📋 Key Information Summary
- NSCLC accounts for approximately 80–85% of all lung cancers in Australia; lung cancer is the leading cause of cancer death nationally, with over 14,000 new diagnoses annually (AIHW 2024).
- Staging follows the AJCC/UICC 8th edition TNM system; accurate staging with PET-CT, brain MRI, and mediastinal tissue sampling is essential before treatment decisions.
- Early-stage (Stage I–II) NSCLC is treated with surgical resection (lobectomy preferred via VATS), with adjuvant cisplatin-based chemotherapy for Stage II and select Stage IB tumours ≥4 cm.
- Stereotactic body radiotherapy (SBRT) is the standard of care for medically inoperable Stage I–II NSCLC, delivering biologically effective doses ≥100 Gy.
- Platinum-doublet chemotherapy (cisplatin or carboplatin + pemetrexed, paclitaxel, gemcitabine, or docetaxel) remains the backbone for advanced non-squamous and squamous NSCLC without driver mutations.
- Comprehensive molecular testing (EGFR, ALK, ROS1, BRAF V600E, KRAS G12C, MET exon 14, RET, NTRK, HER2) is mandatory for all advanced non-squamous NSCLC and should be considered for squamous histology in never/light smokers.
- First-line EGFR TKIs (osimertinib), ALK inhibitors (alectinib, lorlatinib), and ROS1 inhibitors (crizotinib, entrectinib) produce superior progression-free survival compared with chemotherapy.
- Immunotherapy with PD-1/PD-L1 inhibitors (pembrolizumab, nivolumab, atezolizumab, durvalumab) has transformed outcomes; PD-L1 tumour proportion score (TPS) guides first-line use as monotherapy or in combination.
- Pembrolizumab monotherapy is first-line for PD-L1 TPS ≥50% without targetable mutations; pembrolizumab + platinum-pemetrexed is standard for PD-L1 <50% non-squamous NSCLC.
- Immune-related adverse events (irAEs) — pneumonitis, colitis, hepatitis, endocrinopathy, nephritis — require early recognition, steroid therapy, and potential permanent discontinuation of immunotherapy.
- Stage III unresectable NSCLC is treated with concurrent chemoradiation followed by durvalumab consolidation (PACIFIC regimen) for up to 12 months.
- Palliative radiotherapy, bone-modifying agents, and multimodal analgesia are essential components of supportive care for metastatic disease.
- Aboriginal and Torres Strait Islander Australians have significantly higher lung cancer incidence and mortality, later-stage diagnosis, and lower treatment uptake — culturally safe care pathways and equitable access are critical.
Introduction & Australian Epidemiology
Non-small cell lung cancer (NSCLC) is the most common histological subtype of lung cancer, comprising approximately 80–85% of all primary lung malignancies. The three principal histological subtypes are adenocarcinoma (~40%), squamous cell carcinoma (~25–30%), and large cell carcinoma (~5–10%). Lung cancer remains the leading cause of cancer-related death in Australia for both men and women, responsible for more deaths than breast, prostate, and colorectal cancers combined.
In Australia, the age-standardised incidence of lung cancer is approximately 38 per 100,000 population, with over 14,000 new cases diagnosed annually. Five-year overall survival remains approximately 20–22% nationally, though this varies dramatically by stage — exceeding 70% for Stage IA disease and falling below 10% for Stage IV. The most significant modifiable risk factor is tobacco smoking (responsible for ~80% of cases), though approximately 10–15% of lung cancers occur in never-smokers, driven increasingly by targetable molecular alterations.
Lung cancer screening — new in Australia: The National Lung Cancer Screening Programme commenced in 2025, offering annual low-dose CT (LDCT) to high-risk Australians aged 50–74 with ≥30 pack-year smoking history (current or quit within 10 years). This is expected to shift stage-at-diagnosis towards earlier, curable disease. MBS items for LDCT screening are now available.
The molecular landscape of NSCLC has been increasingly characterised, with actionable driver mutations identified in 50–70% of adenocarcinomas in never-smokers and approximately 10–30% in smokers. This has ushered in the era of precision oncology, where treatment selection is guided by molecular profiling and PD-L1 expression rather than histology alone.
| Parameter | Australian Data |
|---|---|
| Annual new cases | ~14,000 (2024 estimate, AIHW) |
| 5-year survival (all stages) | ~20–22% |
| 5-year survival (Stage IA) | ~77% |
| 5-year survival (Stage IV) | ~6–8% |
| Proportion presenting at Stage IV | ~45% |
| ATSI rate ratio vs non-Indigenous | 1.6× incidence, 1.8× mortality |
| Median age at diagnosis | 72 years |
| Smoking-related proportion | ~80% |
Pathophysiology & Molecular Classification
NSCLC arises through the sequential accumulation of genetic and epigenetic alterations in bronchial epithelial cells and alveolar cells, driven primarily by carcinogen exposure (tobacco smoke, radon, asbestos) or, in never-smokers, by endogenous mutagenic processes and oncogenic driver mutations.
Histological Subtypes
- Adenocarcinoma: Arises from peripheral glandular epithelium; most common subtype. Defined by glandular differentiation, mucin production, or specific immunohistochemical markers (TTF-1, Napsin-A). Subclassified as lepidic, acinar, papillary, micropapillary, or solid pattern. Highest prevalence of actionable driver mutations.
- Squamous cell carcinoma: Arises from central bronchial epithelium, strongly associated with smoking. CK5/6 and p40 positive. Fewer targetable mutations (PD-L1 expression often higher; FGFR alterations, PIK3CA mutations).
- Large cell carcinoma: Diagnosis of exclusion — lacks glandular, squamous, or neuroendocrine differentiation. Aggressive; large cell neuroendocrine carcinoma (LCNEC) is classified separately and managed like small cell lung cancer.
