Targeted Therapy Flashcards
(298 cards)
1
Q
What is the definition of targeted therapy in oncology?
A
- Treatment that interferes with specific molecular targets involved in cancer growth and progression
- Designed to block proliferation, angiogenesis, or survival signals
2
Q
What are the two major categories of targeted therapies?
A
- Small molecule inhibitors
- Monoclonal antibodies (including ADCs)
3
Q
How do small molecule inhibitors work?
A
- Typically enter cells and inhibit intracellular signaling proteins like kinases
- Block downstream oncogenic pathways
4
Q
How do monoclonal antibodies exert anti-cancer effects?
A
- Bind extracellular receptors or ligands
- May trigger immune responses (ADCC, CDC)
- Can be conjugated with cytotoxic agents
5
Q
What is an antibody-drug conjugate (ADC)?
A
- Monoclonal antibody linked to cytotoxic agent
- Delivers chemotherapy selectively to tumor cells
6
Q
What are examples of key intracellular pathways targeted by small molecule inhibitors?
A
- EGFR
- BRAF/MEK
- PI3K/AKT/mTOR
- ALK
- FLT3
7
Q
What types of resistance can develop with targeted therapies?
A
- Primary (intrinsic) resistance
- Secondary (acquired) resistance due to mutations or pathway activation
8
Q
What is EGFR and its role in cancer?
A
- Epidermal growth factor receptor, a tyrosine kinase
- Promotes proliferation, survival, and metastasis in many solid tumors
9
Q
Name 3 EGFR inhibitors used in cancer therapy.
A
- Erlotinib
- Afatinib
- Osimertinib
10
Q
What is the mechanism of action of erlotinib?
A
- Reversible EGFR tyrosine kinase inhibitor (1st generation)
11
Q
What distinguishes afatinib from erlotinib?
A
- Afatinib is an irreversible pan-ErbB inhibitor (2nd gen)
- Also inhibits HER2 and HER4
12
Q
What is osimertinib’s key clinical niche?
A
- Targets EGFR T790M mutation in NSCLC
- 3rd-generation irreversible inhibitor with CNS penetration
13
Q
What are common adverse effects of EGFR TKIs?
A
- Rash
- Diarrhea
- Nail changes
- Interstitial lung disease (ILD)
14
Q
How is EGFR rash managed?
A
- Topical steroids
- Doxycycline or minocycline
- Dose modification if severe
15
Q
Which EGFR inhibitor is most associated with QTc prolongation?
A
- Osimertinib
16
Q
What type of mutation predicts response to EGFR TKIs?
A
- Exon 19 deletion or L858R mutation in exon 21
17
Q
Which mutation causes resistance to 1st and 2nd generation EGFR inhibitors?
A
- T790M
18
Q
What diagnostic test is used to detect EGFR mutations?
A
- PCR or NGS on tumor tissue
- Liquid biopsy (ctDNA)
19
Q
What is HER2 and its role in cancer?
A
- Human epidermal growth factor receptor 2
- Overexpressed in some breast, gastric, and lung cancers
20
Q
What are examples of HER2-targeted agents?
A
- Trastuzumab
- Pertuzumab
- Lapatinib
- Tucatinib
- Trastuzumab deruxtecan
21
Q
What is trastuzumab’s mechanism of action?
A
- Binds HER2 extracellular domain
- Inhibits signaling
- Activates ADCC
22
Q
What is pertuzumab’s unique mechanism?
A
- Binds HER2 at different domain than trastuzumab
- Blocks HER2 dimerization with HER3
23
Q
What is lapatinib’s mechanism of action?
A
- Oral small molecule TKI that inhibits HER2 and EGFR
24
Q
What is tucatinib’s selectivity advantage?
A
- More selective for HER2
- Less EGFR inhibition → fewer skin/GI side effects
25
What is trastuzumab deruxtecan?
- HER2-directed antibody-drug conjugate
- Contains topoisomerase I payload
- For HER2+ and HER2-low tumors
26
What serious toxicity is associated with trastuzumab deruxtecan?
- Interstitial lung disease (ILD)
27
What is the standard monitoring strategy for HER2 cardiotoxicity?
- Baseline and periodic LVEF (e.g., every 3 months)
28
What is a unique toxicity of lapatinib compared to trastuzumab?
- Diarrhea
- Hand-foot syndrome
29
When should HER2-targeted therapy be discontinued due to cardiotoxicity?
- LVEF drop ≥16% from baseline
- LVEF <50% with symptoms
30
What is HER2-low breast cancer?
- IHC 1+ or 2+ with negative ISH
- Not classically HER2+ but can respond to trastuzumab deruxtecan
31
What distinguishes reversible from irreversible TKIs?
- Reversible: bind non-covalently (e.g., erlotinib)
- Irreversible: form covalent bonds (e.g., afatinib, osimertinib)
32
What are class-wide toxicities of HER2-targeted mAbs?
