Teaching pack: Resectable stage I to III non-small-cell lung cancer

Surgery has cured lung cancer since Evarts Graham's pneumonectomy in 1933, and lobectomy with mediastinal node dissection became the standard after the 1995 Lung Cancer Study Group trial found more recurrences with lesser resections. Staging rests on PET-CT and, for central or node-suspicious tumours, endobronchial ultrasound sampling of the mediastinum; brain MRI is added from stage II. Two trials in 2022 and 2023, JCOG0802 and CALGB 140503, showed that segmentectomy or wedge resection is as good as lobectomy for peripheral tumours of 2 cm or less, the tumours that screening finds, and most resections are now by video-assisted or robotic thoracoscopy. Stereotactic radiotherapy cures most stage I tumours in patients who cannot have surgery (CHISEL, JCOG0403). Adjuvant cisplatin doublet chemotherapy, established by the LACE meta-analysis in 2008, adds about 5 percent to five-year survival in stage II and III.

The decade since 2020 has added systemic therapy on both sides of the operation. ADAURA (2020) showed that three years of adjuvant osimertinib in EGFR-mutated stage IB to IIIA cut recurrence by 83 percent and improved five-year survival from 78 to 88 percent, and ALINA (2024) did the same for two years of alectinib in ALK-positive disease (hazard ratio 0.24). For the majority without a driver, IMpower010 (2021) showed adjuvant atezolizumab improved disease-free survival in PD-L1-positive stage II to IIIA (hazard ratio 0.66), CheckMate 816 (2022) showed that three cycles of nivolumab with chemotherapy before surgery raised pathological complete response from 2 to 24 percent and improved event-free and, later, overall survival, and the perioperative trials that give immunotherapy before and after surgery, KEYNOTE-671 (pembrolizumab, event-free survival hazard ratio 0.58, overall survival hazard ratio 0.72), AEGEAN (durvalumab, hazard ratio 0.68) and CheckMate 77T (nivolumab, hazard ratio 0.58), all followed, with approvals between 2022 and 2024.

• Perioperative chemoimmunotherapy (CheckMate 816, KEYNOTE-671, AEGEAN, CheckMate 77T) cuts recurrence by about 40 percent and improves survival in driver-negative disease.
• Targeted adjuvant therapy for EGFR (ADAURA) and ALK (ALINA) tumours with hazard ratios of 0.17 and 0.24 for recurrence.
• Sublobar resection is an accepted standard for small peripheral tumours.
• Low-dose CT screening is shifting diagnoses toward stage I.

1. 1933Evarts Graham performs the first successful pneumonectomy for lung cancer
2. 1995Lung Cancer Study Group: lobectomy beats limited resection, setting the standard for 30 years
3. 2008LACE meta-analysis: adjuvant cisplatin chemotherapy adds about 5 percent to five-year survival
4. 2011NLST: low-dose CT screening cuts lung cancer mortality by 20 percent, finding more early-stage tumours
5. 2020ADAURA: adjuvant osimertinib for EGFR-mutated disease
6. 2021IMpower010: adjuvant atezolizumab improves disease-free survival in PD-L1-positive stage II to IIIA
7. 2022CheckMate 816: neoadjuvant nivolumab plus chemotherapy raises pathological complete response from 2 to 24 percent
8. 2023KEYNOTE-671 and AEGEAN: perioperative pembrolizumab and durvalumab; CALGB 140503: sublobar resection non-inferior
9. 2024ALINA: adjuvant alectinib for ALK-positive disease; CheckMate 77T perioperative nivolumab approved

• MRD / molecular residual disease testing (technology)
• Circulating tumour DNA (ctDNA) (term)
• A Study of Neoadjuvant Chemotherapy Plus Nivolumab Versus Neoadjuvant Chemotherapy Plus Placebo, Followed by Surgical Removal and Adjuvant Treatment With Nivolumab or Placebo for Participants With Surgically Removable Early Stage Non-small Cell Lung Cancer (trial)
• Formally qualify tumour-DNA blood tests as a surrogate endpoint for adjuvant trials (idea)
• Pre-surgery platform trials that test combinations on pathological response in months (idea)
• Use pre-surgery immunotherapy windows as the field's biomarker engine (idea)
• Low-dose CT lung screening (technology)
• Robotic and navigational bronchoscopy (technology)