- Adenosquamous carcinoma: Mixed adenocarcinoma and squamous components (each ≥10%); managed according to predominant molecular profile.
Key Oncogenic Driver Mutations
Oncogenic driver mutations are mutually exclusive in most cases and define therapeutic targets. Their prevalence varies by smoking status and ethnicity:
| Driver Alteration | Frequency (Adenocarcinoma) | Smoking Association | Approved Targeted Therapy |
|---|---|---|---|
| EGFR mutation (exon 19 del, L858R) | 15–25% | Never/light smokers | Osimertinib, gefitinib, erlotinib, afatinib, dacomitinib |
| ALK rearrangement | 3–7% | Younger, never/light smokers | Alectinib, lorlatinib, crizotinib, brigatinib, ceritinib |
| KRAS G12C | 10–15% | Smokers | Sotorasib, adagrasib |
| ROS1 rearrangement | 1–2% | Never/light smokers | Crizotinib, entrectinib |
| BRAF V600E | 1–3% | Smokers | Dabrafenib + trametinib |
| MET exon 14 skipping | 2–4% | Elderly, smokers | Capmatinib, tepotinib |
| RET rearrangement | 1–2% | Never/light smokers | Selpercatinib, pralsetinib |
| NTRK fusion | <1% | Variable | Larotrectinib, entrectinib |
| HER2 mutation | 2–4% | Never/light smokers | Trastuzumab deruxtecan |
Clinical Presentation & Diagnostic Criteria
NSCLC presents across a wide spectrum from asymptomatic incidental findings on imaging to advanced symptomatic disease. Approximately 10–15% are detected incidentally.
Common Presenting Features
- Pulmonary symptoms: Persistent cough (>3 weeks), haemoptysis, dyspnoea, recurrent pneumonia, pleuritic chest pain, wheeze
- Systemic symptoms: Weight loss (>5% body weight), fatigue, anorexia, night sweats
- Locally advanced features: Superior vena cava (SVC) obstruction (facial swelling, plethora), hoarseness (recurrent laryngeal nerve), Horner syndrome (Pancoast tumour), phrenic nerve palsy, dysphagia (oesophageal compression), Pancoast syndrome (shoulder/arm pain, Horner's)
- Metastatic presentations: Bone pain, pathological fracture, seizures/focal neurology (brain metastases), jaundice (hepatic metastases), spinal cord compression, lymphangitis carcinomatosis
- Paraneoplastic syndromes: SIADH (small cell more common but occurs in NSCLC), hypercalcaemia (PTHrP — squamous cell), Cushing syndrome (ectopic ACTH), clubbing, hypertrophic pulmonary osteoarthropathy, Lambert-Eaton myasthenic syndrome, dermatomyositis
Red flags requiring urgent investigation: Haemoptysis in a current/former smoker, SVC obstruction, suspected spinal cord compression, superior sulcus (Pancoast) tumour, and new neurological deficits suggestive of brain metastases require same-day assessment and urgent referral to respiratory medicine or oncology.
Diagnostic Confirmation
A tissue diagnosis (histological or cytological) is required before initiating treatment in most clinical scenarios. Adequate tissue must be obtained for histological subtype determination and molecular testing. Methods include:
- CT-guided transthoracic core biopsy: For peripheral lesions (sensitivity 85–93%)
- Bronchoscopy with endobronchial biopsy/EBUS-TBNA: For central lesions and mediastinal staging
- Endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA): Gold standard for mediastinal lymph node sampling (N staging)
- Surgical biopsy (VATS wedge): When less invasive methods are non-diagnostic
- Liquid biopsy (ctDNA): Acceptable for molecular testing when tissue is insufficient or unavailable; complement to tissue biopsy
Pathology reporting must include histological subtype, differentiation grade, immunohistochemical markers (TTF-1, Napsin-A, p40, CK5/6, PD-L1 [22C3 pharmDx assay preferred for pembrolizumab eligibility]), and sufficient material for next-generation sequencing (NGS) panel testing.
Investigations
Staging Investigations
Essential
CT chest/abdomen with IV contrast
Primary tumour characterisation, nodal assessment, hepatic/adrenal metastases. MBS Item 5630/5632.
Essential
PET-CT (18F-FDG)
Whole-body metabolic staging; sensitivity ~95% for mediastinal nodal involvement. Detects occult distant metastases in ~15% of patients. MBS Item 61365 (skeletal scintigraphy alternative where PET unavailable).
Essential
Brain MRI with gadolinium
Mandatory for all Stage II–IV NSCLC and selected high-risk Stage I. Superior sensitivity for cerebral metastases vs CT (sensitivity ~95%).
Available
EBUS-TBNA / Mediastinoscopy
Tissue confirmation of mediastinal lymph node involvement (N2/N3 disease) for surgical planning. EBUS-TBNA is first-line; mediastinoscopy if EBUS non-diagnostic. Major centres available.
Available
Pulmonary function tests (PFTs)
FEV1 and DLCO required pre-operatively to assess operability. Predicted postoperative FEV1 >40% predicted and DLCO >40% predicted generally required for lobectomy.
Essential
Next-generation sequencing (NGS) molecular panel
Comprehensive panel (EGFR, ALK, ROS1, BRAF, KRAS G12C, MET ex14, RET, NTRK, HER2, PD-L1) — mandatory for all advanced non-squamous NSCLC. MBS Item 73344 (Medicare-funded comprehensive genomic profiling for advanced cancers from 2024).
Essential
PD-L1 immunohistochemistry (22C3 pharmDx)
Tumour proportion score (TPS) reported as <1%, 1–49%, ≥50%. Guides first-line immunotherapy selection. MBS-funded as part of molecular pathology.
Available
Liquid biopsy (ctDNA)
Circulating tumour DNA analysis when tissue biopsy insufficient or not feasible. Sensitivity ~70–80% for targetable mutations. Available through specialised pathology providers.
