Pharmacology V

Yellow = Emphasized in lecture slides

Name all the classes of small molecule inhibitors

BCL2, PI3K, IDH, CDK4/6, PARP, BRAF/MEK

What is the MOA of BCL2?

Anti-apoptotic protein

What inhibits BCL2?

BH3

Name the BCL2 inhibitor(s)

Venetoclax

What is the MOA of venetoclax?

Binds directly to BCL2 protein, leading to apoptosis

BCL2 Inhibitor

Indications: AML in 75+ OR w/ comorbidities that prevent intensive chemo, CLL

Dose reduction: Comcomitant use w/ moderate or strong CYP3A4 inhibitor, hepatic, hematologic

Metabolism: CYP3A4

Toxicities: tumor lysis syndrome, bone marrow suppression, infection, gastrointestinal (N/V/D/C)

Venetoclex

Select the risk factor for Tumor Lysis Syndrome (TLS)

All lymph nodes < 5 cm

AND

Absolute lymphocyte count (ALC) < 25 x 10⁹

^{A. Low}

^{B. Medium}

^{C. High}

Low

Select the risk factor for Tumor Lysis Syndrome (TLS)

Any lymph node 5 cm to < 10 cm

OR

ALC ≥ 25 x 10⁹/L

^{A. Low}

^{B. Medium}

^{C. High}

Medium

Select the risk factor for Tumor Lysis Syndrome (TLS)

Any lymph node ≥ 10 cm

OR

ALC ≥ 25 x 10⁹/L AND any lymph node ≥ 5 cm

^{A. Low}

^{B. Medium}

^{C. High}

High

Match the TLS risk category with the following management regimen:

Oral hydration + Allopurinol

A. Low

B. Medium

C. High

Low

Match the TLS risk category with the following management regimen:

Oral hydration (± IV hydration) + Allopurinol

A. Low

B. Medium

C. High

Medium

Match the TLS risk category with the following management regimen:

Oral hydration + IV hydration + allopurinol ± rasburicase (if baseline uric acid is elevated)

A. Low

B. Medium

C. High

High

What is the MOA of PI3K?

PI3K-AKT-mTOR pathway is involved in cell growth and survival

What do class 1 PI3K inhibitors target?

one or more PI3K isoforms: ⍺, δ, and ɣ, as well as B-cell signaling pathways

What does inhibition of PI3k isoforms lead to?

Malignant B-cell apoptosis

Name the PI3k Inhibitor(s)

Idelalisib, Alpelisib

PI3K Inhibitor

Class: Selective PI3Kδ Inhibitor

Indication: CLL w/ rituxumab

Dose Adjustments: Hepatic, hematologic

Metabolism: CYP3A4, aldehyde oxidase

Toxicities: BBW: Hepatotoxicity, diarrhea/colitis, pneumonitis (limiting toxicity), infections and intestinal perforation

Idelalisib

PI3K Inhibitor

Class: Selective PI3K⍺ inhibitor

Indication: PIK3CA-mutated, HR (+), HER2 (-) metastatic breast cancer

Dose Adjustments: Hyperglycemia, dermatologic

Metabolism: Chemical/enzymatic hydrolysis to metabolite

Toxicities: Hyperglycemia: (baseline fasting blood glucose and hemoglobin A1C required), diarrhea, decreased appetite

Alpelisib

What is the MOA of Cyclin-dependent kinases (CDK)?

Regulate cell cycle progression

What is the MOA of CDK inhibitors?

bind to CDK 4 and 6 —> blocks retinoblastoma (Rb) protein phosphorylation —> prevents cell cycle progression

Name the CDK 4/6 Inhibitor(s)

Ribociclib, Palbociclib, Abemaciclib

CDK 4/6 Inhibitor

Indications: HR (+), HER2 (-), advanced or metastatic breast cancer

Dose Adjustment: Renal, hepatic, hematologic

Metabolism: CYP3A4, oxidation

Toxicity: Neutropenia, QTc interval prolongation, N/V (MEC/HEC), alopecia, ILD

Ribociclib

CDK 4/6 Inhibitor

Indications: HR (+), HER2 (-), advanced or metastatic breast cancer

Dose Adjustment: Hepatic, hematologic

Metabolism: CYP3A4, oxidation, sulfonation

Toxicity: Neutropenia, alopecia, fatigue, infections, ILD

Palbociclib

CDK 4/6 Inhibitor

Indications: HR (+), HER2 (-), advanced or metastatic breast cancer

Dose Adjustment: Hepatic, hematologic

Metabolism: CYP3A4

Toxicity: Neutropenia, N/V/D (MEC/HEC), alopecia, hepatoxicity, VTE, ILD

Abemaciclib

What is the mechanism of PARP?

