What it is:A solid tumor arising from bronchial epithelial cells that have picked up enough genetic damage to turn malignant. The chapter splits into two completely different diseases that happen to live in the same organ: non-small cell lung cancer (NSCLC, ~85%)and small cell lung cancer (SCLC, ~15%). They have different biology, different staging systems, and different treatment logic, so don't blend them together when you study.
The core problem:Accumulated mutations activate proto-oncogenes, knock out tumor suppressors, and switch on self-stimulatory growth factors. In NSCLC, a subset of those mutations are individually druggable, which is why genetic testing changed this cancer more than almost any other solid tumor. SCLC is biologically nastier: fast-growing, chemosensitive, radiosensitive, but with far fewer targetable drivers.
What you do about it:Test before you treat. Every patient with advanced NSCLC needs histology, PD-L1 expression, and a genetic mutation panel beforepicking a regimen, because the answer to "what's first line" depends entirely on those three results.
For advanced NSCLC without curative surgery on the table, everything funnels into three lanes. Lane 1: a targetable driver mutation is present (EGFR, ALK, ROS1, BRAF V600E, METex14, NTRK, RET, or KRAS G12C) → start an oral targeted agent, chemo comes later. Lane 2: no driver mutation but the tumor is PD-L1 positive → immunotherapy alone or with chemo, sorted by how high the PD-L1 score is. Lane 3: no driver, low or no PD-L1 → chemo backbone, and here histology (squamous vs nonsquamous) decides which chemo partners you can use. Figure out which lane a patient is in first, and the rest of the algorithm falls into place.
Two staging systems exist because the two cancers behave so differently. Mixing them up is an easy way to lose points.
| Cell type | % of lung cancers | Notes |
|---|---|---|
| Adenocarcinoma | ~50% | Most common NSCLC subtype; where most driver mutations concentrate |
| Squamous cell carcinoma | <30% | NSCLC; pemetrexed and bevacizumab are avoided here |
| Large cell carcinoma | Minority | NSCLC; grouped with adeno and squamous as "NSCLC" |
| Small cell lung cancer (SCLC) | ~15% | Not NSCLC; different staging system, different drugs entirely |
Adenocarcinoma, squamous, and large cell are lumped together as "NSCLC" for staging purposes, but they are not interchangeable for drug selection. Pemetrexed and bevacizumab are restricted to nonsquamous histology (mostly adenocarcinoma) because of efficacy and bleeding-risk data in squamous tumors. If a question says "squamous," cross pemetrexed and bevacizumab off the list before you even look at biomarkers.
Formal staging uses the TNM system (tumor size, nodal spread, metastases), but for therapy decisions a simplified four-stage version is what actually drives the algorithm.
| Stage | Extent |
|---|---|
| I | Tumor confined to the lung, no lymphatic spread |
| II | Larger tumor with ipsilateral peribronchial or hilar node involvement |
| III | Other/regional lymph node involvement |
| IV | Any tumor with distant metastases |
SCLC uses a much simpler two-bucket system, because it's almost always systemic by the time it's found.
| Stage | Definition |
|---|---|
| Limited disease | Confined to one hemithorax, small enough to fit in a single radiation port |
| Extensive disease | Everything else |
Mutations do three things in lung cancer cells: switch on proto-oncogenes, switch off tumor suppressor genes, and trigger autocrine growth factor loops that keep the cell dividing without outside signals. Many of these alterations overlap between SCLC and NSCLC, but certain ones cluster in specific subtypes, and that clustering is exactly what makes targeted therapy possible.
Every oral "-tinib" or "-nib" drug in this chapter exists because a specific mutation makes a specific kinase permanently switched on, and the drug shuts that kinase back off. EGFR mutated → EGFR kinase inhibitor. ALK rearranged → ALK inhibitor. That's the whole logic. Checkpoint inhibitors work on a completely separate mechanism: they don't touch the tumor's proliferation machinery at all, they release the brakes the tumor is putting on the immune system (via PD-1/PD-L1 signaling) so the patient's own T cells can attack it.
Smoking causes roughly 80% of lung cancer deaths.Other contributors are environmental carcinogen exposure (asbestos, benzene, arsenic), genetic predisposition, and a prior history of COPD or asthma.
NSCLC, especially adenocarcinoma, is where the payoff for genetic testing is highest: EGFR, KRAS, ALK, ROS1, BRAF V600E, METex14 skipping, NTRK fusion, and RET fusion are all individually druggable. SCLC has far fewer actionable targets in routine practice; c-KIT overexpression is described in SCLC, but SCLC is managed almost entirely with cytotoxic chemotherapy and immunotherapy rather than oral targeted agents.