- Infusion reactions
- Cardiotoxicity
- Rare ILD
33
What is the clinical significance of HER3 in cancer?
- Dimerizes with HER2
- Potent activation of downstream pathways
34
What is the function of HER2 dimerization inhibitors?
- Prevent HER2 from pairing with other HER family receptors (e.g., pertuzumab)
35
How do tyrosine kinase domain mutations impact drug selection?
- Alter drug binding
- Guide selection of 1st, 2nd, or 3rd-gen TKIs
36
Which HER2-targeted therapy is preferred for CNS disease?
- Tucatinib (good CNS penetration)
37
What is the backbone regimen for metastatic HER2+ breast cancer?
- Trastuzumab + pertuzumab + docetaxel (CLEOPATRA trial)
38
What trial led to the approval of trastuzumab deruxtecan in HER2-low disease?
- DESTINY-Breast04
39
What is the dosing schedule for trastuzumab deruxtecan?
- IV infusion every 3 weeks (q3w)
40
What are signs of early ILD with HER2 ADCs?
- Cough
- Dyspnea
- Radiographic infiltrates without infection
41
What is the preferred first-line TKI in EGFR-mutant NSCLC?
- Osimertinib
42
Which EGFR TKI is most effective against brain metastases?
- Osimertinib
43
What are strategies to overcome EGFR TKI resistance?
- Switch to later-gen TKI
- Combine with MET inhibitors
- Use chemotherapy
44
What mutation causes resistance to osimertinib?
- EGFR C797S mutation
45
What is the mechanism of EGFR C797S resistance?
- Prevents covalent binding of osimertinib
46
How are EGFR inhibitors metabolized?
- Primarily CYP3A4
- Watch for drug interactions
47
What drugs can reduce efficacy of osimertinib?
- Strong CYP3A inducers (e.g., phenytoin, rifampin)
48
What supportive care is needed with EGFR inhibitors?
- Rash prophylaxis
- Diarrhea management
- LFT monitoring
49
What class of drugs often causes acneiform rash?
- EGFR inhibitors
50
What patient counseling points are important for EGFR TKIs?
- Rash and diarrhea are common
- Report new respiratory symptoms
- Adherence is key to efficacy
51
What is ALK and in which cancer is it commonly mutated?
- Anaplastic lymphoma kinase
- Mutated/rearranged in NSCLC, ALCL, and other tumors
52
What is the mechanism of action of crizotinib?
- ALK and ROS1 tyrosine kinase inhibitor
- Also inhibits MET
53
What are common toxicities of crizotinib?
- Visual disturbances
- QTc prolongation
- GI symptoms
54
What distinguishes alectinib from crizotinib?
- More potent and CNS-penetrant
- First-line agent for ALK+ NSCLC
55
What is the typical dosing of alectinib?
- 600 mg PO BID with food
56
What ALK inhibitor is associated with elevated CPK and myalgias?
- Alectinib
57
What monitoring is needed for alectinib?
- CPK
- LFTs
- Pulmonary symptoms
58
What ALK inhibitor is used after resistance to alectinib?
- Lorlatinib
59
What are unique side effects of lorlatinib?
- CNS effects (mood, memory)
- Hypercholesterolemia
- Hypertriglyceridemia
60
What is ROS1 and its clinical relevance?
- Receptor tyrosine kinase similar to ALK
- Rearrangements seen in NSCLC
61
What drugs are used for ROS1+ NSCLC?
- Crizotinib
- Entrectinib
- Lorlatinib (off-label)
62
What is the mechanism of action of entrectinib?
- Inhibits ROS1, NTRK, ALK
63
What is RET and its relevance in cancer?
- Receptor tyrosine kinase
- Mutated or rearranged in thyroid and NSCLC
64
What are selective RET inhibitors?
- Selpercatinib
- Pralsetinib
65
What are adverse effects of selpercatinib?
- Hypertension
- Hepatotoxicity
- QT prolongation
66
What are common indications for RET inhibitors?
- RET fusion+ NSCLC
- RET-mutant medullary thyroid cancer (MTC)
67
What is BRAF and where is V600E mutation seen?
- Kinase in MAPK pathway
- Melanoma, colon, thyroid cancers
68
What are approved BRAF inhibitors?
- Vemurafenib
- Dabrafenib
- Encorafenib
69
What is a major toxicity of BRAF inhibitors?
- Cutaneous squamous cell carcinoma
- Arthralgia
- Photosensitivity
70
Why are BRAF and MEK inhibitors used together?
- Reduces resistance
- Lowers skin toxicity
- Improves efficacy
71
What are MEK inhibitors approved for use with BRAF agents?
- Trametinib (with dabrafenib)
- Binimetinib (with encorafenib)
72
What are MEK inhibitor side effects?
- Rash
- Diarrhea
- Cardiotoxicity
- Retinal toxicity
73
What monitoring is needed for MEK inhibitors?
