CONCEPTUAL SUMMARY

Epidemiology and Risk Factors: Lung cancer is the leading cause of cancer death worldwide. NSCLC accounts for ~85% of cases; SCLC ~15%. Primary risk factor is tobacco smoking. Other risk factors include radon exposure, asbestos, air pollution, and genetic predisposition. For mesothelioma: asbestos exposure (primary), radiation exposure, and family history are risk factors — tobacco use is NOT a risk factor for mesothelioma. β-carotene and selenium supplementation have NO preventive role and may actually INCREASE lung cancer risk in smokers (ATBC and CARET trials).

Lung Cancer Screening (NCCN/USPSTF): Annual low-dose CT (LDCT) — NOT chest X-ray — is the recommended screening modality. Eligible patients: age ≥ 50 years + ≥ 20 pack-year smoking history + current smoker or former smoker. Former smokers who quit remain eligible. Chest X-rays are NOT recommended as a screening strategy.

NSCLC Histology and Molecular Testing: EGFR mutations: ~10–15% of Caucasian NSCLC patients; ~30–40% in Asian patients. More common in never-smokers, women, adenocarcinoma histology. ALK rearrangements: ~3–7%; associated with younger, never-smoking patients with adenocarcinoma. KRAS G12C: common in smokers; targetable with sotorasib (second-line). All molecular testing (EGFR, ALK, ROS1, BRAF, KRAS, PD-L1) is mandatory for NSCLC adenocarcinoma before initiating treatment. EGFR prevalence in Caucasians: 10–15%.

NSCLC Histology-Driven Treatment Rules: Pemetrexed and bevacizumab: ONLY for nonsquamous (adenocarcinoma) histology. Bevacizumab is CONTRAINDICATED in squamous cell NSCLC due to severe pulmonary hemorrhage risk. Squamous NSCLC: carboplatin + paclitaxel or gemcitabine are preferred. Cisplatin requires CrCl ≥ 60 mL/min — do NOT give cisplatin if CrCl < 60 mL/min. Carboplatin is dosed via Calvert formula (AUC-based) and is preferred in renal impairment. Pemetrexed supplementation: vitamin B12 1000 mcg IM every 9 weeks + folic acid 350–1000 mcg PO daily — both started 1–2 weeks before first dose and continued 3 weeks after last dose.

NSCLC First-Line Treatment by Biomarker: EGFR mutation positive: osimertinib (preferred, Category 1); afatinib, erlotinib, gefitinib are other options. ALK positive: lorlatinib, alectinib, or brigatinib (preferred Category 1). Crizotinib is "other recommended." After progression on crizotinib → ceritinib or alectinib. After progression on 2nd-generation ALK inhibitor with brain metastases → lorlatinib (3rd-generation, CNS-penetrant). ROS1 positive: crizotinib or entrectinib (first-line). MET exon 14 skipping: capmatinib or tepotinib. KRAS G12C: sotorasib (second-line — CodeBreaK100 showed 37.1% ORR, not > 50%). Sotorasib: avoid concomitant proton pump inhibitors (reduces absorption). PD-L1 ≥ 50%, no driver mutation: pembrolizumab monotherapy (KEYNOTE-024) OR cemiplimab (EMPOWER-Lung 1) as single agents. PD-L1 1–49% or PD-L1 < 50%: platinum doublet + pembrolizumab. For nonsquamous: carboplatin + pemetrexed + pembrolizumab. For squamous: carboplatin + paclitaxel + pembrolizumab.

Adjuvant NSCLC Therapy: Stage II: cisplatin-based doublet chemotherapy (NOT carboplatin-based — carboplatin is for palliative/cisplatin-ineligible patients). Cisplatin + pemetrexed (nonsquamous) or cisplatin + vinorelbine/gemcitabine. After adjuvant chemo with PD-L1 ≥ 1%: atezolizumab for 1 year (IMpower010 — improved DFS). Osimertinib adjuvant: ONLY for EGFR exon 19 del or L858R positive patients. Nivolumab in combination with chemotherapy: only approved for NEOADJUVANT treatment — NOT adjuvant.

Neoadjuvant NSCLC: Nivolumab + cisplatin-based chemo is approved as neoadjuvant (pre-surgical) therapy.

SCLC Treatment: Limited-stage SCLC: cisplatin/carboplatin + etoposide + concurrent thoracic radiation × 4 cycles. Goal is potentially curative. Prophylactic cranial irradiation (PCI) for patients with complete/good response reduces brain mets risk. Extensive-stage SCLC (first-line, Category 1 preferred): carboplatin/cisplatin + etoposide + atezolizumab (IMpower133) OR carboplatin/cisplatin + etoposide + durvalumab (CASPIAN) → maintenance immunotherapy. Platinum-sensitive relapse (> 6 months since last platinum): rechallenge with platinum + etoposide. Platinum-refractory relapse (≤ 6 months): lurbinectedin 3.2 mg/m² IV day 1 every 21 days (FDA-approved, second-line) OR topotecan (monitor renal function — renally cleared). Topotecan IV dose is 1.5 mg/m² days 1–5 every 21 days; oral formulation has a different dose.

SIADH in SCLC: Hyponatremia (Na < 130) from SCLC-related SIADH often improves with successful chemotherapy — carboplatin is preferred over cisplatin in SIADH patients (less nephrotoxicity). Etoposide dose adjustment required for CrCl < 50 mL/min: reduce by 25%.

Durvalumab dosing: 1500 mg IV day 1 every 21 days with chemotherapy → then 1500 mg IV day 1 every 28 days for maintenance.

