Tislelizumab Plus Chemotherapy Demonstrates Strong Anti-Tumor Activity in ESCC

Patients with advanced esophageal cancer who respond to initial treatment with tislelizumab plus chemotherapy, deeper responses and a longer time to maximum response are linked to longer survival.

Patients with locally advanced unresectable or metastatic esophageal squamous cell carcinoma (ESCC) who responded to first-line treatment with tislelizumab (Tevimbra) plus chemotherapy in the phase 3 RATIONALE-306 study (NCT03783442) experienced longer overall survival (OS) if they achieved deeper responses or had a longer time to maximum response (TTMR), as demonstrated in results from a post hoc analysis presented at the 2025 Gastrointestinal Cancers Symposium.¹

As of November 24, 2023, 68.3% (n = 207) of patients in the intention-to-treat (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). Most responses (64.7%) were achieved within 8 weeks of treatment; 22.2% of responses were achieved after 8 weeks, up to and including 14 weeks; and 13.0% of responses were achieved after 14 weeks.

For patients in these 3 TTR groups, the median OS 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-not applicable [NA]), respectively. The median OS after first response in these respective groups was 21.3 months (95% CI, 16.0-24.5), 21.3 months (95% CI, 14.4-24.3), and 23.2 months (95% CI, 15.9-NA).

“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,” lead study author Dr Yi Li, of Fifth Medical Center, Chinese PLA General Hospital in Beijing, China, and colleagues wrote in a poster presentation of the data. “[However,] the OS benefits were comparable between early responders and late responders.”

The depth of response (DpR) rate among responders to tislelizumab plus chemotherapy was 62.1% (range, 30%-100%). Over half (50.2%) of responders achieved a DpR above 50% up to and including 80%; a DpR above 30% up to and including 50% was observed in 29.8% of responders; and a DpR greater than 80% up to and including 100% was observed in 20.0% of responders. Among these 3 DpR groups, the median OS 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.

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.

RATIONALE-306: Overview and Prior Data

RATIONALE-306 was a randomized, double-blind, global trial that enrolled patients at least 18 years of age with unresectable locally advanced or metastatic ESCC, no prior systemic treatment for advanced disease, an ECOG performance status of 0 or 1, and measurable or evaluable disease per RECIST 1.1 criteria.² Upon enrollment, patients were randomly assigned 1:1 to receive 200 mg of tislelizumab or placebo intravenously once every 3 weeks alongside chemotherapy. Treatment continued until disease progression or unacceptable toxicity.

The study’s primary end point was OS in the ITT patient population. Key secondary end points included investigator-assessed progression-free survival (PFS), overall response rate, duration of response, OS in patients with a PD-L1 tumor area positivity score of 10% or greater, and safety. Notably, tumor response was assessed per RECIST 1.1 criteria every 6 weeks for the first 48 weeks and every 9 weeks thereafter.¹

Previously reported results from the interim analysis of RATIONALE-306 demonstrated that the addition of tislelizumab to chemotherapy in the first-line setting produced a clinically meaningful improvement in OS and PFS vs placebo plus chemotherapy, durable antitumor responses, and a manageable safety profile.² At a minimum study follow-up of 36 months, the combination continued to produce superior efficacy outcomes vs placebo.

In the current analysis, investigators outlined the characteristics of responders in the tislelizumab plus chemotherapy arm.¹ Characteristics included TTR, defined as the time from randomization to the first occurrence of a complete or partial response; DpR, defined as the percentage of maximal tumor reduction in the target lesion sum of diameters from baseline; TTMR, defined as the time from randomization to maximum tumor shrinkage; OS; OS following initial response, defined as the time from achievement of first response to death; and OS after achievement of maximum response, defined as the time between the achievement of maximum tumor shrinkage and death.

Disclosures: Dr Li has no relationships to disclose.

References

1. Li Y, Zhao C, Liu R, Xu S, Miao X, Xu J. Response characteristics of tislelizumab (TIS) plus chemotherapy (chemo) in first-line (1L) treatment of locally advanced or metastatic esophageal squamous cell carcinoma (ESCC): a post hoc analysis of RATIONALE-306. J Clin Oncol. 2025;43(suppl 4):413. doi:10.1200/JCO.2025.43.4_suppl.413
2. Yoon HH, Kato K, Raymond E, et al. Global, randomized, phase III study of tislelizumab plus chemotherapy versus placebo plus chemotherapy as first-line treatment for advanced/metastatic esophageal squamous cell carcinoma (RATIONALE-306 update): minimum 3-year survival follow-up. J Clin Oncol. 2024;42(suppl 16):4032. doi:10.1200/JCO.2024.42.16_suppl.4032