- LVEF (echocardiogram)
- Ophthalmologic exams
74
What is NTRK and in what cancers is it altered?
- Neurotrophic tyrosine receptor kinase
- Fusions seen in rare solid tumors across histologies
75
What are TRK inhibitors approved for NTRK+ tumors?
- Larotrectinib
- Entrectinib
76
What is the mechanism of action of larotrectinib?
- Selective TRK inhibitor
- Blocks fusion-driven tumor signaling
77
What are side effects of TRK inhibitors?
- Fatigue
- Dizziness
- Weight gain
- Transaminitis
78
What is the benefit of TRK inhibitors in pediatric cancers?
- High response rate
- Favorable safety profile
79
How are patients selected for TRK inhibitor therapy?
- NGS or fusion panel testing
- Pan-cancer biomarker detection
80
What defines tumor-agnostic approval?
- FDA approval based on biomarker, not tumor type
- Example: NTRK fusion + → TRK inhibitors
81
What is the difference between selective and multikinase inhibitors?
- Selective: target a single kinase (e.g., selpercatinib)
- Multikinase: target multiple kinases (e.g., cabozantinib)
82
Which kinase inhibitors require thyroid function monitoring?
- RET inhibitors
- Multikinase inhibitors (e.g., sunitinib)
83
What targeted therapies commonly cause hypertension?
- RET inhibitors
- VEGF inhibitors
- BRAF/MEK combos
84
What drug class is associated with ocular side effects like blurred vision or retinal detachment?
- MEK inhibitors
85
What baseline tests should precede MEK inhibitor therapy?
- LVEF assessment
- Eye exam
86
What is the advantage of entrectinib over larotrectinib?
- Covers ROS1 and ALK in addition to NTRK
- Greater CNS penetration
87
What unique side effect may occur with lorlatinib but not with alectinib?
- Cognitive/mood disturbances
88
What counseling is important for patients on BRAF inhibitors?
- Sun protection
- Report new skin lesions
- Joint pain management
89
Which pathway do BRAF and MEK inhibitors target?
- MAPK (RAS/RAF/MEK/ERK) pathway
90
What is the benefit of combination BRAF/MEK inhibition in melanoma?
- Improves OS and PFS
- Reduces cutaneous toxicity
91
What labs should be monitored during TRK inhibitor therapy?
- LFTs
- Glucose
- Weight
92
Which cancers most often carry NTRK fusions?
- Infantile fibrosarcoma
- Secretory breast carcinoma
- Some thyroid, colon cancers
93
What is the duration of response to TRK inhibitors?
- Often long-lasting, even in advanced disease
94
How does resistance to TRK inhibitors develop?
- Kinase domain mutations
- Bypass signaling activation
95
What is selitrectinib?
- Next-gen TRK inhibitor for TRK resistance mutations
96
What defines next-generation kinase inhibitors?
- Designed to overcome resistance mutations
- Improved selectivity and CNS penetration
97
What is the mechanism of acquired resistance to ALK inhibitors?
- ALK mutations (e.g., G1202R)
- Activation of bypass pathways
98
What RET mutation is associated with medullary thyroid cancer?
- RET M918T
99
What is the main adverse effect to monitor in ROS1 inhibitors?
- CNS toxicity (especially dizziness, ataxia)
100
What is a key pharmacologic feature of newer ALK inhibitors?
- CNS penetration
- Activity against resistance mutations
101
What is the role of VEGF in cancer?
- Stimulates new blood vessel growth (angiogenesis)
- Supports tumor oxygenation and nutrient supply
102
What is the mechanism of action of bevacizumab?
- Monoclonal antibody against VEGF-A
- Prevents VEGF from binding its receptor
103
What cancers use bevacizumab in treatment?
- Colorectal, lung, renal, ovarian, glioblastoma
104
What are common toxicities of bevacizumab?
- Hypertension
- Proteinuria
- Delayed wound healing
- GI perforation
105
What monitoring is needed for bevacizumab?
- BP
- Urinalysis for protein
- Monitor for bleeding/perforation
106
When should bevacizumab be held around surgery?
- Stop ≥28 days pre-op
- Resume ≥28 days post-op and after wound healing
107
What is ramucirumab and its target?
- VEGFR2 monoclonal antibody
- Blocks VEGF receptor, not ligand
108
What is ziv-aflibercept?
- Recombinant fusion protein
- Acts as decoy receptor for VEGF-A, B, and PlGF
109
What are TKIs that target VEGF receptors?
- Sorafenib
- Sunitinib
- Axitinib
- Cabozantinib
- Lenvatinib
110
What toxicities are associated with VEGFR TKIs?
- Hand-foot syndrome
- Hypertension
- Diarrhea
- Fatigue
111
How are VEGFR TKIs metabolized?
- Mostly via CYP3A4
- Watch for DDIs
112
Which VEGFR TKI is most associated with thyroid dysfunction?
