KEYNOTE 181 Trial

Background

Phase III RCT included 628 patients with advanced/metastatic esophageal squamous cell carcinoma or adenocarcinoma (including Siewert type I GEJ) progressing after one prior line. Second-line setting.

Interventions and follow up

Arm A: Pembrolizumab 200 mg IV q3wk
Arm B: Investigator's choice chemotherapy: paclitaxel 80-100 mg/m² D1,8,15 q4wk, or docetaxel 75 mg/m² q3wk, or irinotecan 180 mg/m² D1 q2wk
Primary endpoint: OS in PD-L1 CPS≥10, in SCC, and in all patients
mFollow up: 7.1 vs 6.9 mo, arm A vs B

Results

mOS, CPS≥10: 9.3 vs 6.7 mo, arm A vs B (HR 0.69; 95% CI 0.52-0.93; P=.0074)
mOS, SCC: 8.2 vs 7.1 mo (HR 0.78; 95% CI 0.63-0.96; P=.0095)
mOS, all patients: 7.1 vs 7.1 mo (HR 0.89; 95% CI 0.75-1.05; P=.0560, NS)

Adverse events

Overall: Grade 3-5 treatment-related events 18% vs 41%, arm A vs B
Common pembrolizumab-related: fatigue, rash, hypothyroidism
Immune-related: pneumonitis and other immune-related events occurred but generally manageable

Conclusions

Pembrolizumab improved OS over chemotherapy in previously treated advanced esophageal cancer with PD-L1 CPS≥10, with a more favorable safety profile, supporting second-line use in this biomarker-selected population.

Key Limitations

No OS benefit in the overall population; benefit confined to PD-L1 CPS≥10. SCC subgroup did not meet prespecified significance threshold. Mixed histology cohort.

Clinical Context

FDA approved pembrolizumab for previously treated esophageal SCC with PD-L1 CPS≥10 (2019). First-line chemoimmunotherapy (KEYNOTE-590) has since shifted PD-1 inhibitors earlier. ESMO recognizes biomarker-driven checkpoint inhibition in esophageal cancer.

References