11. Targeted Therapies Flashcards by J L

What are targeted cancer therapies?

Drugs or other substances blocking cancer growth by interference of specific molecules (targets) for tumor growth and progression

Able to focus on target specific for type of cancer
 Avoidance of healthy cells = less ____ effects
 Target expressed = increased ____

side effects

efficacy

How well did you know this?

Not at all

Perfectly

Activity of Targeted Therapies
 Interference of cancer cell proliferation
-- Ex: \_\_\_\_ against EGFR or BCR-ABL
 Modification of proteins that regulate gene expression or cellular function
-- Ex: \_\_\_\_
 Induction of apoptosis
-- Ex: \_\_\_\_
 Block angiogenesis
-- Ex: \_\_\_\_
 Enhancing activity of immune system
-- Ex: \_\_\_\_, ipilimumab
 Improved delivery of other therapies
-- Ex: \_\_\_\_
 Cancer vaccines and gene therapy

* Induction of monoclonal ab via enhancing activity of the immune system
* Can also be used to conjugate therapies to give an enhanced effect

tyrosine kinase inhibitors (TKIs)
retinoids
bortezomib
bevacizumab
rituximab
tositumomab

How well did you know this?

Not at all

Perfectly

LIST OF DRUGS!

Look at me!

Yay!

How well did you know this?

Not at all

Perfectly

EGFR

____ rash, ____ toxicity

acneiform

pulmonary

How well did you know this?

Not at all

Perfectly

Structure of a monoclonal antibody

\_\_\_\_ chains
Heavy chains
\_\_\_\_ bonds 
Antigen-binding fragment (\_\_\_\_)
Crystallisable (or constant) fragment (\_\_\_\_)

• Can create monoclonal ab specific to \_\_\_\_ on cancer cells

light
disulfide
Fab
Fc
epitopes

How well did you know this?

Not at all

Perfectly

Mechanisms of action

Immune-mediated effects
• ____ dependent cell lysis
• ____-dependent cell mediated cytotoxicity

Direct anti-proliferative/apoptotic effects
• ____ a ligand
• Block a ligand
• Interfere with cell ____

Interact or sensitize with other modalities
• Can interact with radioimmuno conjugates and the ____ conjugates

complement
antibody
mimic
function
ab-drug

How well did you know this?

Not at all

Perfectly

Conjugated monoclonal antibodies
 Can use antibodies as a delivery mechanism
– High concentration at targeted cell sites increases ____
– Specificity decreases dose-limiting side effects

Examples
 ____
 Toxins
 ____

• The therapy is conjugated onto the monoclonal ab
• The cell internalizes both the \_\_\_\_ and \_\_\_\_ via lysosomes
	○ End up getting up a higher cxn of drug directly targeting specific cancer cells
	○ Allows usage of toxic particles, toxins, and chemotherapies
		§ Using mAb the toxicities decrease significantly

efficacy

radioactive particle
chemotherapy

receptor
monoclonal ab

How well did you know this?

Not at all

Perfectly

• Mab will be chimeric, humanized or human mAb - used clinically
• Using murine protein - increasing risk of ____ and hypersensitivity reactions
○ Patient develops ab to that mouse ab; so if try to reinfuse the murine mAb:
§ Enhanced ____ response
§ Inactivation of the murine mAb
○ Not seen that often anymore
• Chimeric mAb
○ Human constant region - area that’s exposed to immune system and activate it
§ Less risk of patients having adverse reactions
○ Murine ____ region
• Humanized mAb
○ ____% human:10% mouse (vs. 70/30 for chimeric)
§ Further decreasing risk of adverse risk
• All human mAb

infusion
hypersensitivity
variable
90

How well did you know this?