- Sunitinib
113
What drug causes hair depigmentation (hair turns white)?
- Pazopanib or sunitinib
114
Which VEGFR TKI requires fasting administration?
- Pazopanib (empty stomach)
115
What is cabozantinib's unique toxicity?
- Palmar-plantar erythrodysesthesia
- Fistula/hemorrhage risk
116
What is the mTOR pathway's role in cancer?
- Controls cell growth, proliferation, metabolism
117
What is everolimus’s mechanism of action?
- Binds FKBP-12 → inhibits mTORC1
118
What cancers is everolimus approved for?
- Breast (HR+), renal cell, neuroendocrine tumors
119
What is a common toxicity of everolimus?
- Stomatitis
120
What is used to prevent everolimus-associated stomatitis?
- Dexamethasone mouthwash
121
What are other adverse effects of everolimus?
- Hyperglycemia
- Hyperlipidemia
- Pneumonitis
- Rash
122
What monitoring is needed for everolimus?
- Fasting glucose, lipids
- CBC
- Pulmonary symptoms
123
What is temsirolimus?
- IV mTOR inhibitor
- Approved for poor-risk advanced RCC
124
What limits the use of temsirolimus?
- IV administration
- Higher risk of hypersensitivity
125
What is the PI3K/AKT/mTOR pathway responsible for?
- Regulates cell survival and growth
- Frequently altered in cancer
126
What is alpelisib and its target?
- Oral PI3K-alpha inhibitor
- Targets PIK3CA-mutated HR+ breast cancer
127
What are common side effects of alpelisib?
- Hyperglycemia
- Rash
- Diarrhea
128
What monitoring is important with alpelisib?
- Fasting glucose
- A1c
- Skin exams
129
What prophylaxis can reduce rash risk with alpelisib?
- Antihistamines (e.g., cetirizine)
130
What companion diagnostic is needed for alpelisib?
- PIK3CA mutation testing (tumor or ctDNA)
131
What is capivasertib and its target?
- Oral AKT inhibitor
- Used in HR+/HER2− breast cancer
132
What trial supports capivasertib + fulvestrant use?
- CAPItello-291
133
What are side effects of capivasertib?
- Diarrhea
- Rash
- Hyperglycemia
134
How is PI3K/AKT/mTOR pathway activated?
- PIK3CA mutation
- PTEN loss
- AKT1 mutation
135
What is ipatasertib and what does it inhibit?
- AKT inhibitor under investigation
- Targets tumors with PTEN loss
136
What drugs inhibit mTOR and may cause pneumonitis?
- Everolimus
- Temsirolimus
137
What is a management strategy for immune-related pneumonitis?
- Hold drug
- Corticosteroids if symptomatic
138
What is the most common metabolic abnormality with PI3K inhibitors?
- Hyperglycemia
139
What are signs of serious stomatitis vs. mucositis?
- Stomatitis: aphthous ulcers, limited to mouth
- Mucositis: more diffuse, painful, affects entire GI tract
140
What are oral agents targeting the PI3K pathway?
- Alpelisib
- Copanlisib (IV for lymphoma)
141
What are class-wide adverse effects of mTOR inhibitors?
- Metabolic (glucose, lipids)
- Rash
- Pneumonitis
- Stomatitis
142
Why are combination regimens with mTOR inhibitors challenging?
- Overlapping toxicities
- Limited tolerability
143
What is the role of PI3K/AKT inhibitors in endocrine resistance?
- Block compensatory survival signaling
- Restore endocrine sensitivity
144
What is the rationale for combining fulvestrant with PI3K/AKT inhibitors?
- Dual pathway inhibition
- Targets ER and survival signaling
145
What baseline labs are needed before PI3K/AKT inhibitors?
- Fasting glucose
- Lipids
- Liver function tests
146
Which PI3K inhibitor is approved for hematologic malignancies?
- Idelalisib (for CLL, FL)
147
What black box warning is associated with idelalisib?
- Hepatotoxicity
- Diarrhea/colitis
- Pneumonitis
- Infections
148
What counseling is important for patients on mTOR inhibitors?
- Report cough, mouth sores
- Monitor blood sugars
- Take with or without food consistently
149
How should everolimus be taken with respect to food?
- Consistently with or without food daily
150
What is the benefit of identifying PI3K/AKT/mTOR mutations in solid tumors?
- Enables targeted therapy selection
- May predict resistance to standard treatments
151
What is the mechanism of action of PARP inhibitors?
- Inhibit PARP enzymes involved in single-strand DNA repair
- Cause synthetic lethality in BRCA-deficient cells
152
Name FDA-approved PARP inhibitors.
- Olaparib
- Rucaparib
- Niraparib
- Talazoparib
153
What cancers are PARP inhibitors approved for?
- Breast (gBRCA)
- Ovarian
- Pancreatic
- Prostate
154
What is the key biomarker for PARP inhibitor therapy?
