Tislelizumab Plus Chemotherapy Meets OS End Point in Advanced Gastric/GEJ Adenocarcinoma

The combination of tislelizumab (BGB-A317) plus chemotherapy elicited a statistically significant and clinically meaningful improvement in overall survival (OS) compared with chemotherapy plus placebo in patients with advanced unresectable or metastatic gastric or gastroesophageal junction (GEJ) adenocarcinoma, irrespective of PD-L1 status, meeting the primary end point of the phase 3 RATIONALE 305 trial (NCT03777657).¹

After previous data from a planned interim analysis demonstrated superior OS for tislelizumab plus chemotherapy in the PD-L1–high patient population, the study continued its prespecified statistical hierarchy testing. The combination then produced a superior OS vs chemotherapy alone in the intent-to-treat (ITT) population.

Full results will be submitted for presentation at an upcoming medical conference.

“At the recent ASCO GI meeting, we presented results from an interim analysis demonstrating a statistically significant and clinically meaningful improvement in overall survival in the high PD-L1 expression group in RATIONALE 305 and we are pleased that the final analysis demonstrated a significant survival benefit and consistent safety profile in the entire study population,” Mark Lanasa, MD, PhD, chief medical officer of Solid Tumors at BeiGene, stated in a news release.

“Gastric cancer is the fifth most common cancer globally, and the prognosis for patients with advanced or metastatic conditions remains inadequate; these data support tislelizumab combined with chemotherapy as a potential first-line treatment option for patients with locally advanced, unresectable or metastatic gastric or GEJ cancer.”

In the interim analysis of the trial presented at the 2023 Gastrointestinal Cancers Symposium, patients with PD-L1–high advanced gastric or GEJ adenocarcinoma treated with tislelizumab plus chemotherapy (n = 274) achieved a median OS of 17.2 months (95% CI, 13.9-21.3) compared with 12.6 months (95% CI, 12.0-14.4) for those given chemotherapy alone (n = 272; HR, 0.74; 95% CI, 0.59-0.94; P = .0056).²

Additionally, the median progression-free survival (PFS) was 7.2 months (95% CI, 5.8-8.4) in the tislelizumab arm vs 5.9 months (95% CI, 5.6-7.0) in the chemotherapy arm (HR, 0.67; 95% CI, 0.55-0.83).

These findings supported approval in China for tislelizumab in combination with fluoropyrimidine and platinum chemotherapy in the frontline treatment of patients with locally advanced unresectable or metastatic gastric or GEJ adenocarcinoma with a high PD-L1 expression in February 2023.³

The randomized, double-blind, global RATIONALE 305 study enrolled patients with histologically confirmed gastric/GEJ adenocarcinoma who received no prior therapy for unresectable, locally advanced or metastatic disease.² Patients with HER2-positive tumors were excluded.

Patients were randomly assigned 1:1 to receive 200 mg of intravenous tislelizumab or placebo once every 3 weeks. Chemotherapy in both arms consisted of oxaliplatin at 130 mg/m² on day 1 plus capecitabine 1000 mg/m² twice daily for days 1 to 14 every 3 weeks (XELOX) or cisplatin at 80 mg/m² on day 1 plus 5-fluororacil at 800 mg/m² daily on days 1 to 5 every 3 weeks (FP). Initial treatment lasted for up to 6 cycles, and patients received maintenance treatment until unacceptable toxicity or progressive disease.

OS in the PD-L1–positive (≥5%) and ITT populations served as the primary end points. Secondary end points included PFS, overall response rate (ORR), duration of response (DOR), disease control rate (DCR), clinical benefit rate, time to response, health-related quality of life, and safety.

Additional data from the PD-L1–positive population showed that tislelizumab plus chemotherapy produced an ORR of 50.4% (95% CI, 44.3%-56.4%), including a complete response rate of 3.3% and a partial response rate of 47.1%, compared with 43.0% (95% CI, 37.1%-49.1%) for chemotherapy alone.

The median DOR was 9.0 months (95% CI, 8.2-19.4) in the tislelizumab arm vs 7.1 months (95% CI, 5.7-8.3) in the placebo arm. The DCR was 88.3% (95% CI, 83.9%-91.9%) for the tislelizumab group vs 83.1% (95% CI, 78.1%-87.3%) for the chemotherapy group.

Regarding safety, findings for tislelizumab plus chemotherapy were consistent with the known profile of each agent, and no new signals were observed. Any-grade treatment-emergent adverse effects (TEAEs) occurred in 99.6% of patients in the tislelizumab arm vs 97.8% of those in the placebo arm. Grade 3 or higher TEAEs were reported in 64.7% and 62.9% of patients, respectively.

The most common TEAEs reported in at least 20% of patients included nausea, decreased appetite, decreased platelet count, vomiting, anemia, decreased neutrophil count, increased aspartate aminotransferase, diarrhea, peripheral sensory neuropathy, increased alanine aminotransferase, decreased white blood cell count, and constipation.

Additionally, 22.4% of patients in the tislelizumab arm discontinued treatment due to TEAEs compared with 12.1% of those in the placebo arm. TEAEs led to death in 8.8% and 7.7% of patients, respectively.

References

1. BeiGene announces positive phase 3 tislelizumab trial in advanced gastric or gastroesophageal junction adenocarcinoma. News release. BeiGene. April 20, 2023. Accessed April 21, 2023. https://ir.beigene.com/news/beigene-announces-positive-phase-3-tislelizumab-trial
2. Moehler MH, Kato K, Arkenau H-T, et al. Rationale 305: phase 3 study of tislelizumab plus chemotherapy vs placebo plus chemotherapy as first-line treatment (1L) of advanced gastric or gastroesophageal junction adenocarcinoma (GC/GEJ). J Clin Oncol. 2023;41(suppl 4):286. doi:10.1200/JCO.2023.41.4_suppl.286
3. BeiGene receives 10th approval for PD-1 inhibitor tislelizumab in China. News release. BeiGene. February 24, 2023. Accessed April 21, 2023. https://ir.beigene.com/news/beigene-receives-10th-approval-for-pd-1-inhibitor-tislelizumab-in-china/