Teaching pack: Non-small-cell lung cancer

Non-small-cell lung cancer is ~85% of lung cancer and the leading cause of cancer death worldwide (~1.8 million deaths a year, all lung cancer). Adenocarcinoma (~50%) and squamous cell carcinoma (~25-30%) dominate; large-cell and other histologies make up the rest. Roughly half of adenocarcinomas carry a targetable driver (EGFR ~15% Western/40-50% East Asian, KRAS ~30% Western, ALK ~5%, MET ex14 ~3%, HER2 ~2-3%, BRAF V600E ~2%, RET ~1-2%, ROS1 ~1-2%, NTRK <1%), which makes broad genomic profiling at diagnosis mandatory. Tobacco drives most squamous and KRAS-mutant disease; never-smoker adenocarcinoma, increasingly common in East Asian women, is EGFR- and ALK-enriched.

Care is organised by stage and driver. Low-dose CT screening (NLST, NELSON) cuts mortality but is under-used. Early-stage disease is resected (lobectomy or, for small peripheral tumours, segmentectomy) or ablated with SBRT; perioperative immunotherapy (CheckMate 816, KEYNOTE-671) and adjuvant targeted therapy (ADAURA for EGFR, ALINA for ALK) are standard. Stage III unresectable disease gets chemoradiation followed by durvalumab (PACIFIC) or osimertinib if EGFR-mutant (LAURA). Metastatic driver-positive disease receives a matched TKI or bispecific first (osimertinib or amivantamab-lazertinib; lorlatinib or alectinib; repotrectinib or zidesamtinib; sotorasib or adagrasib after chemo-IO; selpercatinib; capmatinib or tepotinib; zongertinib or sevabertinib; dabrafenib-trametinib), then chemotherapy and ADCs (Dato-DXd approved 2025 in EGFR-mutant disease). Driver-negative metastatic disease gets PD-(L)1 blockade with or without platinum doublets depending on PD-L1 TPS, with tremelimumab-durvalumab-chemotherapy for PD-L1-negative and STK11/KEAP1-altered tumours.

• 5-year PFS 60% with lorlatinib in ALK+ disease.
• Adjuvant osimertinib halves death risk.
• First regimen to beat osimertinib (MARIPOSA) and first to beat pembrolizumab (ivonescimab, China).
• Lorlatinib: 5-year PFS 60% in ALK-positive disease, the longest for any targeted therapy in metastatic solid tumours.
• Adjuvant osimertinib halves the risk of death (ADAURA, OS HR 0.49); adjuvant alectinib cuts recurrence by 76% (ALINA).
• Amivantamab + lazertinib is the first regimen to beat osimertinib, with median OS more than 12 months longer (MARIPOSA).

1. 2002Gefitinib approved; dramatic responses in a minority
2. 2004EGFR mutations explain gefitinib responses
3. 2004EGFR mutations explain gefitinib responses
4. 2007EML4-ALK fusion discovered
5. 2007EML4-ALK fusion discovered
6. 2011NLST: CT screening reduces mortality 20%
7. 2011NLST: low-dose CT screening reduces mortality 20%
8. 2015Nivolumab beats docetaxel; immunotherapy era
9. 2015Nivolumab beats docetaxel: immunotherapy era
10. 2017PACIFIC: durvalumab consolidation in stage III

• Ivonescimab (product)
• Izalontamab brengitecan (product)
• Sacituzumab tirumotecan (product)
• Tilatamig samrotecan (product)
• Daraxonrasib (product)
• Patritumab deruxtecan (product)
• Intismeran autogene (product)
• Zidesamtinib (product)
• Neladalkib (product)
• ALKOVE-1 (trial)
• Divarasib (product)
• Krascendo 1 (trial)

• KEYNOTE-024 & KEYNOTE-189 (phase 3, n=921): KEYNOTE-024: overall survival at 5 years, PD-L1 ≥50%: 31.9% vs 16.3%, HR 0.62
• KEYNOTE-671 (phase 3, n=797): Event-free survival: 47.2 months vs 18.3 months, HR 0.59
• FLAURA2 (phase 3, n=557): Progression-free survival (investigator): 25.5 months vs 16.7 months, HR 0.62
• PACIFIC (phase 3, n=713): Progression-free survival (BICR): 16.8 months vs 5.6 months, HR 0.52
• CodeBreaK 200 (phase 3, n=345): Progression-free survival (BICR): 5.6 months vs 4.5 months, HR 0.66
• KRYSTAL-12 (phase 3, n=453): Progression-free survival (BICR): 5.5 months vs 3.8 months, HR 0.58

• Resistance to every TKI.
• Squamous histology has few targets.
• Screening uptake below 20% in the US.
• Screening uptake is under 20% in the US and lower elsewhere; never-smoker adenocarcinoma has no screening pathway.
• Resistance to every TKI is near-universal in metastatic disease; C797S has no approved fourth-generation EGFR inhibitor and small-cell transformation is undetectable by ctDNA.
• Squamous cell carcinoma has almost no targeted options and no approved ADC.

1. Which biomarkers must be tested at diagnosis of advanced non-small-cell lung cancer?
   Answer

   EGFR, ALK, ROS1, BRAF V600E, MET exon 14/amplification, RET, NTRK, KRAS G12C, HER2 mutations, and PD-L1 TPS.
2. Which TROP2 ADCs are approved for first-line metastatic triple-negative breast cancer?
   Answer

   Sacituzumab govitecan (Trodelvy), as monotherapy for PD-1-ineligible patients (ASCENT-03) and with pembrolizumab for PD-L1 CPS ≥10 disease (ASCENT-04), and datopotamab deruxtecan (Datroway) for PD-1/PD-L1-ineligible patients (TROPION-Breast02), both approved in 2026.
3. What does 'triple-negative' mean in breast cancer?
   Answer

   The tumour lacks the three receptors other breast cancers can be treated through: oestrogen receptor, progesterone receptor, and HER2 (IHC 0-1+ or 2+/ISH-negative).
4. 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.
5. Which trial showed the first overall survival benefit for a first-line ADC in triple-negative breast cancer?
   Answer

   TROPION-Breast02: datopotamab deruxtecan vs chemotherapy in first-line PD-1/PD-L1-ineligible metastatic TNBC, OS 23.7 vs 18.7 months.
6. What is the first bispecific ADC to succeed in a phase 3 trial, and in which cancer?
   Answer

   Izalontamab brengitecan (iza-bren, BL-B01D1), an EGFR×HER3 bispecific ADC from SystImmune/BMS, met PFS and OS in previously treated TNBC (BL-B01D1-307, February 2026) and also in oesophageal squamous cell carcinoma.

• Wikipedia: https://en.wikipedia.org/wiki/Non-small-cell_lung_cancer
• Guideline: https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1450
• Guideline: https://pmc.ncbi.nlm.nih.gov/articles/PMC11163648/