Overview of Esophageal Cancer Treatment

Esophageal cancer treatment varies by histology (squamous cell vs adenocarcinoma) and HER2 status. Checkpoint inhibitors (nivolumab, pembrolizumab) combined with chemotherapy have become first-line standard. HER2-positive gastroesophageal junction (GEJ) adenocarcinoma benefits from trastuzumab. Ramucirumab with paclitaxel is standard second-line therapy.

Treatment by Histology

Squamous Cell Carcinoma

  • Nivolumab + chemotherapy (CheckMate-648) or Pembrolizumab + chemotherapy (KEYNOTE-590)

Adenocarcinoma / GEJ

  • Pembrolizumab + chemotherapy (KEYNOTE-590)
  • Add trastuzumab if HER2-positive (ToGA)

Second-Line

  • Ramucirumab + paclitaxel (RAINBOW)
  • Nivolumab or pembrolizumab monotherapy

Epidemiology & Impact

Esophageal cancer affects approximately 22,370 people annually in the United States, with an estimated 16,320 deaths in 2025, reflecting its aggressive nature and typically advanced stage at diagnosis. The disease demonstrates two distinct epidemiologic patterns: squamous cell carcinoma (associated with tobacco, alcohol, hot beverages, common in Asia and Africa) and adenocarcinoma (driven by GERD, Barrett's esophagus, and obesity, now the predominant subtype in Western countries). Esophageal adenocarcinoma incidence has increased more than 600% since the 1970s in the United States. The disease has a marked male predominance (approximately 4:1 for adenocarcinoma). Overall 5-year survival is approximately 22%, though localized disease achieves approximately 50% survival.

Molecular Biology & Biomarkers

Esophageal SCC and adenocarcinoma have distinct molecular profiles. SCC commonly harbors TP53 mutations (over 90%), CDKN2A loss, and CCND1 amplification. Adenocarcinoma is characterized by TP53 mutations, HER2 amplification (15-20%), and frequent chromosomal instability. PD-L1 expression is found in 40-50% of esophageal cancers and serves as a key biomarker for immunotherapy selection via the Combined Positive Score (CPS). HER2 overexpression guides trastuzumab-based therapy. Claudin 18.2, expressed in approximately 38% of gastroesophageal junction adenocarcinomas, has emerged as a novel therapeutic target.

Evolving Treatment Landscape

The CheckMate 649 and KEYNOTE-590 trials established immunotherapy-chemotherapy combinations as first-line standard for advanced esophageal cancer. Nivolumab plus chemotherapy and pembrolizumab plus chemotherapy both demonstrated overall survival improvements correlating with PD-L1 expression. For HER2-positive tumors, trastuzumab deruxtecan (Enhertu) has shown remarkable activity in the DESTINY-Gastric trials. In locally advanced disease, the CheckMate 577 trial demonstrated that adjuvant nivolumab after neoadjuvant chemoradiation and surgery significantly improved disease-free survival. The FLOT regimen is the preferred perioperative approach for resectable gastroesophageal adenocarcinoma.

Approved Esophageal Cancer Therapies

Opdivo
nivolumab
FDA Approved 2020 First-line / Adjuvant
Approved Indications (US/FDA)
In combination with fluoropyrimidine- and platinum-containing chemotherapy for advanced or metastatic esophageal SCC; in combination with ipilimumab for advanced esophageal SCC; adjuvant in esophageal or GEJ cancer after neoadjuvant CRT and complete resection (CheckMate 577).
Dosing Schedule
240 mg IV Q2W or 480 mg IV Q4W
Drug Class
Checkpoint Inhibitor (Anti-PD-1)
Manufacturer
Bristol-Myers Squibb
Approval Year
2020
Pivotal Trial
NCT02872116 ↗
Key Publication
Doki et al. NEJM 2022 (CheckMate 648) ↗
Keytruda
pembrolizumab
FDA Approved 2021 First-line (combo)
Approved Indications (US/FDA)
In combination with platinum and fluoropyrimidine-based chemotherapy for patients with locally advanced unresectable or metastatic esophageal or GEJ carcinoma (not amenable to surgical resection or definitive CRT).
Dosing Schedule
200 mg IV Q3W or 400 mg IV Q6W
Drug Class
Checkpoint Inhibitor (Anti-PD-1)
Manufacturer
Merck
Approval Year
2021
Pivotal Trial
NCT03189719 ↗
Key Publication
Enhertu
fam-trastuzumab deruxtecan-nxki
FDA Approved 2021 2nd Line+ NEW
Approved Indications (US/FDA)
Treatment of adult patients with locally advanced or metastatic HER2-positive gastric or gastroesophageal junction adenocarcinoma who have received a prior trastuzumab-based regimen.
Dosing Schedule
6.4 mg/kg IV every 3 weeks
Cycle Length
21-day cycles
Combination Therapy
Monotherapy (HER2-directed antibody-drug conjugate)
Manufacturer
Daiichi Sankyo/AstraZeneca
Approval Year
2021
Pivotal Trial
NCT03329690 ↗
Key Publication
Shitara et al. NEJM 2020 (DESTINY-Gastric01) ↗
Cyramza
ramucirumab
FDA Approved 2014 2nd Line
Approved Indications (US/FDA)
Treatment of advanced gastric or GEJ adenocarcinoma, as single agent or with paclitaxel, after prior fluoropyrimidine- or platinum-containing chemotherapy.
Dosing Schedule
8 mg/kg IV every 2 weeks
Cycle Length
14-day cycles
Combination Therapy
Monotherapy or with paclitaxel (VEGFR-2 antagonist)
Manufacturer
Eli Lilly
Approval Year
2014
Pivotal Trial
NCT01170663 ↗
Key Publication
Wilke et al. Lancet Oncol 2014 (RAINBOW) ↗
Sun et al. Lancet 2021 (KEYNOTE-590) ↗