RATIONALE-306 study: subgroup analysis in LA ESCC patients

Prof Markus Möhler and Prof Eric Van Cutsem convened at ESMO GI to discuss the RATIONALE-306 study, which investigated the efficacy of combining chemotherapy with the PD-1 inhibitor tislelizumab in the first-line treatment of advanced oesophageal squamous cell carcinoma (ESCC).

RATIONALE-306 was a RCT assessing chemotherapy with or without tislelizumab in patients with advanced or metastatic ESCC. Previous analyses demonstrated a significant survival advantage with the addition of tislelizumab across the overall study population. Notably, the benefit was more pronounced in patients whose tumours expressed PD-L1, defined by a TAP score of ≥5%.

At ESMO-GI, Prof Van Cutsem presented a predefined subgroup analysis focusing on patients with locally advanced disease — individuals without distant metastases but deemed ineligible for surgery or radiotherapy, as confirmed by baseline PET-CT imaging and TNM staging criteria. This subgroup represented a substantial proportion of the trial population. The results revealed that the addition of tislelizumab to chemotherapy in these patients led to significant improvements in OS, PFS, ORR and duration of response. Importantly, patient characteristics were well balanced between treatment arms, ensuring robustness of the observed outcomes. Survival analyses showed a clear separation of OS and PFS curves in favour of the chemo-immunotherapy combination, with more than a doubling of median OS in the locally advanced subgroup. While efficacy was evident in all comers, outcomes were notably superior in patients with PD-L1 positive tumours (TAP score ≥5%), a finding consistent with previous checkpoint inhibitor trials in this disease setting.

A future challenge will be determining optimal patient selection for chemo-immunotherapy versus definitive chemoradiotherapy, particularly since data on combining radiotherapy with checkpoint inhibitors in upper GI SCC are still lacking.

Clinically, the rapid onset of response with chemo-tislelizumab may offer prompt symptom relief, particularly for dysphagia, a key consideration in this patient population. While maintenance strategies with checkpoint inhibitors following chemotherapy remain an intriguing concept, prospective data are required to validate this approach and its potential to improve patient quality of life.

In conclusion, the findings from RATIONALE-306 substantiate chemo-immunotherapy with tislelizumab as a valuable therapeutic option for patients with locally advanced ESCC, particularly for those unsuitable for chemoradiotherapy.