Lung cancer is frequently asymptomatic early, which is exactly why it's usually caught late.
| Category | Findings |
|---|---|
| Local/primary tumor | Cough, dyspnea, chest pain or discomfort, with or without hemoptysis |
| Systemic | Anorexia, weight loss, fatigue |
| CNS metastases | Neurologic deficits |
| Bone metastases | Bone pain, pathologic fractures |
| Hepatic involvement | Liver dysfunction |
These are signs and symptoms that show up away from the tumor and its metastasesrather than from direct tumor invasion. Lung cancer produces paraneoplastic syndromes more often than any other tumor type, and they occur more frequently with SCLC than NSCLC. If a vignette describes a symptom that doesn't fit the local mass or the known metastatic sites, think paraneoplastic and think SCLC first.
Getting tissue isn't just about proving "yes, this is cancer." That same sample determines the specific cell type andgets sent for molecular testing (EGFR, ALK, ROS1, PD-L1 expression, and the rest of the driver panel). Skipping or rushing this step means treatment decisions later in the algorithm can't be made correctly.
Goals:definitive cure with early-stage disease, prolonged survival with advanced disease, and quality of life improvement across the board. Surgery, radiation, chemotherapy, immunotherapy, and targeted therapy are all in play, and stage plus patient-specific factors decide which combination applies.
Chemotherapy here is about palliation, quality of life, and survival duration, not cure. Performance status is the single most important patient factor driving what a patient can tolerate. This is where the three-lane framework from the snapshot takes over: immune-sensitive (PD-L1+), driver-mutation positive, or nonbiomarker-driven (split by squamous vs nonsquamous).
Patients with advanced NSCLC and a targetable driver mutation get an oral targeted agent first, not chemotherapy. Consult current guidelines for the latest recommendation, since this space moves fast, but the chapter's framework is below.
| Driver | Preferred first-line agent | Key point |
|---|---|---|
| EGFRexon 19 del or L858R | Osimertinib (3rd-gen) | Best CNS penetration/response; older options afatinib, erlotinib, gefitinib (1st/2nd-gen), dacomitinib (2nd-gen irreversible) |
| ALKrearrangement | Alectinib or brigatinib (2nd-gen), lorlatinib (3rd-gen) | First-gen crizotinib/ceritinib proved ALK inhibition beats chemo, but later generations are now preferred initial therapy |
| ROS1rearrangement | Ceritinib, crizotinib, or entrectinib | Second-line: lorlatinib, entrectinib |
| BRAF V600E | Dabrafenib + trametinib (combination required) | Entrectinib also approved first-line for this mutation |
| METex14 skipping | Capmatinib or tepotinib | Both dosed BID |
| NTRKgene fusion | Larotrectinib | Entrectinib is also NTRK-active |
| RETfusion | Selpercatinib or pralsetinib | Hold before planned surgery, risk of impaired wound healing |
| KRAS G12C | Sotorasib | Studied only after progression on other advanced-disease therapy, not upfront |
A meta-analysis found afatinib, erlotinib, and gefitinib have similar PFS and response rates, roughly double chemotherapy's response rate. Osimertinib is the one that pulled ahead: longer PFS and meaningfully better CNS activity, which is why it's first-line even though it's third-generation, not because it's newest for its own sake. Resistance to first/second-gen EGFR inhibitors is frequently driven by an acquired T790M mutation; osimertinib's activity is not affected by T790M, which is also why it works after progression on earlier-generation inhibitors.
Patients with PD-L1-positive tumors and no sensitizing mutation are candidates for first-line checkpoint inhibitor therapy: pembrolizumab, atezolizumab, nivolumab, or cemiplimab, used alone, combined with chemo, or combined with the CTLA-4 inhibitor ipilimumab. PD-L1 expression is measured as tumor proportion score (TPS)and splits patients into three groups that steer regimen choice.
| PD-L1 TPS | General approach |
|---|---|
| ≥50% | Checkpoint inhibitor monotherapy is often sufficient (e.g., pembrolizumab alone) |
| 1-49% | Chemo-immunotherapy combinations are typically favored |
| <1% | Chemo-immunotherapy combination, since single-agent immunotherapy benefit is weaker |
Adding bevacizumabto chemo is recommended for advanced nonsquamous NSCLC, but only when the patient has no recent hemoptysis, no CNS metastasis, and isn't on therapeutic anticoagulation. The ABCP regimen (atezolizumab + carboplatin + paclitaxel + bevacizumab) is one of the more recent chemoimmunotherapy advances for nonbiomarker-driven, nonsquamous metastatic disease.