- BRCA1/2 mutations (germline or somatic)
155
What are class-wide toxicities of PARP inhibitors?
- Nausea
- Fatigue
- Anemia
- Thrombocytopenia
156
Which PARP inhibitor has the highest risk of hematologic toxicity?
- Talazoparib
157
What lab monitoring is required with PARP inhibitors?
- CBC every 2–4 weeks
- Renal and hepatic function
158
What is synthetic lethality?
- Cell death caused by simultaneous defects in two pathways (e.g., BRCA mutation + PARP inhibition)
159
Which PARP inhibitors are used for maintenance therapy in ovarian cancer?
- Olaparib
- Niraparib
160
What is a notable rare side effect of PARP inhibitors?
- MDS/AML
161
What companion diagnostic is required for olaparib in prostate cancer?
- HRR gene mutation panel (BRCA1/2, ATM, etc.)
162
Which PARP inhibitor does not require BRCA mutation for use in ovarian cancer?
- Niraparib (maintenance regardless of BRCA status)
163
What is the mechanism of CDK4/6 inhibitors?
- Inhibit cyclin-dependent kinases 4 and 6
- Prevent phosphorylation of Rb
- Halt cell cycle at G1 phase
164
Name the 3 main CDK4/6 inhibitors.
- Palbociclib
- Ribociclib
- Abemaciclib
165
Which CDK4/6 inhibitor has the highest rate of diarrhea?
- Abemaciclib
166
Which CDK4/6 inhibitor causes the most neutropenia?
- Palbociclib
167
Which CDK4/6 inhibitor is dosed continuously?
- Abemaciclib
168
Which CDK4/6 inhibitor is associated with QTc prolongation?
- Ribociclib
169
What trial led to approval of ribociclib in early breast cancer?
- NATALEE
170
What is the typical dosing schedule of palbociclib?
- 21 days on, 7 days off (28-day cycle)
171
What labs must be monitored with CDK4/6 inhibitors?
- CBC (esp. ANC)
- LFTs
- ECG for ribociclib
172
What are common side effects of CDK4/6 inhibitors?
- Neutropenia
- Diarrhea
- Fatigue
- Elevated LFTs
173
What is the role of CDK4/6 inhibitors in HR+/HER2− breast cancer?
- First-line therapy with endocrine therapy
- Improves OS and PFS
174
What is the recommended contraceptive counseling with CDK4/6 inhibitors?
- Use effective contraception during and for weeks after treatment
175
What are notable drug interactions with CDK4/6 inhibitors?
- CYP3A4 inhibitors/inducers
176
What is the mechanism of resistance to CDK4/6 inhibitors?
- Rb loss
- Cyclin E amplification
- Bypass of G1/S checkpoint
177
What is the importance of retinoblastoma (Rb) protein in CDK4/6 inhibition?
- CDK4/6 phosphorylates Rb
- Inhibition leads to G1 arrest
178
What defines a functional companion diagnostic?
- Required biomarker test to prescribe a specific therapy
179
What drugs require BRCA testing before use?
- PARP inhibitors: olaparib, talazoparib, etc.
180
What companion diagnostic is used for HER2-targeted therapies?
- IHC and ISH testing for HER2 overexpression or amplification
181
Which targeted therapies require PD-L1 testing?
- Immunotherapies (e.g., atezolizumab in TNBC)
182
How does pharmacogenomics affect targeted therapy?
- Affects drug metabolism (e.g., CYP2D6 & tamoxifen)
- Predicts efficacy/toxicity
183
What is the impact of CYP3A4 inhibitors on TKIs?
- Increases drug exposure
- Risk of toxicity
184
What drugs are strong CYP3A4 inhibitors?
- Ketoconazole
- Itraconazole
- Clarithromycin
185
What drugs are strong CYP3A4 inducers?
- Rifampin
- Carbamazepine
- Phenytoin
186
What are examples of food–drug interactions in targeted therapy?
- Grapefruit juice with TKIs
- Fatty meals increasing bioavailability
187
What is the effect of acid-reducing agents on TKI absorption?
- Can reduce absorption of pH-dependent TKIs (e.g., erlotinib, pazopanib)
188
Which TKIs require acidic environments for absorption?
- Erlotinib
- Pazopanib
- Dasatinib
189
How should acid reducers be managed with pH-dependent TKIs?
- Avoid PPIs
- Space H2 blockers/antacids
190
What are key counseling points for PARP inhibitors?
- Take with/without food per agent
- Monitor fatigue, nausea
- Contraceptive use advised
191
What are key counseling points for CDK4/6 inhibitors?
- Monitor CBC
- Report diarrhea (especially abemaciclib)
- Discuss contraceptive needs
192
How should ribociclib be administered?
- With or without food
- Avoid CYP3A4 interactions
193
What educational point is key for palbociclib?
- Emphasize importance of treatment breaks (7-day off)
194
Which CDK4/6 inhibitor can be used with letrozole or fulvestrant?