Not at all

Perfectly

• Variable prefix that is specific to the mAb
	• Target:
		○ Immune system
			§ \_\_\_\_
		○ Bone
			§ \_\_\_\_
		○ Tumor
			§ \_\_\_\_
		○ Circulatory system
			§ \_\_\_\_
	• Source:
		○ Mouse
			§ \_\_\_\_
		○ Human
			§ \_\_\_\_
		○ Chimeric
			§ \_\_\_\_
		○ Humanized
			§ \_\_\_\_
		○ Chimeric/humanized hybrid
			§ \_\_\_\_

l(im)
(o)s(o)
t(u)
c(ir)

o
u
xi
zu
xizu

How well did you know this?

Not at all

Perfectly

Trastuzumab
____ monoclonal antibody

Denosumab
____ monoclonal antibody

Nivolumab
____ monoclonal antibody

Rituximab
____ monoclonal antibody

tumor-targeting humanized
bone-targeting human
immune system-targeting human
tumor-targeting chimeric

How well did you know this?

Not at all

Perfectly

Small Molecule Inhibitors

• Small molecule inhibitors can target \_\_\_\_ within the receptor

tyrosine kinase

How well did you know this?

Not at all

Perfectly

Tyrosine Kinase Inhibitors (TKI)

 Single Tyrosine Kinase Inhibitor
 Example
 ____ (EGFR)

 Multi-Tyrosine Kinase Inhibitor
 Example
 ____ (CRAF, BRAF, KIT, FLT-3, RET, VEGFR-1, VEGFR-2, VEGFR-3, and PDGFR-ß)

erlotinib

sorafenib

How well did you know this?

Not at all

Perfectly

EGFR inhibitors

Monoclonal antibodies
____
panitumumab

Small molecule inhibitors
\_\_\_\_
gefitinib
\_\_\_\_
osimertinib

cetuximab
erlotinib
afatinib

How well did you know this?

Not at all

Perfectly

Intravenous EGFR-targeting monocolonal antibodies

 Cetuximab (Erbitux)
 Indications: \_\_\_\_ cancer (KRAS negative, Head and neck cancer, Lung cancer)
Side Effects
 \_\_\_\_-like rash (~80%)
Premedication
 \_\_\_\_

Panitumumab (Vectibix)
 Indications: \_\_\_\_ cancer (KRAS negative)
Side Effects:
 \_\_\_\_-like rash (90%)
 \_\_\_\_

• EGFR - acneiform rash, happens commonly when receiving mAb

colorectal
acne
diphenhydramine

colorectal
acne
diarrhea

How well did you know this?

Not at all

Perfectly

Oral EGFR-targeting small molecule inhibitors

Erlotinib (Tarceva)
 Indications: \_\_\_\_, pancreatic cancer
Side Effects:
 Interstitial lung disease (rare)
 Rash (~50%)
-- Rash ≠ \_\_\_\_
 Correlates with \_\_\_\_, can be managed pharmacologically
 \_\_\_\_

Osimertinib (Tagrisso)
 Indications: \_\_\_\_ progressed on EGFR TKI therapy
-- \_\_\_\_ mutation 
Side effects
 \_\_\_\_ (<50%, decreased severity)
 Interstitial lung disease (3.3%)
 Cardiotoxicity
 \_\_\_\_ prolongation 
 \_\_\_\_

• Rash is not as significant with these newer drugs

NSCLC
hypersensitivity
diarrhea

NSCLC
T790M
rash
QTc
cardiomyopathy

How well did you know this?

Not at all

Perfectly

Rash
Ex: ____ inhibitors

Patient education
• Use of gentle cleansers and moisturizers
• Minimize ____ exposure
• ____

Treatment
• Mild: \_\_\_\_ therapy
--• \_\_\_\_ (macular) or antibiotics (pustular)
• Moderate: topical/oral therapy
--• \_\_\_\_ derivative (doxycycline/minocycline)
• Severe: topical/oral therapy
--• Oral \_\_\_\_
--• \_\_\_\_ reductions/discontinuation

• Rash usually occurs on face/trunk of body and occurs 4 weeks into therapy and continues for 6 to 8 weeks
	○ \_\_\_\_ during that time
	○ Using \_\_\_\_ medications will exacerbate the rash
		§ Treatment: gentle moisturizer, and use of topical steroids and antibiotics (tetracycline derivatives - anti-inflammatory effects)
	○ The rash is initially \_\_\_\_, but once it opens to the environment it is prone to infection

sun
sunscreen
steroids
tetracycline
steroid
dose

improves
acne
sterile

How well did you know this?