ALK TKI Toxicities: Lorlatinib: hyperlipidemia, CNS/mood effects. Alectinib: myalgias (> 29% incidence), peripheral edema, photosensitivity. Crizotinib: visual disturbances, bradycardia, QT prolongation, edema. Brigatinib: hypertension, early-onset pulmonary events. Acneiform rash is an EGFR TKI toxicity — NOT ALK TKI toxicity.

Immune Checkpoint Inhibitor Toxicities: Immune-related hypothyroidism (elevated TSH, low T4): HOLD immunotherapy until symptoms resolve + start levothyroxine + recheck TSH/T4 in 6 weeks. Steroids are NOT needed for isolated hypothyroidism (only for severe endocrinopathies like adrenal crisis). Grade ≥ 2 pneumonitis: hold immunotherapy + corticosteroids.

Amivantamab (EGFR exon 20 insertion): Premedication — dexamethasone + diphenhydramine + acetaminophen before all infusions. Montelukast and famotidine are NOT required. Infusion reactions occur in ~2/3 of patients, especially with the first infusion.

Amifostine (cytoprotectant with cisplatin): Dose: 910 mg/m² IV over 15 minutes (NOT 30 minutes). Stop infusion if SBP decreases significantly (e.g., baseline 135 → 100 after 5 min). Monitor BP every 5 minutes during infusion (NOT 20 minutes after).

Pleural Effusion Management: Initial management: thoracentesis (drain the fluid). Chest tube and pleurodesis are reserved based on rate and volume of fluid re-accumulation.

Mesothelioma: First-line treatment for unresectable/metastatic malignant mesothelioma: nivolumab + ipilimumab (CheckMate 743 — improved OS vs chemotherapy, particularly in non-epithelioid/sarcomatoid histology). Chemotherapy (cisplatin/carboplatin + pemetrexed) remains an option but is inferior to immunotherapy combination. Tobacco use is NOT a risk factor for mesothelioma.

Maintenance Therapy NSCLC: Squamous NSCLC maintenance options: pembrolizumab, gemcitabine, or docetaxel (ALL are NCCN-recommended). Nonsquamous NSCLC maintenance: pemetrexed ± immunotherapy.

NCCN Guidelines: The gold-standard, continuously updated resource for cancer treatment recommendations (www.NCCN.org).

MD is a 66-year-old retired schoolteacher who started smoking at age 14 and quit at age 64. She smoked approximately 1 pack per day. Is MD a candidate for lung cancer screening?

A. Yes, she is a candidate for an annual chest X-ray
B. Yes, she is a candidate for an annual chest CT
C. No, she stopped smoking two years ago
D. No, because she smoked < 2 packs per day

[expand] Answer: B. Yes, she is a candidate for an annual chest CT

Explanation: MD meets NCCN and USPSTF criteria for annual low-dose CT lung cancer screening — she is 66 years old (≥ 50 years) with a 50 pack-year smoking history (≥ 20 pack-years required). Former smokers who have quit remain eligible for screening regardless of cessation date — quitting reduces cancer risk over time but does not eliminate eligibility. Chest X-ray (option A) is NOT recommended as a lung cancer screening strategy — it lacks sensitivity for early detection. Option C is incorrect — quitting smoking does not eliminate screening eligibility. Option D is incorrect — the threshold is ≥ 20 pack-years, not ≥ 2 packs per day.

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HN is a 62-year-old man with extensive-stage SCLC (innumerable liver metastases, cervical and thoracic lymphadenopathy). Labs: Na 126 (SIADH). CrCl via Cockcroft-Gault is adequate. ECOG 1. Which treatment option is most appropriate for HN at this time?

1. Carboplatin AUC 5 + etoposide 100 mg/m² days 1–3 every 21 days × 4–6 cycles
2. Carboplatin AUC 5 + etoposide 100 mg/m² days 1–3 + durvalumab 1500 mg day 1 every 28 days × 4 cycles → durvalumab maintenance
3. Cisplatin 75 mg/m² + etoposide 120 mg/m² days 1–3 every 21 days × 4 cycles with radiation (70 Gy)
4. Carboplatin AUC 5 + etoposide 100 mg/m² days 1–3 + atezolizumab 1200 mg day 1 every 21 days × 4 cycles → atezolizumab maintenance every 21 days

[expand] Answer: D. Carboplatin AUC 5 + etoposide 100 mg/m² days 1–3 + atezolizumab 1200 mg day 1 every 21 days × 4 cycles → atezolizumab maintenance every 21 days

Explanation: HN has extensive-stage SCLC — the Category 1 preferred first-line regimen is carboplatin + etoposide + atezolizumab (IMpower133) or carboplatin + etoposide + durvalumab (CASPIAN), followed by immunotherapy maintenance. Carboplatin is preferred over cisplatin given his SIADH (hyponatremia) — cisplatin's nephrotoxicity and electrolyte-wasting effects would worsen SIADH management. Cisplatin + etoposide + thoracic radiation (option C) is for LIMITED-STAGE SCLC — HN has extensive-stage disease. Chemo alone without immunotherapy (option A) is no longer the preferred Category 1 regimen. Option B has incorrect scheduling — durvalumab should be given every 21 days with chemotherapy (not every 28 days with chemo), then every 28 days for maintenance.

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HN completed 4 cycles of carboplatin + etoposide + atezolizumab, achieved stable disease, and proceeded with atezolizumab maintenance. He progressed at 10 months on maintenance therapy with disease recurrence in the chest. What is the appropriate treatment regimen for HN?