- All: palbociclib, ribociclib, abemaciclib
195
What is the major benefit of adding CDK4/6 inhibitors to endocrine therapy?
- Improved progression-free and overall survival
196
What supportive measures are recommended for CDK4/6-induced diarrhea?
- Loperamide
- Hydration
- Dose adjustment if severe
197
What is the half-life of talazoparib?
- Approximately 90 hours
198
Which PARP inhibitor is renally cleared and needs dose adjustments?
- Olaparib
199
What is the mechanism of action of antibody-drug conjugates (ADCs)?
- Monoclonal antibody targets tumor antigen
- Cytotoxic payload is internalized and released inside cancer cell
- Combines specificity of antibody with potency of chemotherapy
200
Name 3 FDA-approved ADCs and their targets.
- Trastuzumab deruxtecan – HER2
- Sacituzumab govitecan – Trop-2
- Brentuximab vedotin – CD30
201
What is the payload in trastuzumab deruxtecan?
- Topoisomerase I inhibitor (deruxtecan)
202
What toxicity is a black box warning for trastuzumab deruxtecan?
- Interstitial lung disease (ILD)
203
What is the mechanism of resistance to ADCs?
- Downregulation or mutation of antigen
- Impaired internalization
- Increased efflux of payload
204
What is sacituzumab govitecan and its target?
- ADC targeting Trop-2
- Contains SN-38 (irinotecan active metabolite) as payload
205
What cancers use sacituzumab govitecan?
- Triple-negative breast cancer (TNBC)
- HR+/HER2– breast cancer
- Bladder cancer
206
What are common toxicities of sacituzumab govitecan?
- Diarrhea
- Neutropenia
- Alopecia
- Fatigue
207
What ADC targets CD30 and is used in Hodgkin lymphoma?
- Brentuximab vedotin
208
What is the payload of brentuximab vedotin?
- MMAE (microtubule inhibitor)
209
What are class-wide toxicities of ADCs?
- Infusion reactions
- Cytopenias
- Peripheral neuropathy (especially MMAE-containing ADCs)
210
What is the mechanism of resistance to small molecule TKIs?
- Target mutations (e.g., EGFR T790M)
- Bypass pathway activation
- Drug efflux or metabolic changes
211
What is the T790M mutation and its significance?
- EGFR mutation causing resistance to 1st/2nd-gen TKIs
- Targeted by osimertinib
212
How can resistance to CDK4/6 inhibitors develop?
- Rb loss
- Cyclin E amplification
- Upregulation of CDK2
213
What strategies are used to overcome targeted therapy resistance?
- Use of next-gen inhibitors
- Combination therapies
- Targeting alternative pathways
214
Why is CNS penetration important for some targeted therapies?
- Many cancers metastasize to brain (e.g., NSCLC, HER2+ breast cancer)
- Requires drugs that cross blood-brain barrier (e.g., osimertinib, tucatinib)
215
Which targeted therapies have good CNS activity?
- Osimertinib
- Tucatinib
- Alectinib
- Lorlatinib
216
What are special considerations for targeted therapy in the elderly?
- Adjust based on renal/hepatic function
- Polypharmacy and drug interactions
- Monitor for fatigue, cytopenias
217
What are renal dose adjustments required for?
- Olaparib
- Niraparib
- Talazoparib
- Crizotinib
218
What targeted agents require hepatic dose adjustments?
- Lenvatinib
- Abemaciclib
- Osimertinib
219
What is the main concern with combining targeted therapy and radiation?
- Overlapping toxicity (e.g., pneumonitis, skin reactions)
- Increased risk of organ damage
220
What is tumor lysis syndrome and which targeted agents can cause it?
- Rapid cell death → electrolyte imbalances
- Seen with venetoclax, BTK inhibitors
221
How is tumor lysis syndrome managed?
- Hydration
- Allopurinol or rasburicase
- Monitor electrolytes and renal function
222
What is cytokine release syndrome (CRS)?
- Immune overactivation causing fever, hypotension, organ dysfunction
- Seen with CAR-T and some bispecific antibodies
223
What are signs and management of CRS?
- Signs: fever, hypoxia, hypotension
- Management: hold drug, give tocilizumab, steroids if needed
224
What is the importance of patient education in targeted therapy?
- Encourages adherence
- Helps recognize early toxicity
- Improves outcomes and safety
225
What counseling is needed regarding contraception in targeted therapy?
- Use effective contraception during and after therapy
- Some drugs are teratogenic (e.g., lenvatinib, palbociclib)
226
What are financial barriers to targeted therapy use?
- High cost
- Insurance approval delays
- Need for financial navigation and assistance
227
How can pharmacists support targeted therapy adherence?
- Medication synchronization
- Side effect counseling
- Refill reminders
228
What is the pharmacist's role in managing DDIs in targeted therapy?
