FDA Approves Tislelizumab/Chemo in Gastric/GEJ Adenocarcinoma

Data from the RATIONALE 305 trial support the approval of tislelizumab/chemotherapy in unresectable or metastatic HER2-negative gastric or GEJ adenocarcinoma.

The News

The FDA has approved first-line tislelizumab-jsgr (Tevimbra) plus fluoropyrimidine- and platinum-based chemotherapy for patients with unresectable or metastatic HER2-negative gastric or gastroesophageal junction (GEJ) adenocarcinoma with PD-L1 tumor expression, according to a press release from BeiGene.¹

Supporting Data

The approval for tislelizumab plus chemotherapy was supported by findings from the phase 3 RATIONALE 305 trial (NCT03777657), in which investigators evaluated tislelizumab plus chemotherapy vs placebo plus chemotherapy as a frontline therapy for patients with advanced gastric or GEJ adenocarcinoma.² Findings from RATIONALE 305 were published in The British Medical Journal (BMJ). Additionally, investigators presented final analysis findings from the intent-to-treat (ITT) population of the trial as part of an oral presentation at the 2023 European Society for Medical Oncology Congress (ESMO).³

Results published in BMJ found that among patients evaluable for efficacy (n = 997), a median overall survival (OS) of 15.0 months (95% CI, 13.6-16.5) was observed with tislelizumab plus chemotherapy vs 12.9 months (95% CI, 12.1-14.1) with placebo plus chemotherapy (HR, 0.80; 95% CI, 0.70-0.92; P = .001).

The 18- and 24- survival rates in the combination and chemotherapy alone arms were 42% vs 33% and 33% vs 23%, respectively. At interim analysis, tislelizumab plus chemotherapy met the criteria for superiority vs chemotherapy alone for OS in patients with a PD-L1 tumor area positivity (TAP) score of 5% or higher; a median OS of 17.2 months (95% CI, 13.9-21.3) in the combination arm vs 12.6 months (95% CI, 12.0-14.4) in the chemotherapy arm (HR, 0.74, 95% CI, 0.59-0.94; P = .006).

Furthermore, a significant improvement in investigator-assessed PFS was observed with tislelizumab plus chemotherapy vs chemotherapy alone in patients with a PD-L1 TAP score of 5% or higher (HR, 0.67; 95% CI, 0.55-0.83; P <.001). Additionally, a higher nonsignificant objective response rate (ORR) and duration of response (DOR) was observed with tislelizumab vs placebo.

“Today’s FDA approval of tislelizumab for the treatment of gastric or gastroesophageal junction cancers in patients who are PD-L1 positive marks a significant step forward in our mission to deliver transformative therapies to patients with cancer,” said Mark Lanasa, MD, PhD, chief medical officer of Solid Tumors at BeiGene. “This is the second US approval for tislelizumab this year, underscoring its potential to address critical needs in oncology. We remain deeply grateful to the patients, clinicians, and researchers whose commitment and courage have made this progress possible—and we look forward to building on this momentum in 2025.”

RATIONALE Trial Design

In the trial, the primary end point was OS in patients with a PD-L1 TAP score of 5% or higher and the entire ITT population. Secondary end points included PFS, confirmed ORR, and DOR of patients with PD-L1 TAP score of 5% or higher and the entire ITT population; safety; and quality of life. A total of 1657 patients screened between December 13, 2018, and February 9, 2021 were randomly assigned 1:1 to receive either tislelizumab plus chemotherapy (n = 501) or placebo plus chemotherapy (n = 496).

Stratification of patients was based on geographic region, PD-L1 expression, the presence of peritoneal metastases, and chemotherapy choice of either capecitabine and oxaliplatin or 5-fluorouracil and cisplatin. Treatment in respective groups included a 200 mg fixed dose of intravenous tislelizumab or placebo and investigator’s choice of chemotherapy every 3 weeks.

Chemotherapy dosing consisted of either 1000 mg/m² of capecitabine twice daily days 1 to 14 and 130 mg/m² of oxaliplatin on day 1 or 800 mg/m² of 5-fluorouracil on days 1 to 5 and 80 mg/m² of cisplatin on day 1. Both regimens occurred for up to 6 cycles.

Minimum follow-up was 24.6 months at final analysis at the data cutoff date of February 28, 2023. A total of 498 (99%) patients in the investigational arm and 494 (>99%) of the placebo arm received at least a single dose of the study agent. Additionally, 800 patients (80%) had gastric cancer, and 196 (20%) had GEJ adenocarcinoma. Furthermore, 546 (55%) of patients had a PD-L1 TAP score of 5% or greater.

Safety Data

Grade 3 or greater treatment-related adverse events (TRAEs) were observed in 268 (54%) patients in the tislelizumab arm and 246 (50%) patients in the placebo arm. Common grade 3 or 4 TRAEs in the investigational and placebo arms, respectively, included decreased neutrophil count (12% vs 12%), decreased platelet count (11% vs 12%), and anemia (5% vs 7%). Furthermore, serious AEs occurred in 23% and 15% of respective arms.

TRAEs led to discontinuation in 16% of the tislelizumab arm and 8% of the placebo arm. Dose modification due to TRAEs occurred in 71% and 72% of the respective arms. Additionally, TRAEs led to 6 deaths in the investigational arm and 2 in the placebo arm. Of note, 4 in the investigational arm were unspecified deaths, 1 was due to colitis, and 1 was due to sepsis; the 2 deaths in the placebo arm were due to pneumonia.

The FDA previously accepted a biologics license application BLA for tislelizumab plus chemotherapy to treat patients with locally advanced or metastatic gastric or GEJ adenocarcinoma in February 2024.⁴

References

1. 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 December 27, 2024. https://tinyurl.com/rwaw5cee
2. Qiu MZ, Oh DY, Kato K, et al. Tislelizumab plus chemotherapy versus placebo plus chemotherapy as first line treatment for advanced gastric or gastro-oesophageal junction adenocarcinoma: RATIONALE-305 randomised, double blind, phase 3 trial. Br Med J. 2024;385:e078876. doi:10.1136/bmj-2023-078876
3. BeiGene announces late-breaking data at ESMO showing tislelizumab plus chemotherapy significantly improved overall survival at final analysis in first-line advanced gastric or gastroesophageal junction adenocarcinoma. BeiGene, Ltd. October 17, 2023. Accessed December 6, 2024. http://tinyurl.com/9rcjx4ye
4. BeiGene’s biologics license application for TEVIMBRA® (tislelizumab) for first-line gastric or gastroesophageal junction cancers accepted by FDA. News release. BeiGene, Ltd. February 27, 2024. Accessed December 6, 2024. http://tinyurl.com/ymbdbm58