A new analysis of the phase 3 RATIONALE-306 trial indicates that tislelizumab (Tevimbra) in combination with chemotherapy significantly improves overall survival (OS) in patients with advanced or metastatic esophageal squamous cell carcinoma (ESCC). The study, presented at the 2025 Gastrointestinal Cancers Symposium, highlights that the depth of tumor response and the time taken to reach maximum response (TTMR) are strongly associated with longer OS.
The RATIONALE-306 trial was a randomized, double-blind study that enrolled patients with unresectable locally advanced or metastatic ESCC who had not received prior systemic treatment for advanced disease. Patients were randomized 1:1 to receive 200 mg of tislelizumab or placebo intravenously every 3 weeks in combination with chemotherapy. The primary endpoint of the study was OS in the intention-to-treat (ITT) population.
Response Rates and Overall Survival
As of November 24, 2023, 68.3% (n = 207) of patients in the ITT population who received tislelizumab plus chemotherapy achieved a response, with a median time to response (TTR) of 6.1 weeks (range, 3.3-101.3). The data showed that 64.7% of responders achieved a response within 8 weeks of treatment, while 22.2% responded between 8 and 14 weeks, and 13.0% responded after 14 weeks.
Median OS for these TTR groups was 21.8 months (95% CI, 16.3-25.0), 23.1 months (95% CI, 16.3-26.0), and 29.0 months (95% CI, 20.4-NA), respectively. According to Dr. Yi Li, of Fifth Medical Center, Chinese PLA General Hospital in Beijing, China, and colleagues, "In the tislelizumab plus chemotherapy arm, 64.7% of responders achieved a response within 8 weeks, while still 35.2% of responders achieved response at later assessments... However, the OS benefits were comparable between early responders and late responders."
Depth of Response and Time to Maximum Response
The depth of response (DpR) rate among responders to tislelizumab plus chemotherapy was 62.1% (range, 30%-100%). Specifically, 50.2% of responders achieved a DpR above 50% up to and including 80%, 29.8% achieved a DpR above 30% up to and including 50%, and 20.0% achieved a DpR greater than 80% up to and including 100%.
The median OS for these DpR groups was 23.7 months (95% CI, 18.4-25.6), 16.1 months (95% CI, 13.2-20.4), and 34.5 months (95% CI, 23.7-NA), respectively. These results indicate that deeper tumor responses are associated with significantly improved survival outcomes.
Among responders, the median TTMR was 19 weeks (range, 3.3-201). Maximum response was achieved within 14 weeks, after 14 weeks up to and including 28 weeks, and after 28 weeks in 32.7%, 34.6%, and 32.7% of responders, respectively. The median OS for patients in these respective TTMR categories was 14.3 months (95% CI, 8.7-17.6), 17.4 months (95% CI, 15.8-24.1), and 39.9 months (95% CI, 28.6-NA).
The median OS after maximum response was 12.6 months (95% CI, 8.1-15.4), 14.3 months (95% CI, 11.8-20.1), and 24.8 months (95% CI, 17.5-39.4), respectively, further emphasizing the importance of achieving and maintaining deep tumor responses over time.
Implications for Treatment
The findings from this analysis of the RATIONALE-306 trial suggest that tislelizumab plus chemotherapy offers a significant benefit in terms of overall survival for patients with advanced ESCC. The correlation between deeper responses, longer TTMR, and improved OS underscores the importance of optimizing treatment strategies to achieve maximal tumor reduction and sustained response.
