Chapter 34 — Anti-Cancer Drugs Part 2 — Module 3 — Monoclonal Antibodies and Antibody-Drug Conjugates
1. A 54-year-old woman receiving trastuzumab deruxtecan (T-DXd) for HER2-positive (human epidermal growth factor receptor 2-positive) metastatic breast cancer develops a dry cough and progressive exertional dyspnea over two weeks. She is afebrile. Computed tomography of the chest shows bilateral ground-glass opacities without consolidation or effusion; infectious workup is unremarkable. She is symptomatic but able to perform self-care. What is the most appropriate next step?
A) Continue T-DXd at full dose and add an inhaled bronchodilator, attributing symptoms to deconditioning
B) Hold T-DXd and initiate systemic corticosteroids for presumed grade 2 interstitial lung disease (drug-induced pneumonitis), with close monitoring and resumption decisions based on recovery
C) Continue T-DXd unchanged and obtain a repeat scan in three months, since ground-glass opacities are always benign
D) Switch immediately to trastuzumab emtansine without evaluating the pulmonary findings
E) Begin empiric broad-spectrum antibiotics and continue T-DXd, since pneumonitis does not occur with this agent
ANSWER: B
Rationale:
Interstitial lung disease/pneumonitis is the most serious characteristic toxicity of T-DXd. New dyspnea with bilateral ground-glass opacities and a negative infectious workup in a patient on T-DXd should be treated as drug-induced pneumonitis. For symptomatic disease not limiting self-care (grade 2), the drug is held and systemic corticosteroids are initiated, with resumption guided by recovery; grade 3 or higher requires permanent discontinuation.
Option A: Option A is incorrect because continuing full-dose T-DXd in the face of probable pneumonitis risks progression to fatal lung injury.
Option C: Option C is incorrect because these opacities in this context are not benign and demand action.
Option D: Option D is incorrect because switching agents without evaluating and managing the pneumonitis is unsafe and premature.
Option E: Option E is incorrect because pneumonitis does occur with T-DXd and is not addressed by antibiotics alone.
2. A 61-year-old man with newly diagnosed metastatic colorectal cancer has molecular testing showing a KRAS (Kirsten rat sarcoma proto-oncogene) exon 2 codon 12 mutation. An oncology trainee proposes adding cetuximab (an anti-EGFR [epidermal growth factor receptor] antibody) to chemotherapy. What is the most appropriate response?
A) Proceed with cetuximab, because KRAS mutations enhance the response to anti-EGFR antibodies
B) Proceed with cetuximab but at a reduced dose to account for the mutation
C) Proceed with cetuximab only if the tumor is right-sided
D) Do not give cetuximab; any activating RAS mutation, including KRAS exon 2, constitutively activates downstream signaling and predicts lack of benefit, so anti-EGFR therapy would expose the patient to toxicity without efficacy and is a prescribing error in this setting
E) Order panitumumab instead, since fully human anti-EGFR antibodies retain efficacy despite RAS mutations
ANSWER: D
Rationale:
Anti-EGFR antibodies require wild-type RAS to be effective. An activating mutation such as KRAS exon 2 codon 12 constitutively activates the downstream RAS/MAPK pathway independent of the receptor, so EGFR blockade no longer suppresses signaling and the patient derives no benefit; prescribing an anti-EGFR antibody in this setting exposes the patient to rash, hypomagnesemia, and infusion reactions without efficacy and is a prescribing error.
Option A: Option A is incorrect because a RAS mutation predicts lack of benefit, not enhancement.
Option B: Option B is incorrect because no dose adjustment restores efficacy in RAS-mutant disease.
Option C: Option C is incorrect because right-sided location further reduces, rather than restores, anti-EGFR benefit.
Option E: Option E is incorrect because the RAS mutation predicts lack of benefit regardless of whether the anti-EGFR antibody is chimeric or fully human.
3. A 48-year-old woman with diffuse large B-cell lymphoma is to begin a rituximab (anti-CD20 [a B-cell surface antigen])-containing regimen. Pre-treatment serologies show hepatitis B surface antigen negative but hepatitis B core antibody positive, indicating prior resolved infection with possible occult viral persistence. Hepatitis B virus DNA is currently undetectable. What is the most appropriate management?