Not at all

Perfectly

• Not an allergy
• Short-lived
• Correlation between development and response to the ____
○ Seeing the rash is a ____ sign!

therapy

positive

How well did you know this?

Not at all

Perfectly

HER2 Inhibitors

Monoclonal antibodies
____
ado-trastuzumab emtansine
____

Small molecule inhibitors
____

trastuzumab
pertuzumab

lapatinib

How well did you know this?

Not at all

Perfectly

HER2 inhibitors

Trastuzumab
 ____ expressing breast cancer and gastric cancer
Side Effects:
 ____ (decreased
LVEF)
 Premedication
– If well tolerated, can be given without ____

Pertuzumab
 HER2-neu positive breast cancer, neoadjuvant or metastatic, WITH \_\_\_\_
-- Increased response than \_\_\_\_ alone
Side Effects
 \_\_\_\_

• Hallmark toxicity: cardiotoxicity
	○ Heart failure
		§ HER2 heart failure is \_\_\_\_, and \_\_\_\_ heart failure is not
• Combining targeted with conventional toxicities (such as anthracyclines)
	○ You're not combining HER2 mAb with \_\_\_\_
	○ They finish the anthracycline first, then later on you're treated with HER2 mAb
• No increase in cardiotoxicity as you see with anthracyclines

Study These Flashcards

HER2
cardiotoxicity
premedication

trastuzumab
trastuzumab
cardiotoxicity

reversible
anthracyclines

anthracyclines

Ado-Trastuzumab Emtansine

 Indications: ____+ metastatic breast cancer
 Special Considerations
– Conjugated to ____ (____ agent)
 Side Effects
– ____, hepatotoxicity, peripheral neuropathy

• Ab-drug conjugate for patient's with HER2+ breast cancer
• Anti-MT agent
	○ Hallmark toxicity: \_\_\_\_
	○ DM1 is way more toxic than \_\_\_\_
	○ The toxicities \_\_\_\_ significantly when using with ab

Study These Flashcards

HER2-neu
DM-1
antimicrotubule
cardiotoxicity
neurotoxicity
vincristine
decrease

Cardiotoxicity - Cardiomyopathy

Ex: ____ inhibitors, sunitinib, ____
Risk assessment
• Caution in use in patients with pre-existing ____ conditions (LV dysfunction)
• Educate patient on symptoms (Chest pain, shortness of breath, etc.)
• Discuss risks and benefits prior to therapy

Monitoring
• Left ventricular ejection fraction (LVEF)
–• ____: LVEF at baseline, every 3 months of treatment, then every 6 months after treatment for 2 years
–• ____: LVEF every 8 weeks

Treatment
• Hold treatment with LVEF decline, consider ____ if resolves
• Discontinue offending agent if ____, persistent LVEF decline, ____

Study These Flashcards

HER2
pazopanib
cardiac

herceptin
lapatinib
restart
infarction
CHF

Pulmonary Toxicity
Ex: ____ inhibitors, ____ inhibitors

Risk assessment
• Caution in use in patients with pre-existing ____ conditions

Monitoring
• Changes in breathing, fevers, cough
• ____ scan for concerning symptoms

Treatment
• ____
• Discontinue treatment of ____ agent

• Pneumonitis (pulmonary toxicity)
	○ Upon development, the therapy is discontinued and it's very sensitive to steroids

Study These Flashcards

EGFR
HER2
pulmonary
CT
corticosteroids
offending

Diarrhea
Ex: ____ inhibitors, ____ inhibitors

Prevention
• Avoid
--• Raw \_\_\_\_, nuts, seeds, greasy foods 
--• \_\_\_\_, alcohol, lactose
• Increase consumption of foods to bulk stool and replete electrolytes 
--• Ex: \_\_\_\_, oatmeal, bananas, eggs
• Increase \_\_\_\_ intake