A. Carboplatin AUC 5 + etoposide 100 mg/m² days 1–3 every 21 days
B. Irinotecan 60 mg/m² IV days 1, 8, 15 every 21 days
C. Cisplatin 30 mg/m² days 1, 8 + irinotecan 65 mg/m² days 1, 8 every 21 days
D. Carboplatin AUC 5 + etoposide 100 mg/m² days 1–3 + durvalumab 1500 mg every 21 days

[expand] Answer: A. Carboplatin AUC 5 + etoposide 100 mg/m² days 1–3 every 21 days

Explanation: HN progressed 10 months after completing initial platinum-based chemotherapy — this is PLATINUM-SENSITIVE relapse (> 6 months from last platinum). For platinum-sensitive SCLC relapse, rechallenging with the same platinum doublet (carboplatin + etoposide) is the appropriate approach. Since HN progressed on atezolizumab maintenance, switching to a different immunotherapy (durvalumab — option D) is not supported by evidence — no data supports switching immunotherapy agents at progression on maintenance IO. Irinotecan-based options (B and C) are less preferred when platinum-sensitive disease allows rechallenge with the proven prior regimen.

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HN completed 4 cycles of carboplatin + etoposide re-challenge with partial response, then underwent active surveillance. One month later, he developed disease progression within the chest and liver. ECOG 1–2. What is the most appropriate treatment option for HN's recurrent SCLC?

A. Lurbinectedin 3.2 mg/m² IV day 1 every 21 days
B. Carboplatin AUC 5 + irinotecan 50 mg/m² days 1, 8, and 15 every 21 days
C. Etoposide 200 mg/m² PO days 1–3 every 21 days
D. Topotecan 1.5 mg/m² PO days 1–5 every 21 days

[expand] Answer: A. Lurbinectedin 3.2 mg/m² IV day 1 every 21 days

Explanation: HN has now received two lines of platinum-based therapy and has rapid progression — his disease is PLATINUM-RESISTANT. Lurbinectedin is FDA-approved for relapsed/refractory SCLC and is appropriate here. Monitoring includes CBC before each cycle (ANC ≥ 1,500 and platelets ≥ 100,000 required) and close LFT monitoring given baseline liver disease. Options B and C are incorrect — a second platinum rechallenge is inappropriate after two platinum exposures with progressive disease. Option C is also incorrect because etoposide should not be continued after multiple prior exposures when switching to a different active agent is more appropriate. Option D uses the IV topotecan dose (1.5 mg/m²) — if oral topotecan were intended, the dose would be different; additionally, topotecan is for platinum-resistant/refractory disease but lurbinectedin is preferred in this clinical scenario.

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SJ is a 72-year-old man with extensive-stage SCLC and SIADH (Na 126). CrCl = 45 mL/min (Cockcroft-Gault). ECOG 1. Wt 72 kg, Ht 165 cm. Which treatment option is most appropriate for SJ?

1. Cisplatin 75 mg/m² + etoposide 120 mg/m² days 1–3
2. Cisplatin 75 mg/m² + etoposide 100 mg/m² days 1–3 every 21 days × 4–6 cycles
3. Carboplatin AUC 5 + etoposide 100 mg/m² days 1–3 + durvalumab 1500 mg day 1 every 28 days × 4 cycles → durvalumab maintenance
4. Carboplatin AUC 5 + etoposide 75 mg/m² days 1–3 + atezolizumab 1200 mg day 1 every 21 days × 4 cycles → atezolizumab maintenance

[expand] Answer: D. Carboplatin AUC 5 + etoposide 75 mg/m² days 1–3 + atezolizumab 1200 mg day 1 every 21 days × 4 cycles → atezolizumab maintenance

Explanation: SJ has CrCl = 45 mL/min — cisplatin is CONTRAINDICATED (requires CrCl ≥ 60 mL/min), eliminating options A and B. Carboplatin is the appropriate platinum choice. Given CrCl < 50 mL/min, etoposide requires a 25% dose reduction: 100 mg/m² × 75% = 75 mg/m². The Category 1 preferred regimen for extensive-stage SCLC is carboplatin + etoposide + atezolizumab every 21 days → atezolizumab maintenance. Option C has incorrect scheduling — durvalumab should be given every 21 days WITH chemotherapy (not every 28 days during chemo); the every-28-day schedule is for the maintenance phase only. Option D correctly uses dose-adjusted etoposide and the correct atezolizumab schedule.

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SJ had stable disease after 4 cycles of chemoimmunotherapy → atezolizumab maintenance. He developed pneumonitis after cycle 6 of atezolizumab and immunotherapy was held. Four months after stopping immunotherapy, routine CT shows stable systemic disease but he has balance issues and daily headaches. Brain MRI reveals 4 lesions with localized edema. What is the most appropriate treatment for SJ at this time?

A. Refer to radiation oncology for possible stereotactic brain radiation and start etoposide
B. Refer to radiation oncology for possible stereotactic brain radiation
C. Lurbinectedin
D. Carboplatin, etoposide, and durvalumab

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Answer: B. Refer to radiation oncology for possible stereotactic brain radiation

Explanation: SJ has ISOLATED brain progression (symptomatic brain metastases) with stable systemic (chest/liver) disease. The appropriate treatment is targeted radiation (stereotactic radiosurgery) for the brain lesions — not systemic therapy at this time. Adding etoposide chemotherapy (option A) is not recommended when progression is localized to the brain without systemic progression. Lurbinectedin (option C) was studied in patients WITHOUT brain metastases and disease relapse ≤ 6 months — SJ has stable systemic disease beyond 6 months, making lurbinectedin inappropriate here. Restarting chemoimmunotherapy (option D) is not recommended when only brain progression is present AND given the prior grade 3 pneumonitis from immunotherapy, resuming immunotherapy carries significant risk.

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SJ completed stereotactic radiation to 4 brain lesions and 3 months later develops disease progression in the chest and liver. ECOG 1. What is the most appropriate treatment option?

