Frontline Tislelizumab Combo Improves Long-Term Survival in ES-SCLC

"These data support tislelizumab plus chemotherapy as a [frontline] treatment option for patients with ES-SCLC," according to the study authors.

Combining tislelizumab-jsgr (Tevimbra) with chemotherapy produced improvements in overall survival (OS) vs placebo plus chemotherapy among patients with extensive-stage small cell lung cancer (ES-SCLC), according to long-term follow-up data from the phase 3 RATIONALE-312 trial (NCT04005716) in a poster presentation at the European Society for Medical Oncology (ESMO) Congress 2025.1

With a median follow-up of 39.8 months (95% CI, 36.2-41.4) in the tislelizumab arm and 36.4 months (95% CI, 35.0-40.9) in the placebo arm, the median OS was 15.5 months (95% CI, 13.5-17.1) vs 13.5 months (95% CI, 12.1-14.9) in each respective arm (HR, 0.78; 95% CI, 0.63-0.95). Additionally, data showed OS rates of 33.1% vs 22.4% at 24 months and 22.1% vs 13.1% at 36 months in each arm. The OS benefit with the tislelizumab combination extended across prespecified patient subgroups, including those with an ECOG performance status of 1 (HR, 0.78; 95% CI, 0.63-0.97) and those with liver metastases (HR, 0.66; 95% CI, 0.45-0.96).

An exploratory analysis showed that among patients with evaluable PD-L1 expression, the median OS was 20.7 months (95% CI, 12.6-26.3) with the tislelizumab combination vs 13.5 months (95% CI, 10.4-19.4) with chemotherapy plus placebo (HR, 0.71; 95% CI, 0.48-1.06). The OS benefit with tislelizumab/chemotherapy appeared to be favorable across all PD-L1 subgroups, although investigators noted that wide confidence intervals occurred due to limited sample sizes.

Based on investigator assessment, the median progression-free survival (PFS) in the intent-to-treat (ITT) population was 4.7 months with tislelizumab plus chemotherapy vs 4.3 months with placebo plus chemotherapy (stratified HR, 0.65; 95% CI, 0.53-0.80).

“Long-term follow-up data from RATIONALE-312 showed that patients with [ES-SCLC] who were treated with first-line tislelizumab plus chemotherapy had clinically meaningful and sustained improvements in OS in the ITT and PD-L1–evaluable populations, and improved investigator-assessed PFS in the ITT population vs those treated with placebo plus chemotherapy,” lead study author Yun Fa, from the Department of Thoracic Oncology at Zhejiang Cancer Hospital in Hangzhou, China, wrote with coauthors in the poster.1 “These data support tislelizumab plus chemotherapy as a [frontline] treatment option for patients with ES-SCLC.”

In the double-blind RATIONALE-312 trial, patients in China with ES-SCLC were randomly assigned 1:1 to receive tislelizumab plus chemotherapy (n = 227) or placebo plus chemotherapy (n = 230). Initial treatment occurred every 3 weeks across 4 cycles and consisted of tislelizumab at 200 mg on day 1 or matched placebo in combination with carboplatin area under the curve 5 or cisplatin at 75 mg/m2 on day 1 plus etoposide at 100 mg/m2 on days 1 to 3. Additionally, maintenance therapy occurred every 3 weeks with tislelizumab at 200 mg or matched placebo.

The trial’s primary end point was OS. Secondary end points included PFS, objective response rate, duration of response, safety, and tolerability. Investigators assessed OS in the PD-L1–evaluable population as an exploratory end point.

Patients 18 years and older with an ECOG performance status of 0 or 1, histologically or cytologically confirmed ES-SCLC, no prior treatment for ES-SCLC, and adequate hematologic and end organ function were eligible for enrollment on the trial.2 Those with active leptomeningeal disease or uncontrolled, untreated brain metastases were unable to enroll.

The median age was 63.0 years (IQR, 56.0-66.0) in the tislelizumab arm and 62.0 years (IQR, 55.0-67.0) in the placebo arm, with most patients in each arm being male (81.9% vs 80.9%). Additionally, most patients in each arm had an ECOG performance status of 1 (84.6% vs 85.2%), current smoking status (66.5% vs 58.7%), stage IV disease (91.2% vs 87.4%), liver metastases (28.2% vs 25.7%), no brain metastases (99.6% vs 98.3%), and platinum-based treatment with carboplatin (79.3% vs 78.7%).

Treatment-emergent adverse effects (TEAEs) of any grade occurred in 99.6% of the tislelizumab arm and 99.6% of the placebo arm, with 89.0% and 90.0% experiencing grade 3 or higher TEAEs. TEAEs resulted in treatment discontinuation, treatment modification, and death in 13.2% vs 3.1%, 68.3% vs 66.8%, and 6.2% vs 1.7% of each respective arm.

The most common any-grade TEAEs in the tislelizumab and placebo arms, respectively, included anemia (85.0% vs 84.7%), alopecia (79.3% vs 79.5%), and neutropenia (68.7% vs 70.3%). Moreover, the most frequent immune-mediated AEs in each arm included adverse skin reactions (16.7% vs 8.7%) and hypothyroidism (16.3% vs 4.8%). Overall, investigators noted no new safety signals associated with the tislelizumab-based regimen.

References

1. Fan Y, Zhao Y, Huang D, et al. First-line (1L) tislelizumab (TIS) + chemotherapy (CT) vs placebo (PBO) + CT in extensive-stage small cell lung cancer (ES-SCLC): long-term follow-up (LTFU) of RATIONALE-312. Presented at the European Society for Medical Oncology (ESMO) Congress 2025; October 17-21, 2025; Berlin, Germany. Abstract 2765P.
2. Study of platinum plus etoposide with or without tislelizumab in participants with untreated extensive-stage small cell lung cancer. ClinicalTrials.gov. Updated February 28, 2025. Accessed October 22, 2025. https://tinyurl.com/4cntkfn2