Staging & Risk Stratification
NSCLC is staged using the AJCC/UICC 8th edition TNM classification (2017). Accurate staging dictates treatment intent (curative vs palliative) and modality selection.
| Stage | TNM | 5-Year Survival | Treatment Intent |
|---|---|---|---|
| IA1–IA3 | T1a–T1c N0 M0 | 77–92% | Curative — surgery ± adjuvant |
| IB | T2a N0 M0 | 68% | Curative — surgery ± adjuvant chemo if ≥4 cm |
| IIA–IIB | T2b–T3, N0–N1 M0 | 53–60% | Curative — surgery + adjuvant chemo ± atezolizumab (if PD-L1 ≥1%) |
| IIIA | T1–T4, N2 M0 | 36% | Curative — neoadjuvant chemo/immuno + surgery or concurrent CRT |
| IIIB–IIIC | T any, N3 M0 | 13–26% | Curative intent — concurrent CRT → durvalumab |
| IVA | T any, N any, M1a–M1b | 10% | Palliative — systemic therapy |
| IVB | T any, N any, M1c | ~1–3% | Palliative — systemic therapy + supportive care |
Performance Status Assessment
Eastern Cooperative Oncology Group (ECOG) performance status (PS) is the strongest independent prognostic factor and guides treatment intensity:
ECOG 0–1
Fit
Fully active or restricted in strenuous activity only. Able to tolerate full-dose systemic therapy, combination regimens, and surgery.
Setting: Standard treatment protocols
ECOG 2
Intermediate
Ambulatory and capable of self-care; unable to carry out work activities. Up to 50% of waking hours. May tolerate single-agent or reduced-dose regimens. Targeted therapy and immunotherapy often well tolerated.
Setting: Modified regimens, monotherapy preferred
ECOG 3–4
Frail / Bedbound
Limited self-care capacity or completely disabled. Chemotherapy generally contraindicated. Best supportive care ± palliative radiotherapy. Consider targeted therapy if driver mutation-positive with preserved organ function.
Setting: Palliative care, BSC, targeted therapy if driver+
Early Stage Management (Stage I–II)
Surgical resection with lobectomy remains the gold standard for early-stage NSCLC in medically fit patients. The goal is complete (R0) resection with systematic mediastinal lymph node dissection. Five-year survival for Stage IA following complete resection exceeds 80%.
Surgical Approaches
| Approach | Indications | Advantages | Considerations |
|---|---|---|---|
| VATS lobectomy | Preferred for Stage I–II, peripheral tumours ≤5 cm | Reduced pain, shorter hospital stay (3–5 days), lower morbidity, equivalent oncological outcomes | Requires experienced thoracic surgeon; conversion to open in ~5–10% |
| Robotic-assisted thoracoscopic surgery (RATS) | As per VATS; increased dexterity for complex resections | Enhanced 3D visualisation, wristed instruments | Higher cost; limited availability in regional Australia |
| Open thoracotomy | Large/central tumours, chest wall invasion, completion pneumonectomy, N2 disease requiring extensive dissection | Direct visualisation, tactile assessment | Greater postoperative pain, longer recovery (7–10 days) |
| Segmentectomy / Wedge | Stage IA1 (≤1 cm, ≥50% ground glass), poor surgical candidates, elderly with limited pulmonary reserve | Parenchymal preservation; comparable for ≤2 cm tumours (JCOG0802 trial) | Higher local recurrence risk vs lobectomy for larger tumours |
VATS as standard: The Royal Australasian College of Surgeons (RACS) and the Thoracic Society of Australia and New Zealand recommend VATS lobectomy as the preferred approach for early-stage NSCLC where technically feasible. Approximately 60–70% of lobectomies in major Australian centres are now performed via VATS.
Adjuvant Chemotherapy
Adjuvant platinum-based chemotherapy improves overall survival following complete resection for Stage II and select high-risk Stage IB (≥4 cm) NSCLC. The benefit is greatest when initiated within 6–8 weeks of surgery.
Cisplatin + Vinorelbine
Cisplatin (DBL) + Navelbine® · Standard adjuvant regimen
Adult dose
Cisplatin 75 mg/m² IV Day 1 + Vinorelbine 25 mg/m² IV Days 1 and 8; 21-day cycle × 4 cycles
Paediatric dose
Not applicable (adult malignancy)
Renal adjustment
Cisplatin contraindicated if eGFR <60 mL/min; switch to carboplatin AUC 5. Vinorelbine no adjustment but caution if eGFR <30.
Hepatic adjustment
Reduce vinorelbine if bilirubin >1.5× ULN; avoid if severe hepatic impairment
PBS status
✔ PBS General Benefit
Carboplatin + Pemetrexed
Carboplatin (DBL) + Alimta® · Non-squamous alternative
Adult dose
Carboplatin AUC 5 IV Day 1 + Pemetrexed 500 mg/m² IV Day 1; 21-day cycle × 4 cycles (non-squamous only)
Renal adjustment
Pemetrexed contraindicated if eGFR <45 mL/min. Carboplatin: Calvert formula with measured GFR.
PBS status
⚕ PBS Authority Required
Atezolizumab (Adjuvant)
Tecentriq® · PD-L1 inhibitor (Stage II–IIIA, PD-L1 ≥1%)
Adult dose
840 mg IV every 2 weeks OR 1200 mg IV every 3 weeks OR 1680 mg IV every 4 weeks; for up to 12 months (following adjuvant platinum chemo)
Eligibility
Stage II–IIIA NSCLC, PD-L1 TC ≥1% (by SP263 or 22C3), complete resection, prior adjuvant platinum chemotherapy, EGFR/ALK negative
Renal adjustment
No adjustment required
PBS status
⚕ PBS Authority Required
Neoadjuvant Immunotherapy + Chemotherapy
Based on the CheckMate 816 trial, neoadjuvant nivolumab + platinum-doublet chemotherapy followed by surgery is now an approved option for resectable Stage IB (≥4 cm) to IIIA NSCLC. This approach significantly improved pathological complete response (pCR 24% vs 2.2%) and event-free survival.