A) Initiate antiviral prophylaxis (entecavir or tenofovir) before or with rituximab, or institute close hepatitis B virus DNA monitoring, because B-cell depletion can reactivate occult hepatitis B even in surface-antigen-negative, core-antibody-positive patients
B) Proceed with rituximab and take no hepatitis B precautions, since the surface antigen is negative
C) Cancel rituximab permanently, since prior hepatitis B exposure is an absolute contraindication
D) Vaccinate against hepatitis B during rituximab therapy to prevent reactivation
E) Begin antiviral therapy only if the patient develops jaundice during treatment
ANSWER: A
Rationale:
B-cell depletion can trigger hepatitis B reactivation not only in surface-antigen-positive patients but also, at lower rates, in surface-antigen-negative/core-antibody-positive patients with occult infection. Such patients should receive antiviral prophylaxis (entecavir or tenofovir) or, per institutional protocol, undergo close hepatitis B virus DNA monitoring, started before or with rituximab.
Option B: Option B is incorrect because a negative surface antigen does not exclude reactivation risk in a core-antibody-positive patient.
Option C: Option C is incorrect because prior exposure is managed with prophylaxis or monitoring, not permanent cancellation.
Option D: Option D is incorrect because B-cell depletion abolishes vaccine responses, so vaccination during therapy is ineffective.
Option E: Option E is incorrect because waiting for jaundice means waiting for established, potentially fulminant reactivation; prophylaxis or monitoring must begin up front.
4. A 67-year-old man on daratumumab (an anti-CD38 [cyclic ADP-ribose hydrolase] antibody) for multiple myeloma develops symptomatic anemia requiring transfusion. The blood bank reports a pan-reactive antibody screen, and the technologist is concerned about masked alloantibodies. There is no clinical or laboratory evidence of hemolysis. What is the most appropriate course?
A) Withhold all transfusion indefinitely because compatible blood can never be found in a daratumumab-treated patient
B) Transfuse uncrossmatched type O-negative blood without informing the blood bank of the daratumumab exposure
C) Inform the blood bank that the patient is receiving daratumumab and use special techniques such as dithiothreitol treatment of reagent red cells to overcome the interference and detect true alloantibodies; in an emergency, provide least-incompatible units
D) Diagnose an acute hemolytic transfusion reaction and treat with high-dose corticosteroids before transfusing
E) Repeat ABO typing daily because daratumumab progressively changes the patient's blood group
ANSWER: C
Rationale:
Daratumumab binds CD38 on red blood cells, producing a pan-reactive false-positive indirect antiglobulin test that can mask clinically significant alloantibodies. The correct approach is to notify the blood bank of daratumumab exposure and use special techniques such as dithiothreitol treatment of reagent red cells to allow detection of true alloantibodies; if transfusion is emergent, least-incompatible units are provided.
Option A: Option A is incorrect because safe transfusion is achievable using the appropriate techniques.
Option B: Option B is incorrect because failing to inform the blood bank risks missing dangerous alloantibodies.
Option D: Option D is incorrect because the pan-reactivity is laboratory interference, not an acute hemolytic transfusion reaction.
Option E: Option E is incorrect because daratumumab does not alter the patient's ABO type; it interferes with the antibody screen.
5. A 59-year-old woman receiving adjuvant trastuzumab for HER2-positive (human epidermal growth factor receptor 2-positive) breast cancer had a baseline left ventricular ejection fraction (LVEF, the percentage of blood ejected from the left ventricle per beat) of 61 percent. Routine surveillance now shows an asymptomatic LVEF of 44 percent. This is her first qualifying decline. What is the most appropriate management?