Management
• Replete lost fluid
• \_\_\_\_
--• 4 mg with first stool, followed by 2 mg with every loose stool (max 16 mg/day)
• Diphenoxylate/\_\_\_\_
--• Maximum 8 tablets/day
• \_\_\_\_ for refractory diarrhea

* Oral therapies
* Very rare to have refractory diarrhea and to require octreotide

Study These Flashcards

EGFR
HER2
fruits
caffeine
applesauce
fluid

loperamide
atropine
oxtreotide

VEGF inhibitors

Monoclonal antibodies
____
ramucirumab
____

Small molecule inhibitors
____

Study These Flashcards

bevacizumab
ziv-aflibercept (fusion protein)

axitinib

Angiogenesis ____ mutation > small avascular tumor > ____ factors secreted by tumor and stroma > tumor growth and metastasis > ____ inhibitors may prevent neovascularization and induce vascular regression • Cancer cell growth and development of a tumor, if remains avascular, cells will die off • Cancer cells secrete proangiogenic factors > development of new vessels, and the tumor gets more blood flow and nutrients ○ Can use the BV for metastasis • Block angiogenesis preventing the cell from receiving nutrients that the cell needs to survive and to prevent growth you need from the body

somatic proangiogenic angiogenic

Bevacizumab  Indications: ____ cancer, non-small cell lung cancer, ____, kidney cancer Dose:  5-15 mg/kg IV  Infuse first dose over 90 min, second dose over 60 min, & subsequent doses over 30 min (if tolerating) ``` Side Effects:  ____ Perforation  Impaired wound healing  ____  Nausea/Vomiting/Diarrhea ``` • If patient requires surgery you have to hold these agents ○ Increased ____ and impaired ____

colorectal glioblastoma gastrointestinal hypertension bleeding wound healing

Hypertension Ex: ____ inhibitors Risk assessment • Counsel patients on wellness activities and self-monitoring • Increased monitoring in patients already at risk for hypertension Monitoring • Check ____ weekly Treatment • Use standard ____ according to guidelines • Avoid ____/verapamil due to drug interactions • Discontinue treatment if blood pressure uncontrolled * Occurs in 30% of patients taking this drug * Treat with using normal antihypertensive methods * If on ____ inhibitors - avoid use because you don't want to cause additional drug interactions

``` VEGF blood pressure antihypertensives diltiazem small molecule ```

Hemorrhage and Bleeding Ex: ____ inhibitors Risk assessment • Avoid in patients with high risk of ____ (ex: anticoagulation) Nosebleeds • Topical ____ • Call provider for prolonged bleeding or dizziness Surgery • ____ due to poor wound healing / would dehiscience Severe bleeding • Discontinue for any bleeding event requiring medical intervention • Ex: ____, bowel perforation

``` VEGF bleeding pressure hold hemoptysis ```

Anti-CD20 monoclonal antibodies ``` ____ ofatumumab ____ ibritumomab ____ ``` • CD20 - receptor that is expressed on ____ cells ○ Targeted for B-cell malignancies, such as B-cell ____ ○ Patient must have CD20+ disease in order for these mAb to be effective • Also have radioimmuno conjugates for CD20

rituximab obinutuzumab tositumomab B lymphoma

``` Rituximab Indications and dose  ____, ____: 375 mg/m2  ____: 1000 mg IV Adverse effects: infusion reactions, ____ reactivation (HBV), infection, ____ ```

``` non-hodgkin lymphoma CLL rheumatoid arthritis viral progressive multifocal leukoencephalopathy (PML) ```

BRAF Inhibitors ``` Vemurafenib  Indications: ____  Side Effects:  ____  Arthralgia/Myalgia  ____ prolongation  Cutaneous squamous cell carcinoma (cuSCC) ``` ``` Dabrafenib  Indications: ____  Combination with ____  Side Effects:  ____  ____  Arthralgia/Myalgia  ____ prolongation  cuSCC ``` * Used in combination with the ____ inhibitors * SCC less ____ than melanoma; can be excised and curative

melanoma rash/photosensitivity Qtc ``` melanoma trametinib rash hyperglycemia QTc ``` MEK malignant