Nivolumab (Neoadjuvant)
Opdivo® · PD-1 inhibitor + platinum chemo (CheckMate 816)
Adult dose
Nivolumab 360 mg IV Day 1 + platinum doublet IV; 21-day cycle × 3 cycles pre-operatively, followed by surgery within 6 weeks
PBS status
⚕ PBS Authority Required
Stereotactic Body Radiotherapy (SBRT) / SABR
Stereotactic ablative body radiotherapy (SABR/SBRT) is the standard of care for medically inoperable Stage I–II NSCLC and is increasingly discussed as an alternative to surgery for high-risk operable patients. Local control rates exceed 90% at 3 years.
SBRT dose regimens (per TROG guidelines): Peripheral tumours: 54 Gy in 3 fractions (BED₁₀ >100 Gy). Central tumours: 50–60 Gy in 5–8 fractions (risk-adapted). Ultra-central tumours (touching proximal bronchial tree/oesophagus): 50–60 Gy in 8 fractions. Treatment delivery typically completed in 1–2 weeks.
- CT simulation with 4D-CT for respiratory motion management is mandatory
- Image-guided radiotherapy (IGRT) with cone-beam CT at each fraction
- Available at all major radiation oncology centres across Australia; regional access via telehealth-linked treatment planning
- Local control >90% at 3 years; comparable to surgery for T1 tumours in propensity-matched analyses
- Toxicity: radiation pneumonitis (Grade 2+ ~5–10%), rib fracture, chest wall pain
Advanced Stage Treatment (Stage IIIB–IV)
Treatment of advanced NSCLC is guided by three key assessments: (1) PD-L1 expression, (2) molecular driver mutation status, and (3) patient fitness (ECOG PS). The treatment algorithm has become increasingly complex with multiple concurrent testing modalities informing treatment selection.
First-Line Treatment Algorithm
1
Molecular Testing Priority
Request comprehensive NGS panel (EGFR, ALK, ROS1, BRAF, KRAS G12C, MET ex14, RET, NTRK, HER2) AND PD-L1 IHC on all biopsy specimens. Results guide treatment selection.
2
Driver Mutation Positive?
If actionable mutation identified → targeted therapy as first-line. If no actionable mutation → proceed to PD-L1-based immunotherapy algorithm.
3
PD-L1-Based Selection (Driver Negative)
PD-L1 ≥50% → pembrolizumab monotherapy OR pembrolizumab + chemo. PD-L1 1–49% → pembrolizumab + platinum doublet. PD-L1 <1% → pembrolizumab + platinum doublet OR carboplatin + paclitaxel + bevacizumab + atezolizumab.
Platinum-Doublet Chemotherapy Regimens
For patients without targetable mutations and where immunotherapy is contraindicated or as the chemotherapy backbone in chemoimmunotherapy combinations:
| Regimen | Histology | Schedule | Cycles |
|---|---|---|---|
| Cisplatin + Pemetrexed | Non-squamous | Cisplatin 75 mg/m² + Pemetrexed 500 mg/m² q21d | 4–6 + maintenance pemetrexed |
| Carboplatin + Pemetrexed | Non-squamous | Carboplatin AUC 5 + Pemetrexed 500 mg/m² q21d | 4–6 + maintenance pemetrexed |
| Carboplatin + Paclitaxel | Squamous or non-squamous | Carboplatin AUC 6 + Paclitaxel 200 mg/m² q21d | 4–6 cycles |
| Carboplatin + Gemcitabine | Squamous | Carboplatin AUC 5 Day 1 + Gemcitabine 1000 mg/m² Days 1,8 q21d | 4–6 cycles |
| Cisplatin + Gemcitabine | Squamous | Cisplatin 75 mg/m² Day 1 + Gemcitabine 1250 mg/m² Days 1,8 q21d | 4–6 cycles |
| Carboplatin + Docetaxel | Squamous or non-squamous | Carboplatin AUC 6 + Docetaxel 75 mg/m² q21d | 4–6 cycles |
Important: Cisplatin-based regimens are preferred over carboplatin in patients with adequate renal function (eGFR ≥60 mL/min) and good PS (ECOG 0–1), as cisplatin is associated with a modest survival advantage. Carboplatin is the default for eGFR <60, ECOG 2, elderly (≥70), or comorbid patients. All patients require antiemetic prophylaxis (5-HT3 antagonist + dexamethasone ± NK1 antagonist for cisplatin).
Immunotherapy
Immune checkpoint inhibitors (ICIs) targeting the PD-1/PD-L1 axis have transformed the treatment landscape for NSCLC, producing durable responses in 15–25% of patients and significantly improving overall survival. Immunotherapy is now standard of care in the first-line, second-line, adjuvant, consolidation (Stage III), and neoadjuvant settings.