A. Pembrolizumab 400 mg IV day 1 every 28 days
B. Carboplatin AUC 5 + etoposide 80 mg/m² days 1–3 every 21 days × 4 cycles
C. Lurbinectedin 3.2 mg/m² IV day 1 every 21 days
D. Topotecan 1.5 mg/m² PO days 1–5 every 21 days

[expand]Answer: B. Carboplatin AUC 5 + etoposide 80 mg/m² days 1–3 every 21 days × 4 cycles

Explanation: SJ's systemic progression occurs approximately 10+ months after his initial platinum-based chemotherapy — he has PLATINUM-SENSITIVE disease. With good performance status and no contraindications, rechallenging with carboplatin + etoposide is preferred. Etoposide is dose-adjusted to 80 mg/m² given his renal impairment (CrCl ~45 mL/min). Pembrolizumab (option A) — the dose/schedule listed is incorrect (should be 200 mg every 21 days or 400 mg every 42 days, not every 28 days); additionally, extreme caution is warranted with immunotherapy after prior grade 3 pneumonitis. Lurbinectedin (option C) would be appropriate for platinum-resistant/refractory relapse — but SJ's disease is platinum-sensitive with > 6 months response. Topotecan (option D) — the dose listed (1.5 mg/m²) is for the IV route, not the oral route; topotecan is used for platinum-resistant disease, which SJ does not have.

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FS is a 48-year-old woman with stage IIA (T1bN1M0) NSCLC, adenocarcinoma histology. All driver mutations are negative. She undergoes curative-intent resection. Which adjuvant treatment regimen would be most appropriate for FS?

A. Observation
B. Pembrolizumab
C. Cisplatin and pemetrexed
D. Carboplatin and paclitaxel

[expand]Answer: C. Cisplatin and pemetrexed

Explanation: Stage IIA NSCLC after complete surgical resection requires adjuvant chemotherapy — observation alone (option A) is insufficient for this stage. Adjuvant chemotherapy for resected Stage II NSCLC must be CISPLATIN-based — carboplatin-based doublets (option D) are appropriate only in the palliative/metastatic setting or for cisplatin-ineligible patients. Pemetrexed is the appropriate partner for nonsquamous (adenocarcinoma) histology. Pembrolizumab (option B) as single-agent immunotherapy in early-stage disease is not recommended in this adjuvant setting based on current guidelines; atezolizumab is the approved immunotherapy adjuvant agent (after chemotherapy completion, for PD-L1 ≥ 1%).

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EM is a 58-year-old woman with stage IIA (T1bN1M0) NSCLC, adenocarcinoma. EGFR negative, ALK negative, PD-L1 = 50%. She undergoes curative-intent resection. Which adjuvant treatment regimen would be most appropriate?

A. Osimertinib × 3 years
B. Nivolumab + cisplatin + pemetrexed × 3 cycles
C. Cisplatin + pemetrexed × 4 cycles followed by atezolizumab × 1 year
D. Carboplatin + paclitaxel × 4 cycles

[expand] Answer: C. Cisplatin + pemetrexed × 4 cycles followed by atezolizumab × 1 year

Explanation: EM is EGFR-negative — osimertinib (option A) is only approved adjuvantly for EGFR exon 19del or L858R positive patients. Nivolumab + chemo (option B) is approved for NEOADJUVANT (pre-surgical) treatment — not adjuvant (post-surgical) treatment. Carboplatin (option D) is not preferred for adjuvant therapy — cisplatin-based doublets are the standard. EM has PD-L1 ≥ 1% (50%), qualifying her for adjuvant atezolizumab after completing cisplatin + pemetrexed × 4 cycles, based on IMpower010 demonstrating improved disease-free survival in this population.

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FS developed recurrent metastatic NSCLC (bone and lung metastases) after adjuvant cisplatin + pemetrexed. Repeat biopsy: adenocarcinoma, EGFR negative, ALK negative, PD-L1 80%. What is the most appropriate next line of treatment for FS?

A. Pembrolizumab
B. Pemetrexed
C. Nivolumab
D. Docetaxel

[expand] Answer: A. Pembrolizumab

Explanation: FS has recurrent metastatic NSCLC with no driver mutations and PD-L1 > 50%. Based on KEYNOTE-024, single-agent pembrolizumab is the appropriate first-line treatment for metastatic NSCLC with PD-L1 ≥ 50% in patients without prior immunotherapy. Pemetrexed (option B) was used in her prior adjuvant setting — it is not appropriate in the second-line setting after progression on pemetrexed. Nivolumab (option C) is NOT approved as first-line single-agent therapy for newly metastatic NSCLC patients who have not previously received immunotherapy. Docetaxel (option D) is typically a second-line option after prior chemotherapy and immunotherapy failure — immunotherapy has superior outcomes when available.

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FS developed a new pleural effusion while on pembrolizumab. What plan would you recommend for FS?

A. Drain the fluid (thoracentesis)
B. Placement of chest tube on wall suction
C. Place a small pigtail catheter in the chest wall
D. Pleurodesis with doxycycline

[expand] Answer: A. Drain the fluid (thoracentesis)

Explanation: Thoracentesis is the appropriate INITIAL management for a new malignant pleural effusion — it provides both diagnostic information (cytology, chemistry, culture) and symptomatic relief. The need for a chest tube (option B), pigtail catheter (option C), or pleurodesis (option D) is determined by the rate and volume of fluid re-accumulation after the initial therapeutic tap. These more invasive procedures are reserved for recurrent or rapidly accumulating effusions requiring ongoing drainage or definitive management.

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DG is a 73-year-old female never-smoker with a large spiculated right upper lobe mass on CT — biopsy confirms NSCLC adenocarcinoma. Which mutation is most likely associated with DG's cancer and what is the most appropriate first-line treatment?