Cardiotoxicity – QTc prolongation Ex: ____, sunitinib, vandetanib, pazopanib, BRAF inhibitors Risk assessment • Caution in use in patients with pre-existing ____ conditions • Educate patient on symptoms --• Chest pain, palpitations • Review medications for drug interactions • Discuss risks and benefits prior to therapy Monitoring • ____ monitoring prior and during therapy • Electrolytes Treatment • > ____ msec • Hold ____, replete ____, consider restarting with dose adjustment • QTc prolongation ○ Echocardiograms - the patient can have prolonging of heart rhythms that puts them at risk for ____ - torsades de point • Replete K and Mg

``` sorafenib cardiac ECG 500 treatment electrolytes arhythmias ```

MEK Inhibitors ``` Cobimetinib  Indications: ____  Combination with ____ Toxicities  ____, nausea, severe ____, rhabdomyolysis (12%), retinopathy, ____ ``` ``` Trametinib  Indications: ____  Combination with ____  Take on ____ stomach Toxicities  ____, diarrhea, lymphedema, ____, interstitial lung disease  ____ inducer ``` • B-raf inhibitors, given in conjunction with MEK inhibitor ○ When combined, decreases risk of developing ____

``` melanoma vemurafenib diarrhea photosensitivity cardiomyopathy ``` ``` melanoma trametinib empty rash cardiomyopathy CYP3A4 ``` cancers

Gleevac, Sprycel, and Tasigna • Used for philadelphia chromosome+ disease • Bcr-abl - ____ ○ ____, ALL patients • Toxicity: ○ May see a ____ (doesn't require therapy) ○ Dasatinib - ____ bleeds, and pleural/cardio ○ Nilotinib - ____ prolongation and more liver toxicity

``` non-receptor Tyr kinase CML rash GI QTc ```

Ibrutinib ```  Target: ____  Indication: ____, Mantle cell lymphoma Side effects  ____, fatigue, diarrhea, ____, neutropenia, atrial fibrillation (6-9%)  ____ malignancies (5-10%), renal failure, hemorrhage  ____ substrate -- ____ adjustments required! ``` • Watch out for drug interactions with this medication

``` bruton tyrosine kinase chronic lymphocytic leukemia edema thrombocytopenia secondary MAJOR CYP3A4 dose ```

``` Ipilimumab  Target: ____  Indications: ____ Mechanism of action:  Augmentation of T-cell ____, increasing T-cell mediated anti-tumor immune responses  Dose:  3 mg/kg over 90 minutes every 3 weeks for 4 doses Side Effects:  ____  Hepatitis  ____  Neuropathies  ____ ``` • The T-cell activation is not ____ to the cancer cell

cytotoxic T-lymphocyte antigen 4 (CTLA-4) activation enterocolitis dermatitis endocrinopathies specific

PD1 Inhibitors: Nivolumab, Pembrolizumab ```  MOA: Anti-PD-1 inhibitor -> inhibition of the ____ caused by PD-1 receptor signaling -> enhanced ____ response Dose and Administration  Nivolumab: -- 3 mg/kg IV Q 2 weeks  Pembrolizumab -- 2 mg/kg IV Q 3 weeks ```  Toxicities: Immune mediated toxicities (____, colitis, hepatotoxicity, ____, thyroid disorders), fatigue, infusion reactions -- Managed by ____  Other Considerations: LFTs and ____ function at baseline • Treat AI side-effects with steroids ○ Large dosage scales