PD-1/PD-L1 Inhibitors — Approved Agents
Pembrolizumab
Keytruda® · PD-1 inhibitor · First-line backbone
Monotherapy (PD-L1 ≥50%)
200 mg IV q3 weeks or 400 mg IV q6 weeks; until progression or max 24 months
Combo with chemo
200 mg IV q3 weeks + carboplatin AUC 5 + pemetrexed 500 mg/m² (non-squamous); 4 cycles chemo then pemetrexed + pembrolizumab maintenance
2nd line
200 mg IV q3 weeks for PD-L1 TPS ≥1% (previously treated)
Renal adjustment
No adjustment required
PBS status
⚕ PBS Authority Required
Nivolumab
Opdivo® · PD-1 inhibitor · Neoadjuvant + 2nd line
2nd line dose
240 mg IV q2 weeks or 480 mg IV q4 weeks; until progression
Neoadjuvant (CheckMate 816)
360 mg IV q3 weeks × 3 cycles + platinum chemo, then surgery
PBS status
⚕ PBS Authority Required
Atezolizumab
Tecentriq® · PD-L1 inhibitor · Multiple indications
First-line combo
1200 mg IV q3 weeks + carboplatin AUC 6 + paclitaxel 200 mg/m² ± bevacizumab 15 mg/kg (IMpower150 — non-squamous)
Adjuvant
840 mg q2w / 1200 mg q3w / 1680 mg q4w for 12 months post-chemo (Stage II–IIIA, PD-L1 ≥1%)
PBS status
⚕ PBS Authority Required
Durvalumab
Imfinzi® · PD-L1 inhibitor · Stage III consolidation
Consolidation dose
10 mg/kg IV q2 weeks or 1500 mg IV q4 weeks; for up to 12 months (PACIFIC regimen)
Eligibility
Unresectable Stage III NSCLC, no progression after concurrent chemoradiation, ECOG 0–1
PBS status
⚕ PBS Authority Required
Combination Strategies
| Setting | Regimen | Key Trial | PD-L1 Requirement |
|---|---|---|---|
| 1st line, PD-L1 ≥50% | Pembrolizumab monotherapy | KEYNOTE-024 | TPS ≥50% |
| 1st line, non-squamous | Pembrolizumab + carboplatin + pemetrexed | KEYNOTE-189 | All comers |
| 1st line, squamous | Pembrolizumab + carboplatin + paclitaxel/nab-paclitaxel | KEYNOTE-407 | All comers |
| 1st line, non-squamous (bevacizumab eligible) | Atezolizumab + bevacizumab + carboplatin + paclitaxel | IMpower150 | All comers (no EGFR/ALK) |
| Stage III, post-CRT | Durvalumab consolidation | PACIFIC | All comers |
| 2nd line | Nivolumab monotherapy | CheckMate 017/057 | Not required |
| Nivo + Ipi (1st line, PD-L1 ≥1%) | Nivolumab + ipilimumab ± chemo | CheckMate 227 / 9LA | TC ≥1% (227) / All comers (9LA) |
Immune-Related Adverse Events (irAEs)
Critical safety information: irAEs can affect any organ system and may occur weeks to months after treatment initiation, or even after discontinuation. Grade 3–4 irAEs occur in 10–20% of patients. Pneumonitis is the most dangerous irAE in NSCLC (mortality 10–50% if Grade ≥3 and treatment delayed). Any new or worsening respiratory symptoms on immunotherapy require urgent CT chest and specialist review.
| irAE | Incidence | Key Features | Management |
|---|---|---|---|
| Pneumonitis | 3–5% (Grade ≥3: 1–2%) | Cough, dyspnoea, new ground-glass opacities on CT | Grade 2: Hold ICI, prednisolone 1–2 mg/kg/day, taper over ≥4 weeks. Grade 3–4: Permanently discontinue, methylprednisolone 1–2 mg/kg IV, add infliximab or mycophenolate if refractory. |
| Colitis | 1–4% | Diarrhoea, abdominal pain, raised CRP/faecal calprotectin | Grade 2: Hold ICI, prednisolone 1 mg/kg. Grade 3–4: Discontinue, IV steroids, infliximab if steroid-refractory. |
| Hepatitis | 1–3% | Elevated ALT/AST, may be asymptomatic | Grade 2: Hold, prednisolone 0.5–1 mg/kg. Grade 3–4: Discontinue, IV steroids, mycophenolate if refractory (avoid infliximab). |
| Endocrinopathy | 5–10% | Thyroiditis/hypothyroidism, hypophysitis, adrenal insufficiency, Type 1 DM | Thyroid: levothyroxine replacement; continue ICI if mild. Hypophysitis: hydrocortisone replacement, may continue ICI. Adrenal crisis: urgent IV hydrocortisone 100 mg stat. |
| Nephritis | 1–2% | Rising creatinine, proteinuria, eosinophiluria | Grade 2: Hold, prednisolone 0.5–1 mg/kg. Grade 3–4: Discontinue, IV steroids. |
| Dermatological | 15–30% | Maculopapular rash, pruritus, vitiligo (associated with response) | Topical corticosteroids for mild; oral steroids for severe. May continue ICI for mild–moderate. |
Biomarker Testing for Immunotherapy
- PD-L1 TPS (22C3 pharmDx): Required for all advanced NSCLC. TPS ≥50%: high expression; TPS 1–49%: low expression; TPS <1%: negative. Used to guide pembrolizumab monotherapy eligibility.
- PD-L1 TC/IC (SP142 and SP263): Used for atezolizumab (IMpower studies). Different assays may give discordant results — assays are not interchangeable.
- Tumour mutational burden (TMB): Not routinely recommended in Australia. High TMB (≥10 mutations/Mb) may predict benefit from immunotherapy but is not a required companion diagnostic.
- Microsatellite instability (MSI-H) / dMMR: Rare in NSCLC (<1%) but pembrolizumab approved as tumour-agnostic indication (KEYNOTE-158).
Targeted Therapy
Molecular-targeted therapies represent the most significant advance in NSCLC treatment for patients with actionable driver mutations. These agents produce superior progression-free survival, response rates, and quality of life compared with chemotherapy, and should be used as first-line therapy when a targetable alteration is identified.
Testing before treatment: Comprehensive molecular testing (NGS panel) must be completed before initiating first-line therapy for advanced NSCLC. Do not start empiric chemotherapy while awaiting results — treatment should be guided by molecular profile. If tissue is insufficient, use liquid biopsy (ctDNA) as a complementary approach.