NSCLC and SCLC regimen tables. Doses are per the handbook's selected regimens; confirm against current protocols before clinical use.
| Regimen | Drugs and doses | Schedule |
|---|---|---|
| Cisplatin/etoposide | Cisplatin 100 mg/m² IV day 1; etoposide 100 mg/m² IV days 1-3 | Every 28 days × 4 cycles |
| Cisplatin/vinorelbine | Cisplatin 50 mg/m² IV days 1, 8; vinorelbine 25 mg/m² IV days 1, 8, 15, 22 (or cisplatin 100 mg/m² day 1 with vinorelbine 30 mg/m² days 1, 8, 15, 22) | Every 28 days × 4 cycles |
| Carboplatin/paclitaxel | Carboplatin AUC 6 IV day 1; paclitaxel 200 mg/m² IV day 1 | Every 21 days × 4 cycles |
| Cisplatin/pemetrexed | Cisplatin 75 mg/m² IV day 1; pemetrexed 500 mg/m² IV day 1 | Every 21 days × 4 cycles - nonsquamous only |
| Regimen | Typical use case | Schedule notes |
|---|---|---|
| Pembrolizumab monotherapy | PD-L1 ≥50%, any histology | 200 mg IV q3wk or 400 mg IV q6wk, up to 2 years |
| Platinum + pemetrexed + pembrolizumab | Nonsquamous, PD-L1 1-49% (or <1%) | q3wk × 4 cycles, then pembrolizumab maintenance up to 31 more doses |
| Carboplatin + paclitaxel + pembrolizumab | Squamous, PD-L1 1-49% (or <1%) | q3wk × 4 cycles, then pembrolizumab maintenance |
| Atezolizumab + carboplatin + paclitaxel + bevacizumab (ABCP) | Nonsquamous, nonbiomarker-driven | q3wk × 6 cycles, then atezolizumab + bevacizumab maintenance |
| Nivolumab + ipilimumab ± chemo | Various PD-L1 categories | Nivolumab q2-4wk + ipilimumab q6wk pattern; up to 2 years |
| Cemiplimab monotherapy | PD-L1 ≥50% | 350 mg IV q21d until progression |
| Carboplatin + pemetrexed | Nonsquamous, PD-1/PD-L1 inhibitor contraindicated | q3wk × 4-6 cycles, then pemetrexed maintenance |
| Gemcitabine + cisplatin | PD-1/PD-L1 inhibitor contraindicated | q28 days |
| Regimen | Setting |
|---|---|
| Nivolumab, atezolizumab, or pembrolizumab monotherapy | No prior checkpoint inhibitor |
| Docetaxel + ramucirumab | Alternative second-line option |
| EGFR exon 19 del / L858R | ||
| Drug | Dose | Timing note |
|---|---|---|
| Osimertinib | 80 mg once daily | Without regard to meals |
| Erlotinib | 150 mg once daily | 1 hr before / 2 hr after meals |
| Afatinib | 40 mg once daily | 1 hr before / 2 hr after meals |
| ALK rearrangement | ||
| Alectinib | 600 mg twice daily | Take with food |
| Brigatinib | 90 mg daily × 7 days, then 180 mg daily if tolerated | Without regard to meals |
| Lorlatinib | 100 mg once daily | Without regard to meals |
| ROS1 rearrangement | ||
| Crizotinib | 250 mg twice daily | Without regard to meals |
| Entrectinib | 600 mg once daily | Without regard to meals |
| BRAF V600E | ||
| Trametinib | 2 mg once daily | Without regard to meals; must pair with dabrafenib |
| Dabrafenib | 150 mg twice daily | 1 hr before / 2 hr after meals; must pair with trametinib |
| METex14 skipping | ||
| Capmatinib | 400 mg twice daily | Without regard to meals |
| Tepotinib | 450 mg once daily | Take with food |
| RET rearrangement | ||
| Selpercatinib | 160 mg twice daily (120 mg if <50 kg) | Without regard to meals |
| Pralsetinib | 400 mg once daily | 1 hr before / 2 hr after meals |
| NTRK fusion / KRAS G12C | ||
| Larotrectinib | 100 mg twice daily | Without regard to meals |
| Sotorasib | 960 mg once daily | Without regard to meals; avoid with acid-reducing drugs |
| First line | ||
| Regimen | Drugs and doses | Schedule |
|---|---|---|
| Etoposide/cisplatin (EP) | Cisplatin 75 mg/m² day 1 + etoposide 100 mg/m² days 1-3 (or cisplatin 60 + etoposide 120 mg/m²) | q3wk × 4-6 cycles |
| Etoposide/carboplatin (EC) | Carboplatin AUC 5-6 day 1 + etoposide 100 mg/m² days 1-3 | q3wk × 4-6 cycles |
| EC + atezolizumab* | Add atezolizumab 1200 mg day 1 | q3wk × 4, then maintenance q3wk (1200 mg) or q4wk (1680 mg) |
| EP or EC + durvalumab* | Add durvalumab 1500 mg day 1 | q3wk × 4, then maintenance 1500 mg q4wk |
| Second line | ||
| Topotecan | 1.5 mg/m²/day IV days 1-5 | Every 3 weeks |
| Lurbinectedin | 3.2 mg/m²/day IV day 1 | Every 3 weeks |
*Extensive-stage only.