A) Permanently discontinue trastuzumab now, because any LVEF below 50 percent is an absolute, irreversible endpoint
B) Hold trastuzumab and reassess LVEF after an interval (typically 4 to 8 weeks); because trastuzumab cardiotoxicity is largely reversible, reinitiation is appropriate in most cases after recovery, reserving permanent discontinuation for persistent decline after hold-and-reassess cycles
C) Continue trastuzumab at full dose, since asymptomatic LVEF changes never warrant action
D) Switch to an anthracycline to improve cardiac function
E) Add a second HER2-directed antibody to overcome the resistance implied by the LVEF drop
ANSWER: B
Rationale:
Trastuzumab is held for an LVEF below 50 percent or a decline of 16 or more percentage points; here the LVEF of 44 percent (a 17-point drop) meets the threshold. Because trastuzumab cardiotoxicity is largely reversible, the standard response is to hold the drug and reassess LVEF after roughly 4 to 8 weeks, reinitiating in most cases after recovery; permanent discontinuation is reserved for persistent decline after hold-and-reassess cycles.
Option A: Option A is incorrect because the first qualifying decline triggers hold and reassessment, not immediate permanent discontinuation, and the toxicity is usually reversible.
Option C: Option C is incorrect because an LVEF of 44 percent clearly meets the hold threshold and requires action.
Option D: Option D is incorrect because anthracyclines worsen, not improve, cardiac function.
Option E: Option E is incorrect because the LVEF decline reflects cardiotoxicity, not tumor resistance, and adding another agent does not address it.
6. A 63-year-old woman has hormone receptor-positive metastatic breast cancer that has progressed after endocrine therapy and one line of chemotherapy. Her tumor is HER2 (human epidermal growth factor receptor 2) immunohistochemistry 1+ (HER2-low), not meeting the historical threshold for HER2-positivity. A randomized trial established a new standard of care for exactly this HER2-low, previously HER2-negative population by showing superior progression-free and overall survival versus physician's choice chemotherapy. Which agent does that trial support for her?
A) Trastuzumab emtansine, on the basis of its activity in HER2-low disease
B) Cetuximab, an anti-EGFR antibody, for HER2-low breast cancer
C) Pertuzumab monotherapy for HER2-low disease
D) Bevacizumab plus chemotherapy as the HER2-low standard
E) Trastuzumab deruxtecan, whose high drug-to-antibody ratio and membrane-permeable, bystander-capable payload produce activity even at low HER2 expression, establishing it as standard of care in HER2-low breast cancer in the trial of T-DXd versus physician's choice chemotherapy
ANSWER: E
Rationale:
The relevant trial randomized patients with HER2-low breast cancer to trastuzumab deruxtecan versus physician's choice chemotherapy and demonstrated superior progression-free and overall survival, establishing T-DXd as standard of care in this newly defined population. Its high drug-to-antibody ratio and membrane-permeable, bystander-capable payload account for activity at low HER2 expression.
Option A: Option A is incorrect because trastuzumab emtansine, with its non-cleavable linker and membrane-impermeant metabolite, is not the agent that defined the HER2-low standard.
Option B: Option B is incorrect because cetuximab targets EGFR in colorectal and head and neck cancers, not HER2-low breast cancer.
Option C: Option C is incorrect because pertuzumab is used in combination for HER2-positive disease, not as HER2-low monotherapy.
Option D: Option D is incorrect because bevacizumab is not the HER2-low standard of care established by this trial.
7. A 66-year-old man with newly diagnosed metastatic non-small cell lung cancer is reviewed at tumor board. Pathology confirms squamous cell carcinoma with a centrally located cavitating mass. A team member proposes adding bevacizumab (an anti-VEGF [vascular endothelial growth factor] antibody) to platinum-based chemotherapy. What is the most appropriate response?
A) Do not add bevacizumab; squamous cell histology is a contraindication because of the risk of catastrophic pulmonary hemorrhage from tumor cavitation, and the pivotal trial excluded squamous histology for this reason
B) Add bevacizumab, since squamous histology is the preferred setting for anti-VEGF therapy
C) Add bevacizumab but reduce the dose to mitigate the bleeding risk in squamous tumors
D) Add bevacizumab only after the cavitating mass is irradiated, which eliminates the hemorrhage risk
E) Substitute an anti-EGFR antibody for bevacizumab, since both are interchangeable in squamous lung cancer
ANSWER: A
Rationale:
Bevacizumab is contraindicated in squamous cell non-small cell lung cancer because of the risk of catastrophic pulmonary hemorrhage from tumor cavitation; the pivotal trial excluded squamous histology precisely for this reason, and a central cavitating mass further heightens concern.