EGFR-Mutant NSCLC
EGFR mutations (exon 19 deletion and L858R point mutation account for ~85% of EGFR mutations) are the most common actionable drivers in Australian NSCLC, found in 15–25% of adenocarcinomas, predominantly in never-smokers and those of Asian ancestry.
Osimertinib
Tagrisso® · 3rd-generation EGFR TKI · Preferred first-line
Adult dose
80 mg PO once daily; continue until progression or unacceptable toxicity
Key indications
1st line: EGFR ex19del or L858R (FLAURA trial). 2nd line: T790M resistance mutation. Adjuvant: Stage IB–IIIA (ADAURA trial)
Renal adjustment
No adjustment for mild–moderate impairment. Caution if eGFR <15 mL/min.
Hepatic adjustment
No adjustment for mild impairment. Monitor closely if moderate–severe.
Key AEs
Diarrhoea (47%), rash (40%), paronychia (25%), QTc prolongation, interstitial lung disease (3–4%)
PBS status
⚕ PBS Authority Required
Gefitinib
Iressa® · 1st-generation EGFR TKI
Adult dose
250 mg PO once daily
Renal adjustment
No adjustment
PBS status
⚕ PBS Authority Required
Erlotinib
Tarceva® · 1st-generation EGFR TKI
Adult dose
150 mg PO once daily (100 mg if hepatic impairment)
PBS status
⚕ PBS Authority Required
ALK-Rearranged NSCLC
ALK rearrangements are found in 3–7% of NSCLC adenocarcinomas, predominantly in younger patients and never/light smokers. Multiple generations of ALK inhibitors are available with sequential benefit at progression.
Alectinib
Alecensa® · 2nd-generation ALK TKI · Preferred first-line
Adult dose
600 mg PO BD with food; continue until progression
Key advantage
Superior CNS penetration; 81% intracranial response rate. ALEX trial: median PFS 34.8 months vs 10.9 months (crizotinib)
Key AEs
Myalgia, oedema, constipation, elevated LFTs, bradycardia
PBS status
⚕ PBS Authority Required
Lorlatinib
Lorviqua® · 3rd-generation ALK TKI · Preferred after alectinib
Adult dose
100 mg PO once daily; can be used 1st line (CROWN trial: median PFS not reached at 5 years)
Key advantage
Broadest ALK resistance coverage; excellent CNS activity. CROWN trial 5-year PFS 60% (1st line).
Key AEs
Hypercholesterolaemia (81%), hypertriglyceridaemia, weight gain, cognitive effects, peripheral neuropathy, oedema
PBS status
⚕ PBS Authority Required
ROS1-Rearranged NSCLC
Crizotinib
Xalkori® · Multi-kinase inhibitor (ALK/ROS1/MET)
Adult dose
250 mg PO BD; ORR ~72% in ROS1+ NSCLC
Key limitation
Poor CNS penetration — limited efficacy for brain metastases
PBS status
⚕ PBS Authority Required
Entrectinib
Rozlytrek® · TRK/ROS1/ALK TKI · CNS-active
Adult dose
600 mg PO once daily with food; preferred for CNS metastases
PBS status
⚕ PBS Authority Required
BRAF V600E-Mutant NSCLC
Dabrafenib + Trametinib
Tafinlar® + Mekinist® · BRAF + MEK inhibitor combination
Adult dose
Dabrafenib 150 mg PO BD + Trametinib 2 mg PO once daily; ORR ~64%, median PFS 10.2 months
Key AEs
Pyrexia (50%), fatigue, nausea, skin rash, peripheral oedema, decreased LVEF
PBS status
⚕ PBS Authority Required
KRAS G12C-Mutant NSCLC
Sotorasib
Lumakras® · First-in-class KRAS G12C inhibitor
Adult dose
960 mg PO once daily with food; for previously treated KRAS G12C+ NSCLC. ORR 28%, median PFS 6.8 months (CodeBreaK 200)
Key AEs
Diarrhoea, hepatotoxicity (monitor LFTs), nausea, fatigue
PBS status
✖ Not PBS-listed (access via compassionate/SAS)
Other Emerging Targets
| Target | Agent | Key Data | Australian Access |
|---|---|---|---|
| MET exon 14 skipping | Capmatinib (Tabrecta®), tepotinib (Tepmetko®) | ORR 41–68%; responses in treatment-naïve and pre-treated | SAS / compassionate access |
| RET rearrangement | Selpercatinib (Retevmo®), pralsetinib (Gavreto®) | ORR 61–85% (treatment-naïve); LIBRETTO-431, ARROW trials | PBS Authority Required (selpercatinib — 2024 listing) |
| NTRK fusion | Larotrectinib (Vitrakvi®), entrectinib (Rozlytrek®) | ORR 57–75% (tumour-agnostic); rare in NSCLC | SAS / compassionate access |
| HER2 mutation | Trastuzumab deruxtecan (Enhertu®) | DESTINY-Lung02: ORR ~49%; antibody-drug conjugate | SAS / compassionate access |
Resistance Mechanisms
Resistance to targeted therapy is inevitable and is broadly classified as on-target (alteration in the target itself) or off-target (activation of bypass signalling pathways):
- EGFR TKI resistance: T790M (1st/2nd gen TKIs — treat with osimertinib); C797S (osimertinib); MET amplification (15–20%); SCLC histological transformation (3–10%); HER2 amplification; RAS-MAPK pathway activation
- ALK TKI resistance: ALK secondary mutations (G1202R — sensitive to lorlatinib); ALK amplification; bypass signalling (EGFR, KIT, RAS)
- Management at progression: Re-biopsy (tissue and/or liquid) to identify resistance mechanism and guide subsequent therapy. Participation in clinical trials encouraged.
Supportive Care & Palliative Management
Supportive care is integral to NSCLC management at all stages and should be introduced early alongside active treatment. Early palliative care integration has been shown to improve quality of life and overall survival in metastatic NSCLC (Temel et al., NEJM 2010).
