First-Line Tislelizumab Plus Chemo Elicits Deep Responses Linked to OS Benefits in ESCC

OS benefits with tislelizumab plus chemotherapy were comparable between early and late responders in the phase 3 RATIONALE-306 study in patients with ESCC.

Among patients with locally advanced unresectable or metastatic esophageal squamous cell carcinoma (ESCC) who achieved a response with first-line tislelizumab (Tevimbra) plus chemotherapy in the phase 3 RATIONALE-306 study (NCT03783442), deeper responses and a longer time to maximum response (TTMR) were both associated with prolonged overall survival (OS), according to findings 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