Option B: Option B is incorrect because squamous histology is the contraindicated, not preferred, setting.
Option C: Option C is incorrect because dose reduction does not make bevacizumab safe in squamous histology.
Option D: Option D is incorrect because irradiation does not reliably eliminate the cavitation-related hemorrhage risk and does not lift the contraindication.
Option E: Option E is incorrect because anti-EGFR antibodies and bevacizumab are not interchangeable and anti-EGFR antibodies are not indicated here.
8. A 57-year-old woman with metastatic triple-negative breast cancer receives her first cycle of sacituzumab govitecan (an antibody-drug conjugate whose payload is SN-38, the active metabolite of irinotecan). Within days she develops grade 4 neutropenia and severe diarrhea. Which explanation and management plan best fits this presentation?
A) The toxicity reflects an allergic reaction to the antibody component; future cycles need only added antihistamine pre-medication
B) The toxicity is unrelated to the payload and is most likely incidental viral gastroenteritis; continue full-dose therapy
C) Severe early neutropenia and diarrhea suggest impaired SN-38 detoxification; UGT1A1 (uridine diphosphate-glucuronosyltransferase 1A1) genotyping is warranted, and a UGT1A1*28/*28 result would explain reduced glucuronidation and SN-38 accumulation, prompting dose reduction, growth factor support, and intensified monitoring
D) The findings indicate interstitial lung disease from the payload and require corticosteroids
E) The presentation reflects tumor lysis syndrome and is managed with rasburicase rather than dose modification
ANSWER: C
Rationale:
SN-38 is detoxified by UGT1A1-mediated glucuronidation. Patients homozygous for UGT1A1*28 have reduced UGT1A1 activity, impairing SN-38 clearance and producing SN-38 accumulation that manifests as severe neutropenia and diarrhea. Early severe toxicity should prompt UGT1A1 genotyping; a UGT1A1*28/*28 result supports dose reduction, growth factor support for neutropenia, aggressive diarrhea management, and intensified monitoring.
Option A: Option A is incorrect because the picture is payload-mediated myelosuppression and diarrhea, not an antibody hypersensitivity reaction.
Option B: Option B is incorrect because the toxicity is characteristic of the SN-38 payload, not incidental, and continuing full dose would be unsafe.
Option D: Option D is incorrect because interstitial lung disease is the signature toxicity of the deruxtecan payload, not SN-38, and would not present as neutropenia and diarrhea.
Option E: Option E is incorrect because the findings are payload toxicity, not tumor lysis syndrome.
9. A 35-year-old man with classical Hodgkin lymphoma on brentuximab vedotin (an antibody-drug conjugate delivering monomethyl auristatin E, a microtubule polymerization inhibitor) reports progressive numbness and tingling in his feet that now interferes with buttoning his shirt. Examination confirms a length-dependent sensory neuropathy. Which explanation and management approach is most appropriate?
A) The symptoms reflect leptomeningeal disease and require intrathecal chemotherapy
B) The symptoms indicate an acute infusion reaction and call for corticosteroid pre-medication only
C) The symptoms are unrelated to the drug and warrant no change in therapy
D) The neuropathy results from monomethyl auristatin E disruption of axonal microtubule transport in dorsal root ganglion neurons; management uses graded dose modification (dose delay, reduction, or discontinuation) according to severity, analogous to managing bortezomib-induced neuropathy
E) The neuropathy reflects interstitial lung disease equivalent and should be treated with high-dose corticosteroids
ANSWER: D
Rationale:
Peripheral neuropathy is the dose-limiting toxicity of brentuximab vedotin, driven by monomethyl auristatin E disruption of axonal microtubule dynamics in dorsal root ganglion neurons. It is predominantly sensory and managed with graded dose modification—delay, reduction, or discontinuation—according to severity, paralleling management of bortezomib-induced neuropathy.
