C) Third Generation (NSCLC)
Patients of _____ descent are at a higher risk of developing HFS.
What are some management methods to prevent HFS?
Asian
- Manicure/pedicure to remove hyperkeratotic areas/calluses which may predispose to HFSR
- Mechanical support/correction for abnormal weight bearing prior to treatment.
- Alcohol-free moisturizers liberally
- Reduce exposure to hot water
- Avoid constrictive footwear and excessive skin friction
- Avoid vigorous exercise/activities that may stress hands or feet
- Thick cotton gloves/socks and shoes with padded insoles.
**DAILY DOUBLE**
How do you manage dabrafenib induced fevers?
Dabrafenib-induced fevers (50%)
Management (no strict guidelines): APAP, ibuprofen, drug holiday, steroids, switch to alternative BRAF/MEK combination
Mr. Burbige went on vacation to Peru and accidentally left his suitcase carrying his all his medications (including brigatinib 180 mg PO once daily) on a taxi. Aside from that incident, he had a wonderful 16-day trip. He strangely missed his morning medications + glass of water routine though. Upon returning, what special instructions should he be aware of regarding restarting his brigatinib?
If therapy is interrupted for ≥14 days due to reasons other than adverse reactions, resume treatment at 90 mg once daily for 7 days before escalating dose to the previously tolerated dose.
A patient is starting niraparib 200 mg daily, what monitoring parameters are recommended?