Teaching pack: Oesophageal cancer

Oesophageal cancer is two diseases: squamous cell carcinoma (ESCC, ~85% globally, driven by tobacco, alcohol, hot beverages, and nutritional factors along a belt from Iran through Central Asia to China) and adenocarcinoma (EAC, dominant in the West, arising from Barrett's oesophagus through reflux and obesity). Japan and parts of China screen high-risk populations endoscopically and cure early squamous cancers with endoscopic resection; elsewhere most patients present with dysphagia and locally advanced or metastatic disease. It causes about 510,000 new cases a year (the seventh most common cancer) and, because of late presentation, 445,000 deaths (sixth among cancers); five-year survival is about 20% overall.

Localised disease is treated with multimodality therapy. CROSS chemoradiation followed by oesophagectomy gives 10-year survival of 38% versus 25% for surgery alone; perioperative FLOT is the alternative for adenocarcinoma (ESOPEC favoured it). Definitive chemoradiation is used for cervical tumours and unfit patients. CheckMate 577 added a year of adjuvant nivolumab for residual disease after chemoradiation (DFS 22.4 vs 11.0 months), and SANO showed that patients with a clinical complete response can be watched rather than operated on with non-inferior survival. Advanced disease is treated with chemotherapy plus PD-1 blockade: pembrolizumab (KEYNOTE-590, both histologies), nivolumab ± ipilimumab (CheckMate 648, squamous), tislelizumab (RATIONALE-306, squamous PD-L1 ≥1%), and camrelizumab or sintilimab in China. HER2-positive adenocarcinoma follows the gastric pathway (trastuzumab, zanidatamab after HERIZON-GEA-01, T-DXd second line). In 2026 the EGFR×HER3 bispecific ADC izalontamab brengitecan became the first agent to improve overall survival in second-line ESCC after immunotherapy (PANKU-Esophagus01).

• Immunotherapy in first line and adjuvant.
• First bispecific ADC phase 3 success in ESCC.
• Chemoradiation before surgery (CROSS) has a durable 13-point 10-year survival gain; organ preservation after complete response is non-inferior (SANO).
• Adjuvant nivolumab doubles disease-free survival after incomplete response to chemoradiation (CheckMate 577), though OS was not significantly improved.
• Chemo-immunotherapy is first-line standard in both histologies, replicated in five phase 3 trials; PD-L1 defines the size of benefit.
• A chemotherapy-free immunotherapy doublet (nivolumab + ipilimumab) is an option in squamous disease.

1. 1913Torek performs the first successful oesophagectomy for cancer
2. 1980Cisplatin/5-FU chemoradiation defined (RTOG 85-01 reported 1992)
3. 1990Endoscopic mucosal resection for early oesophageal cancer (Japan)
4. 2006MAGIC: perioperative chemotherapy for GEJ adenocarcinoma
5. 2010ToGA includes GEJ adenocarcinoma: trastuzumab for HER2-positive disease
6. 2012CROSS: neoadjuvant chemoradiation
7. 2012CROSS: neoadjuvant chemoradiation becomes standard
8. 2019PD-1 blockade second line: pembrolizumab (KEYNOTE-181) and nivolumab (ATTRACTION-3)
9. 2021Checkpoint inhibitors first line
10. 2021CROSS 10-year data; CheckMate 577 adjuvant nivolumab; KEYNOTE-590 and ESCORT-1st first-line chemo-IO

• Izalontamab brengitecan (treatment)
• PF-08634404 (treatment)
• HS-20093 (treatment)
• QLC5508 (treatment)
• KC1036 (treatment)
• HLX43 (treatment)
• Gotistobart (treatment)
• Lerotinib (treatment)
• MCLA-129 (treatment)
• TQB6411 (treatment)
• HMBD-001 (treatment)
• AZD5863 (treatment)

• CheckMate 649 (phase 3, n=1,581): Overall survival, PD-L1 CPS ≥5: 14.4 months vs 11.1 months, HR 0.71
• CheckMate 648 (phase 3, n=970): Overall survival, PD-L1 ≥1% (nivolumab + chemotherapy): 15.4 months vs 9.1 months, HR 0.54
• CLARITY-Gastric 01 (phase 3, n=594): Overall survival, third-line or later (dual primary): Met with a statistically significant, clinically meaningful improvement per the sponsor (27 July 2026); OS in the whole second-line-or-later population (key secondary) also significant. Medians and hazard ratios pending presentation.
• ESCORT-1st (phase 3, n=596): Overall survival: 15.3 months vs 12 months, HR 0.7
• KEYNOTE-590 (phase 3, n=749): Overall survival, all patients: 12.4 months vs 9.8 months, HR 0.73
• RATIONALE-306 (phase 3, n=649): Overall survival, all patients: 17.2 months vs 10.6 months, HR 0.66

• Late presentation.
• Squamous cell carcinoma lacks targets beyond EGFR/HER3.
• Most patients present with advanced disease; no Western screening for squamous cancer and only trial-stage non-endoscopic screening for Barrett's.
• Adjuvant nivolumab improves DFS but not significantly OS; who truly needs it (PD-L1, ctDNA) is unknown.
• Squamous cell carcinoma has no validated molecular targets beyond PD-1 and, since 2026, EGFR/HER3 antigen delivery.
• PD-L1-negative tumours derive little from chemo-immunotherapy; alternatives are lacking.

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 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.
3. Why does trastuzumab deruxtecan work in 'HER2-low' breast cancers that older HER2 drugs ignored?
   Answer

   Its cleavable linker releases a membrane-permeable topoisomerase-I payload (DXd) at high DAR, so a small amount of HER2 is enough to deliver drug and the payload diffuses to kill neighbouring cells (bystander effect); HER2-low is a delivery address, not a driver. DESTINY-Breast04 and -06 proved it.
4. In what setting did T-DXd move into early-stage HER2-positive breast cancer in 2026?
   Answer

   Neoadjuvant (DESTINY-Breast11, T-DXd followed by THP, pCR 67.3% vs 56.3%) and post-neoadjuvant residual disease (DESTINY-Breast05, beating T-DM1), both approved Q2 2026.
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).

• NCCN Esophageal and EGJ Cancers guideline: https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1433
• ESMO oesophageal cancer guideline: https://www.esmo.org/guidelines/esmo-clinical-practice-guidelines-gastrointestinal-cancers/
• NCI PDQ esophageal cancer treatment: https://www.cancer.gov/types/esophageal/hp/esophageal-treatment-pdq
• Wikipedia: https://en.wikipedia.org/wiki/Esophageal_cancer
• Guideline: https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1433
• Guideline: https://www.esmo.org/guidelines/esmo-clinical-practice-guidelines-gastrointestinal-cancers/