RATIONALE-305 Post Hoc Analysis Links an ECOG Performance Status of 1 With Worse PROs in Gastric/GEJ Adenocarcinoma

ECOG performance status captured only part of the patient experience in patients with gastric or gastroesophageal junction (GEJ) adenocarcinoma, with patients with a baseline ECOG performance status of 1 experiencing worsened patient-reported outcomes (PROs), according to findings from a post hoc analysis of the phase 3 RATIONALE-305 trial (NCT03777657) presented at the 2026 Gastrointestinal Cancers Symposium.¹

The post hoc analysis included patients treated during the study with either the experimental regimen of tislelizumab-jsgr (Tevimbra) plus chemotherapy or placebo plus chemotherapy.

Notably, when patients were stratified by ECOG performance status (0 vs 1), the analysis revealed no statistically significant differences across gastric/GEJ-specific symptom domains on the EORTC QLQ-STO22 questionnaire, including dietary restrictions (mean, 86.9 for ECOG 0 vs 86.0 for ECOG 1; odds ratio [OR], 1.00; 95% CI, 0.99-1.01; P = .4243), dysphagia (89.5 vs 88.6; OR, 1.00; 95% CI, 0.99-1.01; P = .4812), pain/discomfort (81.0 vs 78.2; OR, 0.99; 95% CI, 0.99-1.00; P = .0527), and upper GI symptoms (88.5 vs 86.9; OR, 0.99; 95% CI, 0.98-1.00; P = .1551), suggesting ECOG performance status may not fully capture baseline gastric/GEJ cancer–specific symptom burden.

Conversely, patients with baseline ECOG performance status of 1 had lower odds of reporting favorable PROs compared with those with an ECOG performance status of 0. Specifically, an ECOG performance status of 1 was associated with significantly lower odds of reporting better global health status/quality of life (GSH/QOL; 72.5 for ECOG 0 vs 68.0 for ECOG 1; OR, 0.99; 95% CI, 0.98-0.99; P < .001), physical functioning (89.8 vs 87.6; OR, 0.99; 95% CI, 0.98-1.00; P = .0245), and pain (OR, 0.99; 95% CI, 0.99-1.00; P = .0343) on the EORTC QLQ-C30 questionnaire. A trend toward worse outcomes was also observed for role functioning (89.3 vs 86.6; OR, 0.99; 95% CI, 0.99-1.00; P = .0845), although this did not reach statistical significance. No significant associations were observed for constipation (87.0 vs 86.0; OR, 1.00; 95% CI, 0.99-1.00; P = .5509), diarrhea (92.8 vs 93.9; OR, 1.00; 95% CI, 1.00-1.01; P = .3273), or fatigue (79.4 vs 77.5; OR, 1.00; 95% CI, 0.99-1.00; P = .1967).

“Among patients with first-line gastric/GEJ, those with [a] baseline ECOG performance status [of] 1 reported significantly worse GHS/QOL, physical functioning, and pain [vs] those with [an] ECOG performance status [of] 0, irrespective of treatment arm. Multivariable regression analyses confirmed a lower probability of achieving better PRO scores for patients with ECOG performance status 1 compared with ECOG performance status 0,” lead study author Marcia Cruz-Correa, MD, PhD, AGAF, FASGE, concluded in her presentation of the results. “These results suggest that integrating baseline PROs into eligibility and/or stratification criteria may improve risk stratification, support more patient-centered trial design, and foster more meaningful patient-clinician dialogue at treatment initiation.”

What design characteristics were included in the RATIONALE-305 trial?

In December 2024, the FDA approved tislelizumab in combination with platinum- and fluoropyrimidine-based chemotherapy for the first-line treatment of patients with unresectable or metastatic, HER2-negative gastric or GEJ adenocarcinoma whose tumors express PD-L1 (≥1).² This regulatory decision was supported by prior data from RATIONALE-305, which showed that treatment with tislelizumab plus chemotherapy led to a statistically significant and clinically meaningful improvement in overall survival (OS) at 15.0 months compared with 12.9 months for placebo plus chemotherapy (HR, 0.80; 95% CI, 0.70-0.92; P = .0011).

RATIONALE-305 was a randomized, double-blind, phase 3 study that enrolled patients with previously untreated, locally advanced unresectable or metastatic gastric or GEJ adenocarcinoma.^1,3 Eligible patients had histologically confirmed disease, HER2-negative disease, no prior systemic therapy for advanced disease, an ECOG performance status of 0 or 1, and at least 1 measurable or non-measurable lesion per RECIST 1.1 criteria.¹

Patients were randomly assigned 1:1 to receive tislelizumab plus chemotherapy or placebo plus chemotherapy for up to 6 cycles, followed by tislelizumab or placebo with optional capecitabine beginning in cycle 7 and beyond.

The primary end point of the overall trial was OS in patients with a PD-L1 combined positive score of at least 5% and in the intention-to-treat population. Secondary end points included progression-free survival, objective response rate, duration of response, safety, and PROs.

The PRO analysis included 932 randomly assigned patients who completed baseline EORTC QLQ-C30 and QLQ-STO22 questionnaires. Patients were analyzed according to baseline ECOG performance status, with data pooled across treatment arms. Profile analyses were conducted to evaluate differences in overall levels and patterns across 11 PRO domains, and logistic regression sensitivity analyses were performed to identify PRO domains associated with ECOG performance status. Statistical significance was defined at a threshold of P < .05.

“Ongoing work in RATIONALE-305 is assessing the extent to which ECOG performance status meaningfully differentiates PRO trajectories over time and by treatment to further inform how ECOG performance status and PROs can be jointly leveraged in advanced gastric or gastroesophageal junction adenocarcinoma,” Cruz-Correa expressed.

References

1. Cruz-Correa M, Moehler M, Denlinger CS, et al. Associations between ECOG performance status and patient-reported outcomes in patients with gastric or gastroesophageal junction (GC/GEJC) adenocarcinoma: Post hoc analysis from the RATIONALE-305 trial. J Clin Oncol. 2026;44(suppl 2):288. doi:10.1200/JCO.2026.44.2_suppl.288
2. Tevimbra approved in U.S. for first-line treatment of gastric and gastroesophageal junction cancers in combination with chemotherapy. News release. BeiGene. December 27, 2024. Accessed January 9, 2026. https://ir.beigene.com/news/tevimbra-approved-in-u-s-for-first-line-treatment-of-gastric-and-gastroesophageal-junction-cancers-in-combination/cedb475b-fcfe-47a4-8afe-8a501d9cf849/
3. Tislelizumab in combination with chemotherapy as first-line treatment in adults with inoperable, locally advanced, or metastatic gastric or gastroesophageal junction carcinoma. ClinicalTrials.gov. Updated February 14, 2025. Accessed January 9, 2025. https://clinicaltrials.gov/study/NCT03777657