repair of single-strand breaks in DNA

What is the MOA of PARP Inhibitors?

bind to PARP and prevent the repair of single-strand DNA breaks, which can lead to double-strand DNA breaks

True/False:

BRCA-mutated cancers DO NOT have mechanisms (called homologous recombination, or HR) to repair double-strand DNA breaks, leading to disruption of cellular homeostasis and cell death

True

Name the PARP inhibitor(s)

Olaparib, Talazoparib

PARP Inhibitor

Indications: BRCA-mutated breast (early and metastatic), ovarian, pancreatic, and prostate cancers

Dose Adjustment: Renal

Metabolism: CYP3A4, oxidation, glucuronidation, sulfation

Toxicity: Secondary malignancies (MDS, AML), bone marrow suppression, pneumonitis, N/V

Olaparib

PARP Inhibitor

Indications: BRCA-mutated metastatic breast cancer

Dose Adjustment: Renal, hematologic

Metabolism: Glucuronidation and metabolic pathways

Toxicity: Secondary malignancies (MDS, AML), bone marrow suppression, N/V

Talazoparib

BRAF V600 mutations are found in ~45% of cutaneous melanoma.

A. V600M mutation is most common

B. V600E mutation is most common

C. V600Z mutation is most common

D. V600F mutation is most common

V600E mutation is most common

What is the mechanism of BRAF inhibitors?

inhibit mutated RAF protein, which prevents tumor cell growth

What is the mechanism of MEK inhibitors?

inhibit the downstream MEK protein, which allows for synergistic inhibition of the MAPK pathway and cancer cell death

Name the BRAF inhibitor(s)

Dabrafenib, Encorafenib, Vemurafenib

Name the MEK inhibitor(s)

Trametinib, Binimetinib, Cobimetinib

Correctly pair the BRAF inhibitor to the MEK inhibitor.

Binimetinib	Trametinib
Vemurafenib	Encorafenib
Dabrafenib	Cobimetinib

Dabrafenib + Trametinib

Encorafenib + Binimetinib

Vemurafenib + Cobimetinib

Pharmacologic Category	BRAF Inhibitor	MEK Inhibitor
Indications	BRAF V600E or V600K mutated melanoma, non-small cell lung cancer, advanced solid tumors
Dosing	1 hour before or 2 hours after a meal
Dose reductions	Toxicity
Metabolism	CYP2C8, CYP3A4	Deacetylation, glucuronidation
Toxicities	N/A

Dabrafenib + Trametinib

Pharmacologic Category	BRAF Inhibitor	MEK Inhibitor
Indications	BRAF V600E or V600K mutated melanoma, metastatic NSCLC
Dosing		Administer antiemetics to prevent N/V
Dose reductions	Hepatic, toxicity	Hepatic, toxicity
Metabolism	CYP3A4	UGT1A1 glucuronidation, CYP1A2, CYP2C19

Encorafenib + Binimetinib

Pharmacologic Category	BRAF Inhibitor	MEK Inhibitor
Indications	BRAF V600E or V600K mutated melanoma
Dose reductions	Toxicity	Hepatic, toxicity
Metabolism	CYP3A4	CYP3A4 oxidation, UGT2B7 glucuronidation

Vemurafenib + Cobimetinib

What are the most common toxicities of BRAF/MEK inhibitors?

Dermatologic (rash, skin cancers)

Pyrexia

Uveitis

Gastrointestinal

Joint pain

What is the mechanism of IDH (Isocitrate dehydrogenase)?

converts isocitrate to ⍺-ketoglutarate (⍺-KG)

What occurs when there are mutations in IDH enzymes?

⍺-KG converted to 2-hydroxyglutarate (2-HG)

metabolite that drives tumor progression

What is the mechanism of IDH inhibitors?

Binds to mutant IDH enzymes, which decreases 2-HG levels —> reduces leukemic blast counts + induced maturation of myeloid cells

IDH Inhibitor

Class: IDH1 inhibitor

Indication: IDH1 mutated AML

Metabolism: CYP3A4

Toxicities: Differentiation syndrome (BBW), QTc interval prolongation, leukocytosis

Ivosidenib

IDH Inhibitor

Class: IDH2 inhibitor

Indication: IDH2 mutated AML

Metabolism: Multiple CYP enzymes and UGTs

Toxicities: Differentiation syndrome (BBW), N/V (MEC), leukocytosis, hyperbilirubinemia

Enasidenib

Which IDH inhibitor inhibits IDH1?

Ivosidenib

Which IDH inhibitor inhibits IDH2?

Enasidenib