RATIONALE 302

Background

Phase 3, open-label RCT. 512 patients with advanced or metastatic esophageal squamous cell carcinoma (ESCC) progressing after first-line systemic therapy. Tested tislelizumab (anti-PD-1) vs investigator-choice chemotherapy in the second line.

Interventions and follow up

Arm A: Tislelizumab 200 mg IV Q3W
Arm B: Investigator-choice single-agent chemotherapy (paclitaxel, docetaxel, or irinotecan)
Primary endpoint: Overall survival (OS)
Median follow-up: 8.5 mo (arm A) vs 5.8 mo (arm B)

Results

mOS: 8.6 mo (tislelizumab, arm A) vs 6.3 mo (chemotherapy, arm B); HR 0.70, 95% CI 0.57–0.85, one-sided P=.0001
ORR: Higher with tislelizumab (20.3%) vs chemotherapy (9.8%), with more durable responses

Adverse events

Overall: Grade ≥3 treatment-related events 46.3% (tislelizumab) vs 67.9% (chemotherapy)
Most common TRAEs (tislelizumab): Increased AST 11.4%, anemia 11.0%, hypothyroidism 10.2%

Conclusions

Second-line tislelizumab significantly prolonged overall survival versus chemotherapy in advanced/metastatic ESCC, with a more favorable safety profile.

Key Limitations

Open-label design with chemotherapy comparator. The trial enrolled a largely Asian population, where ESCC biology and prior-therapy patterns may differ from Western cohorts. OS benefit was demonstrated in the overall analysis, but the treatment landscape has since shifted toward first-line PD-1 combinations.

Clinical Context

RATIONALE-302 supported tislelizumab as second-line monotherapy for advanced ESCC and contributed to its regulatory approvals. With first-line PD-1 + chemotherapy now standard for advanced ESCC (per ESMO), the relevance of second-line single-agent PD-1 therapy is reserved for patients not previously exposed to immunotherapy.

References