For NSCLC without a targetable mutation, combination chemotherapy is still the backbone. Standard doublets pair cisplatin or carboplatinwith paclitaxel, gemcitabine, or pemetrexed. In nonsquamous disease specifically, cisplatin + pemetrexedis the preferred combination.
Maintenance therapymeans continuing treatment after 4-6 cycles of induction chemo in a patient who responded, rather than stopping and watching. Continuation maintenancekeeps at least one drug from the original regimen going; switch maintenanceintroduces a new agent that wasn't part of induction. Multiple studies show continuation or switch maintenance improves survival specifically in nonsquamous histology, and pemetrexed is the best-established maintenance option.
Why squamous keeps losing drugs:pemetrexed is restricted to nonsquamous histology, and bevacizumab requires nonsquamous histology plus no recent hemoptysis, no CNS mets, and no therapeutic anticoagulation. When you see "squamous" in a stem, mentally cross both agents off before reading further.
First- and second-generation EGFR kinase inhibitors (afatinib, erlotinib, gefitinib, and the irreversible second-gen dacomitinib) perform similarly to each other, roughly doubling response rates versus chemotherapy. Osimertinib, third-generation, is now first-line because it delivers longer PFS and, critically, better CNS penetration, meaning fewer CNS relapses and better control of brain metastases, which are common in EGFR-mutant disease.
Every EGFR TKI in this class carries a risk of interstitial lung diseaseas a rare but serious toxicity. Teach patients to report new or worsening dyspnea, cough, and fever immediately, since these are the presenting symptoms.
Resistance:the T790M mutationis a common resistance mechanism against first/second-generation EGFR inhibitors. Osimertinib's activity isn't affected by T790M, which is exactly why it also works as a later-line option after progression on erlotinib, gefitinib, or dacomitinib. Erlotinib is best absorbed in an acidic gastric environment and should be taken away from food; afatinib and erlotinib are both CYP-interaction prone (afatinib via P-glycoprotein, erlotinib via CYP3A4) so watch concurrent drugs closely, and afatinib increases hemorrhage risk when combined with warfarin.
First-generation ALK inhibitors crizotiniband ceritinibwere the original proof that ALK inhibition beats chemotherapy in ALK-rearranged tumors, but second-generation alectinibor brigatinib, and third-generation lorlatinib, are now preferred as initial therapy. Patients who relapse on one generation can move to the next.
ROS1-rearranged tumors respond to ceritinib, crizotinib, or entrectinibfirst-line, with lorlatinib or entrectinibavailable second-line.
Alectinib needs CBC with differential monthly and LFTs every 2 weeks for the first 3 months. Lorlatinib needs fasting glucose, lipid panel, and periodic ECG (it can cause CNS effects including mood changes). Brigatinib and crizotinib both carry bradycardia and QT-prolongation risk requiring periodic ECG and heart rate/blood pressure checks. This is a class where the monitoring plan is almost as complex as the mechanism.
Crizotinib carries a boxed risk of fatal hepatotoxicityand can cause severe, vision-threatening ocular toxicity, both worth flagging to patients explicitly.
BRAF V600Erequires combinationtherapy: trametinib (MEK inhibitor) plus dabrafenib (BRAF inhibitor) are used together, never alone, because dual blockade of the same pathway reduces resistance and paradoxical toxicity seen with BRAF inhibitor monotherapy. Entrectinib is also approved here. Watch ejection fraction with both drugs; permanently discontinue for symptomatic cardiomyopathy or an EF drop >20 percentage points.
METex14 skippingmutations respond to capmatinibor tepotinib; both need frequent LFT monitoring early in treatment (baseline, then every 2 weeks for the first 3 months, then monthly) and photosensitivity precautions with capmatinib.
RET fusion-positivedisease responds to selpercatinibor pralsetinib. Both should be held before planned surgerybecause of impaired wound healing risk, and both carry tumor lysis syndrome and hemorrhage warnings.