A. EGFR: Afatinib
B. ROS-1: Alectinib
C. ROS-1: Capmatinib
D. EGFR: Osimertinib

[expand] Answer: D. EGFR: Osimertinib

Explanation: DG is a 73-year-old female never-smoker — EGFR mutation is the most likely driver mutation in this demographic (common in older women, never-smokers with adenocarcinoma). EGFR first-line PREFERRED therapy is osimertinib (3rd-generation EGFR TKI) — Category 1 recommendation per NCCN. Afatinib (option A) is listed as "other recommended" for EGFR-positive disease — not the preferred option. ALK and ROS1 rearrangements do occur in never-smokers but are more common in younger patients; ROS1 first-line is crizotinib or entrectinib — not lorlatinib or alectinib (option B is incorrect ROS1 pairing). Capmatinib (option C) is for MET exon 14 skipping mutations — not ROS1.

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DM is a 37-year-old female never-smoker with metastatic NSCLC adenocarcinoma. EGFR negative, ALK rearrangement POSITIVE, RET negative, MET14 skipping negative, PD-L1 55%. Which is the most appropriate first-line treatment and is matched with the correct adverse effect?

A. Lorlatinib: Acneiform rash
B. Crizotinib: Bradycardia
C. Alectinib: Myalgias
D. Brigatinib: Mood disorder

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Answer: C. Alectinib: Myalgias

Explanation: For ALK-positive metastatic NSCLC, the Category 1 preferred first-line agents are lorlatinib, alectinib, or brigatinib. Alectinib causes myalgias in > 29% of patients — this is a characteristic and correctly matched adverse effect. Lorlatinib (option A) — acneiform rash is an EGFR TKI toxicity, NOT lorlatinib or ALK TKI toxicity; lorlatinib's key toxicities are hyperlipidemia and CNS/mood effects. Crizotinib (option B) — while bradycardia IS a warning/precaution for crizotinib, it would not be the preferred first-line choice when preferred Category 1 agents (alectinib, brigatinib, lorlatinib) are available. Brigatinib (option D) — mood disorder is incorrectly paired; lorlatinib carries the CNS/mood effects warning, not brigatinib.

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SW is a 65-year-old male with newly diagnosed Stage IV squamous NSCLC. EGFR negative, ALK negative, KRAS G12C positive, PD-L1 88%. What is the most appropriate treatment for SW at this time?

A. Cemiplimab
B. Carboplatin + pemetrexed + pembrolizumab + bevacizumab
C. Carboplatin + nab-paclitaxel + atezolizumab
D. Sotorasib

[expand] Answer: A. Cemiplimab

Explanation: SW has squamous NSCLC with no first-line targetable mutations and PD-L1 ≥ 50% (88%). Based on EMPOWER-Lung 1, single-agent cemiplimab is approved for first-line treatment of metastatic NSCLC with PD-L1 ≥ 50%. Option B is incorrect for two reasons: pemetrexed is contraindicated in squamous histology, and bevacizumab is CONTRAINDICATED in squamous NSCLC due to risk of fatal pulmonary hemorrhage. Option C (carboplatin + nab-paclitaxel + atezolizumab) is not an approved combination. Sotorasib (option D) is approved for KRAS G12C-mutated NSCLC but only in the SECOND-LINE setting after prior therapy — not first-line.

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SW progressed after 9 months of cemiplimab, was started on sotorasib, and developed severe diarrhea requiring two dose reductions. He stopped treatment and progressed 3 months later. What treatment would be most appropriate to recommend at this time?

A. Pembrolizumab
B. Nivolumab + ipilimumab
C. Docetaxel + ramucirumab
D. Carboplatin + etoposide

[expand] Answer: C. Docetaxel + ramucirumab

Explanation: SW has received two lines of prior therapy (immunotherapy, then sotorasib). Returning to immunotherapy (options A and B) after prior IO progression is not generally recommended. Carboplatin + etoposide (option D) is a SCLC regimen — not appropriate for recurrent NSCLC. Docetaxel + ramucirumab (anti-VEGFR2) is a guideline-supported second/third-line option for NSCLC, studied in both squamous and nonsquamous histologies (REVEL trial showed improved OS and PFS). Ramucirumab was avoided in first-line; now it is appropriate in this setting with docetaxel.

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SW received single-agent cemiplimab and returned with a new pleural effusion. What plan would you recommend?

A. Drain the fluid
B. Placement of chest tube on wall suction
C. Place a small pigtail catheter in the chest wall
D. Pleurodesis with doxycycline

[expand] Answer: A. Drain the fluid

Explanation: Initial management of a malignant pleural effusion is thoracentesis (drain the fluid). This provides symptom relief and diagnostic information. The need for chest tube placement, pigtail catheter, or pleurodesis is determined by rate and volume of re-accumulation after the initial drainage. These interventions are not the first-line approach for an initial effusion.

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JR has EGFR exon 20 insertion mutation-positive NSCLC and is starting amivantamab today (cycle 1 day 1). The infusion nurse asks about premedication. Which premedication is most appropriate for JR?

A. No premedication required
B. Dexamethasone, famotidine, diphenhydramine, and montelukast
C. Dexamethasone, diphenhydramine, and acetaminophen
D. Acetaminophen and diphenhydramine

[expand] Answer: C. Dexamethasone, diphenhydramine, and acetaminophen

Explanation: Amivantamab commonly causes infusion-related reactions (IRRs) — occurring in approximately 2/3 of patients, particularly with the first infusion. Per package labeling: acetaminophen + diphenhydramine are required before ALL amivantamab infusions. Glucocorticoids (dexamethasone) are required before week 1 day 1 and day 2 doses, and are optional (recommended) for subsequent infusions. Montelukast and famotidine (option B) are NOT required premedications for amivantamab. Acetaminophen + diphenhydramine alone (option D) omits the glucocorticoid required for cycle 1 day 1.