Palliative Radiotherapy
Brain Metastases — WBRT
Whole Brain Radiotherapy
Regimen
20 Gy in 5 fractions or 30 Gy in 10 fractions; for multiple brain metastases not amenable to SRS
Note
For driver mutation-positive NSCLC with controlled systemic disease and oligometastatic brain mets, TKI therapy alone may be appropriate; defer WBRT if possible.
Brain Metastases — SRS
Stereotactic Radiosurgery
Indication
1–4 brain metastases (up to 10 per some guidelines), each <3 cm, for local control with cognitive preservation
Dose
18–24 Gy single fraction (per lesion size and location); available at major centres
Bone Metastases
Palliative Radiotherapy
Regimen
8 Gy single fraction (preferred for simplicity and equivalence) or 30 Gy in 10 fractions for more durable palliation
Spinal cord compression
URGENT — dexamethasone 16 mg IV stat + 4 mg QID, MRI spine same day, consider surgical decompression + radiotherapy. 20 Gy/5# or 30 Gy/10#.
Pleural Effusion Management
1
Diagnostic Aspiration
Ultrasound-guided thoracentesis for cytology, biochemistry (exudate vs transudate), and symptom relief. Send 50–100 mL for cytology (sensitivity 60% for malignant effusion).
2
Indwelling Pleural Catheter (IPC)
PleurX® catheter for recurrent malignant effusions; preferred over repeated thoracentesis. Allows home drainage, reduces hospital admissions. Inserted as day procedure under local anaesthesia.
3
Talc Pleurodesis
Chemical pleurodesis via chest tube (talc slurry) or VATS (poudrage) for trapped lung with confirmed malignant effusion. Success rate ~80%. Consider only if lung fully re-expands.
Pain Management
Cancer pain in NSCLC is multifactorial (tumour invasion, bone metastases, neuropathic pain from nerve involvement, treatment-related). Use the WHO analgesic ladder with modification:
WHO Step 1 — Mild Pain
Paracetamol ± NSAID
Paracetamol
1 g PO/IV QID (max 4 g/day; 2 g/day if hepatic impairment or body weight <50 kg)
Ibuprofen
200–400 mg PO TDS with food; PPI cover. Contraindicated if eGFR <30 mL/min.
WHO Step 2 — Moderate Pain
Tramadol or low-dose morphine
Tramadol
50–100 mg PO Q4–6H (max 400 mg/day). Reduce dose if eGFR <30. Avoid with SSRIs/SNRIs (serotonin syndrome risk).
Low-dose morphine
Consider directly stepping to morphine 2.5–5 mg PO Q4H (modified-release) + immediate-release for breakthrough.
WHO Step 3 — Severe Pain
Strong opioids: Morphine, oxycodone, fentanyl
Morphine
Oral morphine 5–10 mg Q4H (immediate-release) or 10–30 mg BD (modified-release); titrate. Breakthrough: 1/6th of total 24-hour dose. Reduce dose if eGFR <30 (active metabolites accumulate).
Fentanyl patch
12–25 mcg/hr patch q72H (for stable pain on established oral opioid dose — NOT for opioid-naive). Useful if swallowing difficulty or renal impairment.
Neuropathic component
Add pregabalin 25–75 mg BD, titrate to 150–300 mg BD; or duloxetine 30 mg OD → 60 mg OD; or amitriptyline 10 mg nocte.
Bone-Modifying Agents
Denosumab
Xgeva® · RANK-L inhibitor for bone metastases
Adult dose
120 mg SC every 4 weeks; reduces skeletal-related events (pathological fracture, spinal cord compression, need for radiotherapy)
Key precautions
Monitor calcium (hypocalcaemia risk); supplement calcium + vitamin D. Avoid if dental extraction pending (osteonecrosis of jaw risk). Renal impairment: increased hypocalcaemia risk.
PBS status
⚕ PBS Authority Required
Zoledronic Acid
Aclasta® / Zometa® · Bisphosphonate alternative
Adult dose
4 mg IV over ≥15 minutes every 3–4 weeks. Adjust for renal function: eGFR 50–60: reduce to 3.5 mg; eGFR 40–50: 3.3 mg; eGFR <30: avoid.
PBS status
⚕ PBS Authority Required
Palliative Chemotherapy
Palliative-intent chemotherapy aims to improve symptoms, quality of life, and survival. Treatment decisions balance benefit against toxicity, considering comorbidities, patient preference, and PS. Maintenance therapy (pemetrexed for non-squamous, pembrolizumab for responders) extends benefit after initial response.
Best supportive care (BSC): For patients with ECOG 3–4, poor organ function, or preference for no active treatment, BSC encompasses symptom management (palliative radiotherapy, analgesia, antiemetics, corticosteroids, nutritional support), psychosocial support, and advance care planning. Referral to specialist palliative care should be offered to all patients with advanced NSCLC from the time of diagnosis.
Monitoring
Post-Treatment Surveillance (Curative Intent)
0–2 years
CT chest ± contrast every 6 months; clinical review every 3 months. Low-dose CT preferred if contrast not needed.
2–5 years
CT chest annually; clinical review every 6 months.
After 5 years
Annual low-dose CT; clinical review annually. Continue indefinitely given risk of second primary lung cancer (~2% per year).