- Review CYP interactions
- Adjust doses or recommend alternatives
- Educate on timing with acid suppressants
229
What should be monitored monthly with many oral TKIs?
- CBC
- LFTs
- Renal function
- ECG (for QTc-risk agents)
230
What tools can be used to manage targeted therapy side effects?
- Symptom diaries
- Digital adherence tools
- Structured toxicity checklists
231
What resource provides guidelines on targeted therapies?
- NCCN (National Comprehensive Cancer Network)
232
What are key toxicities of MMAE-containing ADCs?
- Neuropathy
- Neutropenia
- Fatigue
233
What is the difference between Trop-2 expression and HER2-low status?
- Trop-2: surface glycoprotein overexpressed in many epithelial cancers
- HER2-low: IHC 1+ or 2+ with negative ISH; eligible for certain HER2 ADCs
234
Why is HER2-low considered a new therapeutic category?
- Opens ADC use to a broader population
- Represents a paradigm shift in HER2 targeting
235
What is the 'bystander effect' in ADCs?
- Payload diffuses to nearby cells
- Kills both target-positive and adjacent target-negative cells
236
What type of linker affects the bystander effect in ADCs?
- Cleavable linkers enable diffusion
- Non-cleavable restrict to target cell only
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What are examples of non-cleavable ADCs?
- Trastuzumab emtansine (T-DM1)
238
What are examples of cleavable ADCs?
- Trastuzumab deruxtecan
- Sacituzumab govitecan
239
What is the purpose of linker technology in ADCs?
- Controls drug release
- Impacts efficacy and toxicity profile
240
What are challenges in ADC development?
- Target selection
- Toxicity management
- Drug stability and delivery
241
What class of drug is enfortumab vedotin?
- ADC targeting Nectin-4
- Approved for bladder cancer
242
What toxicity is unique to enfortumab vedotin?
- Rash (including SJS)
- Hyperglycemia
243
What are two common ADC payload classes?
- Microtubule inhibitors (e.g., MMAE)
- Topoisomerase I inhibitors (e.g., deruxtecan)
244
Why is close monitoring needed with ADCs in lung disease?
- Risk of ILD, especially with HER2-targeted ADCs
245
What is the function of Trop-2 in cancer biology?
- Promotes tumor growth, migration, and survival
- Overexpressed in many epithelial tumors
246
What patient population benefits from Trop-2 targeting?
- Triple-negative and HR+/HER2– breast cancer
- Urothelial carcinoma
247
Why is infusion reaction prophylaxis used with some ADCs?
- Premedication reduces risk of reactions (e.g., steroids, antihistamines)
248
What is a best practice for ADC dosing and safety?
- Monitor for organ dysfunction
- Educate on delayed toxicities
- Adjust for renal/hepatic function if applicable
249
What are bispecific antibodies in oncology?
- Engineered antibodies with two binding domains
- Bind both a tumor antigen and an immune effector (e.g., CD3 on T-cells)
250
What is the mechanism of bispecific T-cell engagers (BiTEs)?
- Bring T-cells into close proximity to tumor cells
- Trigger T-cell–mediated killing independent of MHC
251
Name a bispecific antibody approved in hematologic malignancies.
- Blinatumomab (CD19/CD3) for B-ALL
252
What is teclistamab and its target?
- Bispecific antibody for multiple myeloma
- Targets BCMA on myeloma cells and CD3 on T-cells
253
What is the major adverse effect of bispecific T-cell engagers?
- Cytokine release syndrome (CRS)
254
What is immune resistance in cancer?
- Tumor evasion of immune detection or destruction
- Involves antigen loss, immune checkpoint upregulation, TME changes
255
What role do targeted therapies play in modulating the immune microenvironment?
- May increase tumor immunogenicity
- Alter cytokine signaling and T-cell infiltration
256
How can VEGF inhibitors affect the immune environment?
- Reduce immunosuppressive cells
- Promote T-cell infiltration
257
What are examples of synergistic combinations of targeted and immunotherapy?
- Atezolizumab + bevacizumab in HCC
- Lenvatinib + pembrolizumab in endometrial cancer
258
What is the rationale for combining VEGF blockade with PD-1/PD-L1 inhibitors?
- VEGF inhibition normalizes vasculature and TME
- Enhances immune cell access and function
259
What are mechanisms of resistance to immune checkpoint inhibitors?
- Loss of tumor antigen presentation (e.g., B2M loss)
- Upregulation of alternate checkpoints (e.g., TIM-3, LAG-3)
- Immunosuppressive TME
260
What targeted therapy combinations are being explored with immunotherapy?
- MEK inhibitors + anti-PD-1
- PARP inhibitors + anti-PD-L1
- VEGF TKIs + immune checkpoint inhibitors
261
What is the impact of MEK inhibitors on the immune response?
- May enhance antigen presentation
- Reduce regulatory T cells
- Can improve response to immunotherapy
262
What are limitations of combining targeted therapy and immunotherapy?