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AD is a 59-year-old female on pembrolizumab for NSCLC. She develops extreme fatigue, weakness, weight gain, hair loss, and constipation. TSH = 15 mIU/L, T4 = 5.1 mcg/dL. Which recommendation is most appropriate?

1. Hold pembrolizumab until symptoms return to baseline. Start levothyroxine and recheck TSH/T4 in 6 weeks
2. Hold pembrolizumab until symptoms return to baseline. Start levothyroxine + prednisone 50 mg/day, then recheck TSH/T4 in 6 weeks
3. Hold pembrolizumab until symptoms return to baseline. Start prednisone 50 mg/day, then recheck TSH/T4 in 6 weeks
4. Continue pembrolizumab at a reduced dose. Monitor TSH/T4 every 6 weeks

[expand] Answer: A. Hold pembrolizumab until symptoms return to baseline. Start levothyroxine and recheck TSH/T4 in 6 weeks

Explanation: AD has immune-related hypothyroidism — a common irAE with checkpoint inhibitors. Elevated TSH + low T4 with classic symptoms confirms this. Management: hold immunotherapy until symptoms resolve + start hormone replacement (levothyroxine) + recheck TSH/T4 in 6 weeks. High-dose corticosteroids (prednisone) are NOT indicated for isolated hypothyroidism — steroids are reserved for higher-grade endocrinopathies (e.g., adrenal crisis, severe hypophysitis). Hypothyroidism from immunotherapy is often permanent and requires ongoing levothyroxine — it is not treated with steroids. Dose reduction of immunotherapy (option D) is not standard practice for managing irAEs.

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Which of the following is correct regarding pemetrexed support?

1. Patient should receive vitamin B12 PO daily + leucovorin 15 mcg IV daily 3 weeks before treatment, continuing for 3 weeks after treatment
2. Patient should receive vitamin B12 IV/IM every 9 weeks + folic acid 350 mcg PO daily 3 weeks before treatment, continuing for 3 weeks after treatment
3. Patient should receive vitamin B12 IV/IM every 9 weeks starting 3 weeks before treatment, continuing for 3 weeks after treatment
4. Patient should receive folic acid 350 mcg PO daily 3 weeks before treatment, continuing for 3 weeks after treatment

[expand] Answer: B. Patient should receive vitamin B12 IV/IM every 9 weeks + folic acid 350 mcg PO daily 3 weeks before treatment, continuing for 3 weeks after treatment

Explanation: Pemetrexed is an antifolate that causes severe hematologic and GI toxicity without adequate vitamin supplementation. Mandatory premedication: Folic acid 350–1000 mcg PO daily beginning 1–2 weeks before first dose and continuing 3 weeks after last dose; Vitamin B12 1000 mcg IM every 9 weeks beginning 1–2 weeks before first dose. Option A is incorrect — leucovorin is NOT used as pemetrexed premedication. Option C omits folic acid. Option D omits vitamin B12.

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PN is a 55-year-old patient with Stage IIIB adenocarcinoma of the lung receiving cisplatin + pemetrexed + concurrent chemoradiation. Before his 2nd cycle, his CrCl is 50 mL/min. Which of the following is correct?

1. Give cisplatin at 75 mg/m² and pemetrexed at 500 mg/m²
2. Give cisplatin at 60 mg/m² and pemetrexed at 300 mg/m²
3. Give cisplatin at 37.5 mg/m² and pemetrexed at 500 mg/m²
4. Do not give cisplatin until CrCl ≥ 60 mL/min

[expand] Answer: D. Do not give cisplatin until CrCl ≥ 60 mL/min

Explanation: Cisplatin is contraindicated when CrCl < 60 mL/min due to high nephrotoxicity risk — administering it in renal impairment can cause permanent, severe kidney damage. The cisplatin must be HELD until renal function recovers to ≥ 60 mL/min, OR the regimen should be switched to carboplatin (dosed by AUC, less nephrotoxic). Options A, B, and C incorrectly suggest dose modifications to cisplatin below the CrCl threshold — dose reducing cisplatin does NOT adequately mitigate nephrotoxicity at this renal function level.

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Which of the following is correct regarding amifostine?

1. Use is encouraged with adjuvant cisplatin to maximize dose and efficacy
2. Dose is 910 mg/m² over 30 minutes, ≤ 30 minutes before cisplatin
3. Stop drug if baseline SBP is 135 and it decreased to 100 after 5 minutes of infusion
4. BP must be monitored 20 minutes after infusion

[expand] Answer: C. Stop drug if baseline SBP is 135 and it decreased to 100 after 5 minutes of infusion

Explanation: Amifostine is a cytoprotective agent used to reduce cisplatin nephrotoxicity. Hypotension is its major adverse effect and requires stopping the infusion when significant blood pressure drops occur. Option A is incorrect — amifostine reduces toxicity, not maximizes cisplatin dose/efficacy; its use is not broadly "encouraged." Option B is incorrect — the dose is 910 mg/m² but is administered over 15 minutes (NOT 30 minutes), 15–30 minutes before cisplatin. Option D is incorrect — BP must be monitored before and every 5 minutes DURING the infusion (not just 20 minutes after). Option C correctly describes the threshold for stopping the infusion due to significant hypotension.

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A 60-year-old man with metastatic NSCLC adenocarcinoma (p53, ATM, STK11 mutations — no standard targetable drivers). PD-L1 = 5% (low). ECOG 1. What is the most appropriate first-line therapy?

