11. Targeted Therapies Flashcards
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
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
LIST OF DRUGS!
Look at me!
Yay!
EGFR
____ rash, ____ toxicity
acneiform
pulmonary
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
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
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
• 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
• 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
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
Small Molecule Inhibitors
• Small molecule inhibitors can target \_\_\_\_ within the receptor
tyrosine kinase
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
EGFR inhibitors
Monoclonal antibodies
____
panitumumab
Small molecule inhibitors \_\_\_\_ gefitinib \_\_\_\_ osimertinib
cetuximab
erlotinib
afatinib
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
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
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
• Not an allergy
• Short-lived
• Correlation between development and response to the ____
○ Seeing the rash is a ____ sign!
therapy
positive
HER2 Inhibitors
Monoclonal antibodies
____
ado-trastuzumab emtansine
____
Small molecule inhibitors
____
trastuzumab
pertuzumab
lapatinib
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
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
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, ____
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
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
EGFR HER2 fruits caffeine applesauce fluid
loperamide
atropine
oxtreotide
VEGF inhibitors
Monoclonal antibodies
____
ramucirumab
____
Small molecule inhibitors
____
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