• IALT (International Adjuvant Lung Cancer Trial) (phase 3, n=1,867): Overall survival at 5 years: 44.5% vs 40.4%, HR 0.86
• ANITA (Adjuvant Navelbine International Trialist Association) (phase 3, n=840): Overall survival (median): 65.7 months vs 43.7 months, HR 0.8
• Study to Assess Safety and Efficacy of Atezolizumab (MPDL3280A) Compared to Best Supportive Care Following Chemotherapy in Patients With Lung Cancer [ (phase 3, n=1,280): Disease-free survival, stage II to IIIA with PD-L1 on 1% or more of tumour cells: 68.5 months vs 37.3 months, HR 0.704
• KEYNOTE-671 (phase 3, n=797): Event-free survival: 47.2 months vs 18.3 months, HR 0.59
• Neotorch (phase 3, n=501): Event-free survival (stage III population): 15.1 months, HR 0.4
• ALINA (phase 3, n=257): Disease-free survival, stage II to IIIA: 44.4 months, HR 0.24

• Whether adjuvant immunotherapy adds anything after neoadjuvant treatment and surgery, especially for complete pathological responders, has not been tested directly.
• Circulating tumour DNA after surgery identifies high-risk patients but no trial yet shows that acting on it improves survival.
• About a fifth of patients given neoadjuvant therapy never reach surgery, from progression, toxicity or decline.
• Screening uptake is low in most countries, so most lung cancers are still found late.

1. What is the standard treatment for stage II-III triple-negative breast cancer today?
   Answer

   Neoadjuvant pembrolizumab with carboplatin/paclitaxel then anthracycline chemotherapy, surgery, and adjuvant pembrolizumab (KEYNOTE-522); adjuvant olaparib for germline BRCA carriers with residual disease (OlympiA); capecitabine for residual disease without BRCA.
2. What is pathologic complete response and why does it matter in TNBC?
   Answer

   pCR means no invasive cancer is left in the breast and lymph nodes when the surgeon removes the tissue after pre-surgery treatment. In TNBC patients with pCR have around 90% five-year event-free survival, and trials now test giving less treatment after pCR.
3. What questions should someone newly diagnosed with triple-negative breast cancer ask before surgery?
   Answer

   Whether chemo-immunotherapy before surgery (KEYNOTE-522) is planned and why; germline BRCA testing; PD-L1 and HER2-low status; TIL score; clinical trial options; fertility preservation; breast-conserving versus mastectomy and sentinel node approach; what response (pCR/RCB) will mean for treatment afterwards.
4. What is the standard adjuvant treatment after resection of EGFR-mutant lung cancer and what did it do to survival?
   Answer

   Three years of osimertinib (ADAURA): DFS HR 0.20 in stage II-IIIA and OS HR 0.49, five-year OS 88% vs 78%.
5. What was the first cancer drug approved on the basis of a blood test for leftover disease?
   Answer

   Atezolizumab for ctDNA-positive muscle-invasive bladder cancer after cystectomy (IMvigor011, using Signatera), approved Q2 2026; DFS HR 0.64, OS HR 0.59.
6. Can a blood test decide who needs chemotherapy after colon cancer surgery?
   Answer

   Yes in stage II: the DYNAMIC trial used ctDNA to guide adjuvant chemotherapy, halving its use (15% vs 28%) with non-inferior recurrence-free survival (93.5% vs 92.4% at two years).

• Wikipedia: https://en.wikipedia.org/wiki/Lung_cancer_surgery
• NCCN Guidelines: Non-Small Cell Lung Cancer: https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1450
• Wikipedia: https://en.wikipedia.org/wiki/Lung_cancer_surgery
• Guideline: https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1450