A. Cisplatin + gemcitabine + bevacizumab × 4 cycles followed by maintenance bevacizumab
B. Carboplatin + pemetrexed + pembrolizumab × 4 cycles followed by maintenance pemetrexed + pembrolizumab
C. Pembrolizumab every 6 weeks (monotherapy)
D. Dabrafenib + trametinib

[expand] Answer: B. Carboplatin + pemetrexed + pembrolizumab × 4 cycles followed by maintenance pemetrexed + pembrolizumab

Explanation: This patient has non-squamous NSCLC without actionable driver mutations and low PD-L1 (5%). Pembrolizumab monotherapy (option C) requires PD-L1 ≥ 50% — PD-L1 5% does not meet this threshold. Dabrafenib + trametinib (option D) is for BRAF V600E mutations — not present here. Bevacizumab + cisplatin + gemcitabine (option A) is not the current standard — pemetrexed-based therapy is preferred for nonsquamous, and the current combination chemo-immunotherapy with carboplatin + pemetrexed + pembrolizumab is the guideline-preferred first-line regimen for nonsquamous NSCLC without driver mutations regardless of PD-L1 expression level.

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A 60-year-old man with ALK-positive metastatic NSCLC received crizotinib (progressed after 5 months) then alectinib (progressed after 10 months) with new brain metastases. Which agent should be used as subsequent therapy?

A. Entrectinib
B. Lorlatinib
C. Erlotinib
D. Observation and palliative care

[expand] Answer: B. Lorlatinib

Explanation: After progression on first-generation (crizotinib) and second-generation (alectinib) ALK inhibitors, the standard next step is lorlatinib — a third-generation ALK TKI with high CNS penetration, specifically studied for this setting and particularly effective against brain metastases. Lorlatinib overcomes resistance to prior ALK inhibitors through its broad spectrum of activity. Entrectinib (option A) is for NTRK fusions or ROS1 gene fusions — not ALK. Erlotinib (option C) is for EGFR mutations — not appropriate here. Observation (option D) is inappropriate when an effective targeted therapy is available.

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NY is a 66-year-old male with Stage IV NSCLC adenocarcinoma, EGFR/ALK/KRAS negative, PD-L1 > 50%, ECOG 1, with history of diabetes mellitus and rheumatoid arthritis. Which regimen would be the preferred option for NY?

A. Cisplatin + pemetrexed
B. Pembrolizumab + cisplatin + pemetrexed
C. Cisplatin + irinotecan
D. Cisplatin + gemcitabine

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Answer: B. Pembrolizumab + cisplatin + pemetrexed

Explanation: NY has no driver mutations with PD-L1 > 50%. While pembrolizumab monotherapy is a strong first-line option for PD-L1 ≥ 50%, among the given choices, pembrolizumab + platinum + pemetrexed (option B) is the correct combination that includes the critical immunotherapy component with appropriate adenocarcinoma-directed chemotherapy. Cisplatin + pemetrexed alone (option A) omits immunotherapy — suboptimal when immunotherapy is available. Irinotecan (option C) and gemcitabine (option D) with cisplatin are not standard first-line regimens for nonsquamous adenocarcinoma. Note: his rheumatoid arthritis warrants close monitoring for immune-related adverse event exacerbation but is not an absolute contraindication to immunotherapy.

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GV is a 56-year-old male who progressed after crizotinib for ALK-positive, EGFR-negative metastatic lung adenocarcinoma. Which treatment is most appropriate for GV at this time?

A. Bevacizumab + carboplatin + paclitaxel
B. Nivolumab
C. Ceritinib
D. Osimertinib

[expand] Answer: C. Ceritinib

Explanation: GV has ALK-positive NSCLC who progressed on the first-generation ALK inhibitor crizotinib. The appropriate next step is a second-generation ALK inhibitor. Ceritinib is a second-generation ALK TKI approved specifically for this scenario — after crizotinib failure. Alectinib or brigatinib are now often preferred over ceritinib but ceritinib remains guideline-approved. Osimertinib (option D) is an EGFR TKI — not applicable to ALK-positive disease. Nivolumab (option B) could be used in later lines but is not preferred when an effective targeted next-line agent is available. Bevacizumab + chemo (option A) would be a later-line option without an available targeted therapy.

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Which of the following drugs are NCCN guideline-recommended options for maintenance therapy in patients with squamous cell NSCLC?

A. Pembrolizumab
B. Gemcitabine
C. Docetaxel
D. All of the above

[expand] Answer: D. All of the above

Explanation: For squamous cell NSCLC patients who have not progressed after first-line platinum-based chemotherapy, all three agents are NCCN-recognized maintenance options: Pembrolizumab — continuation maintenance if it was part of the first-line regimen. Gemcitabine — continuation maintenance (one of the initial non-platinum chemotherapy drugs continued). Docetaxel — switch maintenance (a different chemotherapy agent started after completing initial platinum-based therapy). All three are valid guideline-supported options depending on prior therapy received and patient factors.

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A 72-year-old female with Stage IV NSCLC adenocarcinoma, EGFR/ALK/ROS1/BRAF negative, PD-L1 = 1% (TPS), ECOG 1. What would be an appropriate therapy?

A. Pembrolizumab + carboplatin + pemetrexed
B. Pembrolizumab + carboplatin + paclitaxel
C. Pembrolizumab alone
D. Erlotinib

[expand] Answer: A. Pembrolizumab + carboplatin + pemetrexed

Explanation: This patient has nonsquamous NSCLC (adenocarcinoma), PD-L1 = 1% (1–49% range), no driver mutations. Pembrolizumab monotherapy (option C) requires PD-L1 ≥ 50% — PD-L1 1% does not qualify. Combination chemo-immunotherapy is appropriate for PD-L1 1–49% or even for PD-L1 ≥ 50% as an alternative to monotherapy. Carboplatin + pemetrexed + pembrolizumab is the preferred combination for nonsquamous histology. Carboplatin + paclitaxel + pembrolizumab (option B) is for squamous histology. Erlotinib (option D) is for EGFR-positive disease — this patient is EGFR-negative.