NTRK fusion-positivetumors respond to larotrectinib(or entrectinib). KRAS G12Cmutations respond to sotorasib, but only after progression on other therapy, this is not an upfront option, and it should be separated from acid-reducing drugs since gastric pH affects absorption.
Shared theme across nearly this entire targeted-therapy panel:interstitial lung disease, hepatotoxicity, and the need for baseline-then-periodic liver function monitoring show up again and again. If you're unsure of an agent's specific monitoring, "check LFTs and watch for new dyspnea/cough/fever" is a safe first answer.
Checkpoint inhibitors (pembrolizumab, atezolizumab, nivolumab, cemiplimab, and durvalumab) block PD-1 or PD-L1 signaling, removing the tumor's ability to suppress the immune response against it. PD-L1 tumor proportion score (TPS)from the biopsy sample determines eligibility and regimen: high expression (≥50%) can support checkpoint inhibitor monotherapy, while lower expression usually pairs a checkpoint inhibitor with chemotherapy.
Ipilimumab, a CTLA-4 inhibitor, is combined with a PD-1/PD-L1 agent in some regimens (e.g., nivolumab + ipilimumab, with or without chemo) as dual immune checkpoint blockade.
Two very different settings for the same drug:durvalumab shows up as one-year consolidationtherapy after chemoradiation in unresectable stage III NSCLC, and separately as an extensive-stage SCLCcombination partner with EP chemo. Same PD-L1 inhibitor, two unrelated indications, don't confuse the settings on an exam.
Goals of treatment:cure or prolonged survival, which requires aggressive combination chemotherapy from the start, plus quality of life throughout.
SCLC that recurs within 3 monthsof finishing first-line chemo is considered refractoryand unlikely to respond to a second-line regimen. Those patients should get best supportive care or a clinical trial, not another chemo line. Relapse occurring more than 3 monthsout is more likely to respond again: topotecan(IV or oral) is the second-line agent of choice, though efficacy is modest across this whole relapsed-disease space. Other options at that point include single-agent PD-L1 inhibitor, gemcitabine, irinotecan, paclitaxel, docetaxel, oral etoposide, temozolomide, vinorelbine, the CAV regimen (cyclophosphamide, doxorubicin, vincristine), or a clinical trial.
Across nearly every oral targeted agent in this chapter, three adverse effect themes repeat. Learning the pattern is more efficient than memorizing each drug in isolation.
| Pattern | Shows up with | What to actually do |
|---|---|---|
| Interstitial lung disease | Osimertinib, erlotinib, afatinib, alectinib, brigatinib, lorlatinib, crizotinib, capmatinib, tepotinib, trametinib, sotorasib, pralsetinib | Teach patients to report new/worsening dyspnea, cough, fever right away |
| Hepatotoxicity, monitored by serial LFTs | Nearly the entire targeted-therapy panel | Baseline LFTs, then every 2 weeks for the first 1-3 months, then monthly (exact cadence varies by drug) |
| QT prolongation / cardiac monitoring | Osimertinib, crizotinib, entrectinib, selpercatinib; ejection fraction for trametinib/dabrafenib and entrectinib | Baseline ECG in at-risk patients, periodic rechecks, avoid stacking other QT-prolonging drugs |
Trametinib and dabrafenib are never given alonefor BRAF V600E disease, they're a mandatory pair. Prescribing one without the other is an error worth catching on sight.
| Parameter | When | Watching for |
|---|---|---|
| NSCLC tumor response (imaging) | End of 2nd or 3rd cycle, then every 2 cycles thereafter | Stable disease or objective response → continue to 4-6 total cycles; consider pemetrexed maintenance if nonsquamous |
| Checkpoint inhibitor response pattern | Median time-to-response 10-12 weeks | Radiologic "progression" early on can actually be pseudo-progression, don't panic and switch therapy prematurely |
| SCLC response to first-line chemo | After 2-3 cycles | No response/progression → stop or switch to a non-cross-resistant regimen; responders continue 4-6 cycles total |
| PCI eligibility | After induction therapy in responders | Reduces brain metastasis risk in both limited and extensive SCLC |
| LFTs (targeted agents) | Baseline, then per-drug schedule (commonly q2wk × 1-3 months, then monthly) | Drug-induced hepatotoxicity |
| Renal panel / CMP | Baseline and periodically on most targeted agents | Renal impairment, electrolyte shifts |
| CBC with differential | Baseline and periodically, monthly for alectinib and crizotinib | Myelosuppression, anemia, lymphopenia/neutropenia |
| Overall toxicity burden | Every visit | Lung cancer patients carry a heavy combined drug + radiotherapy toxicity load and frequent comorbidities, close attention is required across the board |