Monitoring During Systemic Therapy
| Therapy | Monitoring Parameters | Frequency |
|---|---|---|
| Chemotherapy | FBC (nadir), LFTs, renal function (eGFR), electrolytes, CT response assessment q6–9 weeks | Pre each cycle; CT every 2–3 cycles |
| Immunotherapy | TFTs, LFTs, cortisol, glucose, renal function, FBC; CT response q9–12 weeks | Every cycle; TFTs/cortisol q6–8 weeks |
| EGFR TKIs | LFTs, ECG (QTc — osimertinib), electrolytes; CT response q6–12 weeks | Monthly LFTs initially; ECG baseline + 1 month |
| ALK inhibitors | LFTs, CPK, lipids (lorlatinib), ECG (bradycardia), blood glucose; CT response q6–12 weeks | Monthly initially; lipid panel with lorlatinib |
| Bone-modifying agents | Calcium, phosphate, magnesium (each cycle); renal function; dental review q6–12 months | Pre each infusion; dental within 3 months of starting |
Response Assessment
- RECIST 1.1: Standard criteria for assessing response on CT — complete response (CR), partial response (PR), stable disease (SD), progressive disease (PD)
- iRECIST: Modified criteria for immunotherapy — allows for pseudoprogression (initial tumour growth followed by response). Confirmation scan at 4–8 weeks recommended before declaring progression on immunotherapy.
- Pseudoprogression: Occurs in ~5–10% of immunotherapy patients. If clinical status stable, continue immunotherapy and re-scan in 4–8 weeks before changing treatment.
Special Populations
Pregnancy
All systemic anti-cancer therapies
Contraindicated in pregnancy (teratogenic). Chemotherapy is teratogenic in the first trimester; platinum agents may be used in the 2nd/3rd trimester in exceptional cases under multidisciplinary guidance. Immunotherapy and targeted therapies lack safety data and should not be used in pregnancy.
Radiotherapy
Avoid during pregnancy if possible. Thoracic radiotherapy may deliver scatter dose to the foetus. Termination of pregnancy may be discussed in the context of curative-intent treatment.
Multidisciplinary approach
Urgent MDT involving oncology, obstetrics, neonatology, and ethics. Treatment delay for early-stage disease is generally not appropriate — early delivery or termination of pregnancy should be discussed.
Paediatrics & Young Adults
NSCLC in young adults
Rare in patients <40 years (<2% of cases). Higher prevalence of targetable driver mutations (EGFR, ALK, ROS1, RET, NTRK). Enrolment in clinical trials and molecular profiling is strongly encouraged.
Fertility preservation
Discuss fertility preservation before initiating chemotherapy or radiotherapy in patients of reproductive age. Sperm banking, oocyte/embryo cryopreservation. Refer to fertility specialist where available.
Elderly (≥70 years)
Chemotherapy
Carboplatin-based doublets preferred over cisplatin (less nephrotoxicity, less emetogenesis). Single-agent chemotherapy (gemcitabine, vinorelbine, or docetaxel) may be appropriate for frail elderly. Geriatric assessment tools (G8, VES-13) should guide fitness evaluation.
Immunotherapy
Well tolerated in elderly; no dose adjustment required. Age alone should not preclude immunotherapy. irAE rates may be slightly higher but manageable.
Targeted therapy
TKIs are generally well tolerated in elderly and are preferred over chemotherapy when driver mutation present. Consider drug interactions (polypharmacy) and renal/hepatic function.
Surgery
Age is not an absolute contraindication to surgery. Physiological age (cardiopulmonary reserve, frailty index) is more important than chronological age. VATS preferred; sublobar resection if marginal pulmonary function.
Renal Impairment
Cisplatin
Contraindicated if eGFR <60 mL/min. Use carboplatin (AUC-based dosing with measured GFR). Adequate IV hydration mandatory with cisplatin (≥3 L NS).
Pemetrexed
Contraindicated if eGFR <45 mL/min. No alternative available — substitute with paclitaxel or gemcitabine-based regimen.
Immunotherapy / TKIs
No dose adjustment for immunotherapy. Most TKIs (osimertinib, alectinib) require no adjustment in mild–moderate renal impairment. Monitor closely for nephritis on immunotherapy.
Hepatic Impairment
Chemotherapy
Reduce vinorelbine if bilirubin >1.5× ULN. Docetaxel: avoid if severe hepatic impairment. Gemcitabine: use with caution if bilirubin >1.5× ULN.
Immunotherapy
No formal dose adjustment but increased risk of immune-mediated hepatitis. Monitor LFTs closely. Hepatotoxicity may be difficult to distinguish from disease progression or irAE.
TKIs
Erlotinib: reduce to 100 mg if moderate hepatic impairment. Osimertinib/alectinib: no adjustment for mild impairment; caution with moderate–severe. Monitor LFTs monthly.
Immunocompromised
Organ transplant recipients
ICIs carry high risk of allograft rejection (30–40%). Use with extreme caution and only after discussion with transplant team. Targeted therapy and chemotherapy are generally safer options.
HIV-positive patients
ICIs can be used safely if CD4 count >100 cells/µL and viral load controlled. irAE rates may be higher but manageable. Continue antiretroviral therapy. Close monitoring required.
Autoimmune disease
ICIs may exacerbate pre-existing autoimmune conditions. Risk–benefit discussion essential. May require increased immunosuppression for flare. TKIs and chemotherapy may be preferred in severe autoimmune disease.
Aboriginal and Torres Strait Islander Health
Aboriginal and Torres Strait Islander Australians experience a disproportionate burden of lung cancer, with incidence approximately 1.6 times and mortality 1.8 times that of non-Indigenous Australians (AIHW 2023). Lung cancer is the most commonly diagnosed cancer and leading cause of cancer death among Indigenous Australians. The disparity is driven by higher smoking prevalence (40% vs 11% in non-Indigenous), later-stage diagnosis, reduced access to specialist services in regional and remote areas, and lower treatment uptake rates.
Closing the gap in lung cancer care: Strategies include embedding Aboriginal health workers/liaison officers in cancer MDTs and treatment centres, supporting regional treatment hubs to reduce patient travel, providing culturally safe patient information resources (e.g., Cancer Council resources in Indigenous languages), integrating smoking cessation into all cancer care touchpoints, and ensuring PBS Close the Gap co-payment is applied to all eligible medications.
📚 References
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