``` negative regulation T-cell hyperglycemia pneumonitis steroids thyroid ```

Targeting CD19+ with CAR- Modified T cells  CARs combine an antigen recognition domain of antibody with intracellular signaling domains into a single ____ protein  Gene transfer (lentiviral vector) to stably express CAR on ____ confers novel antigen specificity * T cells from patient via ____, and the T cells are activated against a specific characteristic of a tumor cell (against ____ - B cell malignancies) * The T cells become active towards the characteristic, and reinfused back into the patient

chimeric T cells aphoresis CD19

CART-Related CRS ____ days after T cell infusion Initially hard to distinguish from ____ Can be reversed with ____ and other anti-cytokine therapy in MOST patients Best timing for anti-cytokine intervention not known ____ should be given STAT ____ and other anti-cytokines given if tocilizumab not effective • Can have a pronounced immune response to the T-cells - CRS ○ Seen the same way as with ____ (low BP, hypertension, hypoxia, intubation, vasopressors) • Can be used with another agent - specific to IL released from T-cells - blocks ____ receptors ○ Mediates the CRS • Tocilizumab does not ____ the response, but will rescue them for CRS

``` 1-10 infection tocilizumab tocilizumab steroids ``` sepsis IL6 decrease

CTL019-Related Cytokine Release Syndrome (CRS) • ____ - usually around low areas in healthy patients ○ Here, peaked at ____ during their CRS ○ Gives a rough estimate of how much ____ they're having

ferritin 600k CRS

Blinatumomab (Blincyto)  Target: Binds to ____ (B-cells) and ____ (T-cells) -> ____ activation -> lysis of malignant ____ cell  Indications: B-cell ____, Ph ____, relapsed/refractory Dose (____ infusion):  Cycle 1: 9 mcg daily Days 1-7, 28 mcg daily Days 8-28 in 6 week cycle  Subsequent cycles: 28 mcg daily Days 1-28 in 6 week cycle  Hospitalization required to start Side Effects:  ____ syndrome  ____ (confusion, seizures)  Premedication -- ____ 20 mg IV before 1st first dose, dose increase, or restarting after ≥ 4 hours • BITE antibody [???] • Bring malignant B cell to a T cell, and the T cell becomes activated and you get T cell mediated cancer activity ○ May develop CRS, but can stop the infusion because it's so ____ and have an improvement in symptoms • Short-lived mAb - require a continuous infusion over four weeks • Requires premedication because of CRS; can receive steroids, ____ patients we try to avoid

``` CD19 CD3 T cell B cell ALL negative IV continuous ``` ``` cytokine release neurotoxicity dexamethasone short-lived ??? ```

Patient Adherence ``` Assessment • ____ • Motivation • ____ skills • Patient- provider relationship ``` ``` Education • Storage • Safe handling • Side effects • Importance of adherence ``` Review • Patient reporting • Evaluate adherence • Clinical response * Most of small molecule inhibitors are oral agents * [NOTES]

patient history | communication

Drug delivery Oral therapies  Ability to administer tablets/capsules ---Ability to ____ ---Use of enteric ____ ---____ burden  Very few oral targeted therapies have commercial ____ Extemporaneous compounding  Not all drugs are created ____!  Almost all prescribing information note not to ____ or crush  ____ may impair reliable drug absorption  May increase risk of ____ to person compounding medication Ex: nurse, family member

swallow feeding tubes pill suspensions equal chew suspensions exposure

Drug interactions Metabolism of many of these medications regulated by CYP3A4 Inhibitors Antifungals: ketoconazole, ____, voriconazole Antibiotics: ____ ____, Seville oranges Inducers Anticonvulsants: ____, carbamazepine Absorption of oral chemotherapy may be affected by gastric ____ change Avoid use of ____ and PPIs * May require dose adjustment of their chemotherapies * Affected gastric pH, may have affected absorption of chemotherapies

fluconazole clarithromycin grapefruit juice phenytoin H2-blockers

Other considerations •____ of therapy --• Biosimilars? •Reimbursement Insurance Coverage – Prior ____/copay Medicare – “____” hole * Patient Assistance Programs  Uninsured/underinsured ____ assistance * ____ trial? * ____ programs * Specialty pharmacies * Clinical trials - ____ drugs

``` cost authorization donut co-pay clinical REMS specialty free ```

11. Targeted Therapies Flashcards

(45 cards)