Background
KEYNOTE-590. Phase III RCT enrolled 749 patients with previously untreated, locally advanced unresectable or metastatic esophageal cancer or Siewert type 1 GE junction cancer with measurable disease (73% squamous cell carcinoma, 27% adenocarcinoma; 51% PD-L1 CPS≥10).
Interventions and follow up
Arm A: Pembrolizumab 200 mg IV Q3W (up to 35 cycles) + chemotherapy (5-FU 800 mg/m² D1-5 + cisplatin 80 mg/m² D1, cisplatin max 6 cycles), Q3W*
Arm B: Placebo + same chemotherapy Q3W*
Primary endpoints: OS and PFS in esophageal SCC with PD-L1 CPS≥10, SCC regardless of CPS, CPS≥10 regardless of histology, and all randomized patients
mFollow up: 22.6 mo
Arm B: Placebo + same chemotherapy Q3W*
Primary endpoints: OS and PFS in esophageal SCC with PD-L1 CPS≥10, SCC regardless of CPS, CPS≥10 regardless of histology, and all randomized patients
mFollow up: 22.6 mo
Results
mOS SCC CPS≥10: 13.9 mo vs 8.8 mo (arm A vs B), HR 0.57; 95%CI 0.43–0.75; P<.0001
mOS SCC: 12.6 mo vs 9.8 mo, HR 0.72; 95%CI 0.60–0.88; P=.0006
mOS CPS≥10: 13.5 mo vs 9.4 mo, HR 0.62; 95%CI 0.49–0.78; P<.0001
mOS all patients: 12.4 mo vs 9.8 mo, HR 0.73; 95%CI 0.62–0.86; P<.0001
mPFS SCC: 6.3 mo vs 5.8 mo; HR 0.65, 95%CI 0.54–0.78; P<.0001
mPFS CPS≥10: 7.5 mo vs 5.5 mo; HR 0.51, 95%CI 0.41–0.65; P<.0001
mPFS all patients: 6.3 mo vs 5.8 mo; HR 0.65, 95%CI 0.55–0.76; P<.0001
mOS SCC: 12.6 mo vs 9.8 mo, HR 0.72; 95%CI 0.60–0.88; P=.0006
mOS CPS≥10: 13.5 mo vs 9.4 mo, HR 0.62; 95%CI 0.49–0.78; P<.0001
mOS all patients: 12.4 mo vs 9.8 mo, HR 0.73; 95%CI 0.62–0.86; P<.0001
mPFS SCC: 6.3 mo vs 5.8 mo; HR 0.65, 95%CI 0.54–0.78; P<.0001
mPFS CPS≥10: 7.5 mo vs 5.5 mo; HR 0.51, 95%CI 0.41–0.65; P<.0001
mPFS all patients: 6.3 mo vs 5.8 mo; HR 0.65, 95%CI 0.55–0.76; P<.0001
Adverse events
Overall: Grade≥3 treatment-related events 72% vs 68% (arm A vs B); any-grade events 96% vs 90%
Immune-related: Hypothyroidism 11% vs 0 (none grade≥3); hyperthyroidism 6% vs 1%; pneumonitis 6% vs 1%
Immune-related: Hypothyroidism 11% vs 0 (none grade≥3); hyperthyroidism 6% vs 1%; pneumonitis 6% vs 1%
Conclusions
First-line pembrolizumab plus chemotherapy improved overall and progression-free survival across all analyzed subgroups versus chemotherapy alone in advanced esophageal/GE junction cancer.
* Continued until disease progression, unacceptable toxicity, or other protocol-defined discontinuation.
* Continued until disease progression, unacceptable toxicity, or other protocol-defined discontinuation.
Key Limitations
Benefit concentrated in CPS≥10 and SCC subgroups; smaller absolute gains in adenocarcinoma and CPS<10; cisplatin/5-FU backbone less commonly used than FOLFOX in some regions; predominantly Asian SCC population.
Clinical Context
Led to FDA approval (2021) of pembrolizumab plus platinum/fluoropyrimidine chemotherapy for first-line advanced esophageal/GE junction cancer; EMA approval restricted to PD-L1 CPS≥10. Endorsed in ESMO/ASCO first-line guidance; complements CheckMate 648 (nivolumab) for esophageal SCC.