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A 72-year-old retired pipefitter with malignant sarcomatoid mesothelioma presents with pericardial effusion and cardiac tamponade. After pericardiocentesis and hemodynamic stabilization, he has good performance status. What is the best next step in management?

A. Bronchoscopy with biopsy of mediastinal lymph nodes
B. PET/CT
C. Pleurectomy/decortication with mediastinal lymph node sampling
D. Nivolumab + ipilimumab

[expand] Answer: D. Nivolumab + ipilimumab

Explanation: Based on the CheckMate 743 trial, nivolumab + ipilimumab (dual immunotherapy) is the first-line standard of care for unresectable malignant mesothelioma in patients with good performance status — it demonstrated significantly improved overall survival compared to cisplatin/carboplatin + pemetrexed. This benefit was particularly pronounced in non-epithelioid histology (which includes sarcomatoid type — this patient's histology). The patient is now hemodynamically stable and has good PS — first-line systemic therapy should be started promptly.

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A 72-year-old retired pipefitter has malignant mesothelioma. Which of the following is NOT a risk factor for the development of mesothelioma?

A. Tobacco use
B. Radiation exposure
C. Family history of mesothelioma
D. Occupational asbestos exposure

[expand] Answer: A. Tobacco use

Explanation: Asbestos exposure (option D) is the primary and overwhelmingly most common cause of mesothelioma. Prior radiation exposure (option B) — as seen in this patient's history of prior Hodgkin lymphoma treated with mantle-field radiation — is a documented risk factor. Family history (option C) can indicate genetic predisposition (e.g., BAP1 mutation syndrome) or shared environmental asbestos exposure. Tobacco use (option A) is NOT a risk factor for mesothelioma. While smoking synergistically increases the risk of bronchogenic lung cancer in asbestos-exposed individuals, it does not independently increase the risk of mesothelioma — this is a classic distinction.

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20. LL is a 67-year-old man with non-squamous cell lung cancer scheduled to receive paclitaxel, carboplatin and bevacizumab chemotherapy. His past medical history is significant for diabetes, hypertension, hyperlipidemia, coronary artery disease with recent (2 months) drug-eluting stent placement. His medications include metformin, lisinopril, simvastatin, clopidogrel, and aspirin. Which scenario would preclude you from initiating bevacizumab therapy?

• A. Since the patient is on clopidogrel and aspirin, bevacizumab may increase this patient’s risk of bleeding (70%)
• B. The patient has diabetes and receiving carboplatin chemotherapy, the addition of bevacizumab may worsen renal function (8%)
• C. The patient is receiving metformin so the addition of bevacizumab may worsen the chance of metabolic acidosis (6%)
• D. Since the patient had a recent procedure, there is a risk of wound dehiscence from the use of bevacizumab (16%)

[expand] Answer (A)

• Bevacizumab is VEGF ligand inhibiting monoclonal antibody.
• This mechanism can lead to a variety of adverse effects leading to bleeding, thrombosis, proteinuria, hypertension, and wound dehiscence. The most pressing issue would be the increased risk of bleeding from the combination of clopidogrel and aspirin with bevacizumab. These drugs are not contraindicated but you need to monitor these patients closely.
• The second answer is incorrect since carboplatin typically does not cause renal insufficiency.
• The third option is incorrect since bevacizumab does not increase metabolic acidosis.
• The last option could be an issue if it was major operation within the last 28 days. However, it was a minor procedure two months ago which does not inhibit the use of bevacizumab.

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[expand] Answer (A)

• Contrary to what many tertiary sources contain, there are no known adverse pharmacokinetic or pharmacodynamic interactions between carboplatin and paclitaxel.
• This is unlike the interaction that occurs with paclitaxel and cisplatin in which paclitaxel should be administered first because the paclitaxel clearance values are 21% lower when paclitaxel followed cisplatin.
• Also, when cisplatin preceded paclitaxel, the absolute neutrophil nadirs were lower, and grade 4 neutropenia was more common than when the paclitaxel was administered first.

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67. Which of the following statements are FALSE regarding nivolumab (Opdivo)?

• A. Nivolumab is FDA-approved for patients with metastatic NSCLC who have progressed on platinum-based chemotherapy (3%)
• B. Patients who experience pneumonitis associated with nivolumab should be treated with corticosteroids. (3%)
• C. The recommended dose of nivolumab for metastatic NSCLC is 3 mg/kg IV q 2 weeks. (6%)
• D. One of the advantages of using nivolumab for NSCLC is that patients have immediate shrinkage in tumor size and symptomatic relief after starting treatment. (71%)
• E. All of the above statements are true. (17%)

[expand] Answer (D)

• Nivolumab is approved for metastatic nonsquamous and squamous NSCLC who have progressed on platinum-based chemotherapy. It is commonly associated with immune-mediated adverse reactions such as pneumonitis, colitis, and hepatitis.
• Patients with moderate or greater pneumonitis may require corticosteroids at 1–2 mg/kg/day prednisone equivalents, followed by a taper.
• Patients treated with immunotherapy may initially experience an increased size in tumor lesions, confirmed by biopsy to be inflammatory cell infiltrates or necrosis, with subsequent decreased tumor burden.
• In the CHECKMATE-017 trial, the median time to response for patients with metastatic squamous NSCLC treated with nivolumab was ≥2 months.

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• A Cisplatin has higher risk of emesis and nephrotoxicity (82%)
• B Carboplatin infusion requires pre- and post-hydration (6%)
• C Cisplatin dose is calculated by Calvert formula (4%)
• D Carboplatin has lesser risk of myelosuppression (8%)