- Increased toxicity
- Limited benefit in some tumor types
- Need for biomarker selection
263
What is the mechanism of lenvatinib + pembrolizumab synergy?
- Lenvatinib inhibits VEGFR, FGFR → alters TME
- Enhances T-cell activity of pembrolizumab
264
In what cancer is the combo of atezolizumab + bevacizumab approved?
- Unresectable hepatocellular carcinoma (HCC)
265
What is the IMbrave150 trial?
- Study supporting atezolizumab + bevacizumab in HCC
- Showed OS and PFS benefit
266
What is the clinical significance of LAG-3?
- Alternate immune checkpoint
- Targeted by relatlimab in melanoma
267
What is the significance of tumor mutational burden (TMB)?
- Higher TMB → more neoantigens → increased immunotherapy response
268
What defines microsatellite instability-high (MSI-H) tumors?
- Defective DNA mismatch repair
- Predictive of immunotherapy benefit
269
Which solid tumors are routinely tested for MSI-H?
- Colorectal
- Endometrial
- Gastric
- Prostate
270
What is the relationship between DDR mutations and immune response?
- DDR mutations increase genomic instability → more neoantigens → enhanced immune response
271
Which drug classes may induce immunogenic cell death?
- PARP inhibitors
- Some chemotherapy agents
- Radiation
272
What is the role of dendritic cells in immune activation?
- Present antigens to T-cells
- Critical for priming effective antitumor immunity
273
What is the significance of the tumor microenvironment (TME)?
- Influences immune cell function, drug access, resistance
- Can be immunosuppressive or immunostimulatory
274
What are hot vs. cold tumors?
- Hot: inflamed, T-cell infiltrated, immunotherapy-responsive
- Cold: non-inflamed, poor immune response, low PD-L1
275
How can targeted therapies turn cold tumors hot?
- Enhance antigen presentation
- Normalize vasculature
- Reduce Tregs and MDSCs
276
What is the function of MDSCs in cancer?
- Suppress T-cell activity
- Promote tumor growth and immune evasion
277
What is the rationale for combining PI3K inhibition and immunotherapy?
- PI3K pathway involved in Treg survival
- Inhibition may promote antitumor immunity
278
What cancer types commonly use PD-L1 testing for treatment decisions?
- NSCLC
- Bladder cancer
- Triple-negative breast cancer
279
What does a Combined Positive Score (CPS) measure?
- PD-L1 expression on tumor and immune cells
- Used for selecting anti-PD-1/PD-L1 therapy
280
What is the role of interferon-gamma in immune activation?
- Increases MHC expression
- Promotes antigen presentation and T-cell recruitment
281
What is the tumor immune cycle?
- Antigen release → presentation → T-cell activation → trafficking → tumor killing → repeat
282
What checkpoint inhibitors target PD-1?
- Nivolumab
- Pembrolizumab
283
What checkpoint inhibitors target PD-L1?
- Atezolizumab
- Durvalumab
- Avelumab
284
What is the function of CTLA-4 in immune regulation?
- Inhibits early T-cell activation in lymph nodes
285
What is ipilimumab’s mechanism of action?
- CTLA-4 inhibitor
- Promotes T-cell priming and expansion
286
What is the significance of dual checkpoint blockade?
- Targets both priming and effector phases of immunity
- Increases response but also toxicity
287
What are common irAEs (immune-related adverse events)?
- Colitis
- Pneumonitis
- Hepatitis
- Endocrinopathies
288
How are irAEs managed?
- Corticosteroids
- Hold or discontinue immunotherapy
- Endocrine replacement if needed
289
How does immunotherapy differ from targeted therapy in onset of action?
- Immunotherapy may take weeks to months
- Targeted therapy usually has rapid onset
290
What is pseudoprogression?
- Apparent tumor growth on imaging due to immune infiltration
- Follow-up imaging may show regression
291
How is pseudoprogression managed?
- Monitor symptoms
- Continue therapy unless clinical deterioration
292
What are key considerations when sequencing immunotherapy and targeted therapy?
- Monitor overlapping toxicities
- Time interval between treatments may be necessary
293
Why must caution be used combining BRAF/MEK and immunotherapy?
- Risk of hepatotoxicity
- Possible additive immune toxicity
294
What is the significance of CD8+ TILs in tumor prognosis?
- High CD8+ TILs correlate with better response to immunotherapy
295
What is the role of LAG-3 in immune suppression?
- Inhibitory receptor on T-cells
- New target for immunotherapy
296
What is relatlimab and how is it used?
- LAG-3 inhibitor
- Combined with nivolumab in melanoma
297
What is the primary challenge with bispecific antibodies?
- CRS and neurotoxicity
- Complex administration and monitoring
298
What is the future direction of immuno-targeted therapy combinations?
- Biomarker-driven selection
- Triple therapies
- Personalized TME modulation