Option A: Option A is incorrect because a length-dependent sensory neuropathy on a microtubule-inhibitor conjugate is a drug toxicity, not leptomeningeal disease.
Option B: Option B is incorrect because progressive sensory neuropathy is not an acute infusion reaction.
Option C: Option C is incorrect because the neuropathy is drug-related and functionally limiting, requiring dose modification.
Option E: Option E is incorrect because peripheral neuropathy is not pulmonary toxicity and is not treated as interstitial lung disease.
10. A 60-year-old woman on bevacizumab (an anti-VEGF [vascular endothelial growth factor] antibody) for metastatic colorectal cancer received her last dose 10 days ago and is scheduled for elective ventral hernia repair in 4 days. The surgeon asks about timing. What is the most appropriate recommendation?
A) Proceed with surgery as scheduled, since 10 days off bevacizumab is adequate
B) Delay the elective surgery so that bevacizumab has been held for at least 28 days beforehand, because its anti-VEGF effect impairs wound healing and increases the risk of dehiscence and anastomotic leak, and its long half-life means the effect persists well beyond 10 days; bevacizumab should also not resume until at least 28 days after surgery with healing confirmed
C) Give one more dose of bevacizumab before surgery to support healing, then operate
D) Cancel the surgery permanently because bevacizumab makes all surgery impossible
E) Proceed with surgery and simply resume bevacizumab the next day, since perioperative timing does not matter
ANSWER: B
Rationale:
Bevacizumab impairs VEGF-dependent wound healing and increases the risk of dehiscence and anastomotic leak, and its half-life of roughly 20 days means the anti-angiogenic effect persists well beyond 10 days. Elective surgery should be timed so the drug has been held for at least 28 days beforehand, and it should not resume until at least 28 days afterward with healing confirmed; the procedure should therefore be delayed.
Option A: Option A is incorrect because 10 days is insufficient given the long half-life and the 28-day rule.
Option C: Option C is incorrect because additional bevacizumab worsens healing.
Option D: Option D is incorrect because surgery is feasible with appropriate timing, not permanently precluded.
Option E: Option E is incorrect because immediate post-operative resumption violates the 28-day post-operative hold and risks impaired healing.
11. A 52-year-old woman with newly diagnosed HER2-positive (human epidermal growth factor receptor 2-positive) metastatic breast cancer is to start first-line therapy. A landmark first-line trial established a regimen providing dual HER2 blockade at two distinct extracellular-domain epitopes combined with a taxane, improving outcomes over trastuzumab plus taxane alone. Which regimen does that trial support as first-line standard?
A) Trastuzumab emtansine monotherapy
B) Bevacizumab plus docetaxel
C) Cetuximab plus a taxane
D) Single-agent trastuzumab without a taxane
E) Pertuzumab plus trastuzumab plus docetaxel, in which pertuzumab (binding HER2 domain II to block dimerization) and trastuzumab (binding domain IV) provide dual HER2 blockade at distinct epitopes, the combination established as first-line standard in the pertuzumab first-line metastatic trial
ANSWER: E
Rationale:
The landmark first-line trial established pertuzumab plus trastuzumab plus docetaxel as standard first-line therapy for HER2-positive metastatic breast cancer. Pertuzumab binds HER2 domain II to block dimerization (particularly the HER2-HER3 heterodimer), while trastuzumab binds domain IV; together they deliver dual HER2 blockade at distinct epitopes, improving outcomes over trastuzumab plus taxane alone.
Option A: Option A is incorrect because trastuzumab emtansine monotherapy is used in later lines, not as this first-line dual-blockade standard.
Option B: Option B is incorrect because bevacizumab plus docetaxel does not provide HER2-directed therapy.
Option C: Option C is incorrect because cetuximab targets EGFR, not HER2, and is not used in breast cancer.
Option D: Option D is incorrect because single-agent trastuzumab without a taxane is not the dual-blockade first-line regimen described.
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