Frontline Tislelizumab/Chemo Approaches EU Approval for Gastric/GEJ Adenocarcinoma and ESCC

The European Medicines Agency’s Committee for Medicinal Products for Human Use has recommended extended authorization for tislelizumab (Tevimbra) paired with chemotherapy in the first-line treatment of select patients with gastric or gastroesophageal junction (GEJ) adenocarcinoma and esophageal squamous cell carcinoma (ESCC).¹

The extension of indication application for frontline tislelizumab plus platinum- and fluoropyrimidine-based chemotherapy in adult patients with HER2-negative, locally advanced unresectable or metastatic gastric/GEJ cancer with a PD-L1 tumor area positivity (TAP) score of at least 5% was supported by data from the phase 3 RATIONALE-305 study (NCT03777657). At a data cutoff date of February 28, 2023, tislelizumab plus chemotherapy (n = 501) led to a median overall survival (OS) of 15.0 months (95% CI, 13.6-16.5) vs 12.9 months (95% CI, 12.1-14.1) with chemotherapy alone (n = 496), translating to a 20% reduction in the risk of death (HR, 0.80; 95% CI, 0.70-0.92; P = .0011).² In the subset of patients with a PD-L1 score of 5% or higher, those who received tislelizumab (n = 274) experienced a median OS of 16.4 months (95% CI, 13.6-19.1) vs 12.8 months (95% CI, 12.0-14.5) in those who only received chemotherapy (n = 272), translating to a 29% reduction in the risk of death (HR, 0.71; 95% CI, 0.58-0.86).

The application seeking approval of first-line tislelizumab plus platinum-based chemotherapy in adult patients with unresectable, locally advanced or metastatic ESCC with a PD-L1 TAP score of at least 5% was based on findings from the phase 3 RATIONALE-306 trial (NCT03783442). At a data cutoff date of February 28, 2022, and with a median follow-up of 16.3 months (interquartile range, 8.6-21.8), the median OS with tislelizumab plus chemotherapy (n = 326) was 17.2 months (95% CI, 15.8-20.1) vs 10.6 months (95% CI, 9.3-12.1) with chemotherapy alone (n = 323; stratified HR, 0.66; 95% CI, 0.54-0.80; 1-sided P < .0001).³ Three-year data in the subset of patients who had a PD-L1 score of 5% or higher showed that the median OS in the respective arms was 19.1 months and 10.0 months, respectively (HR, 0.62; 95% CI, 0.49-0.79).¹

“Survival rates in the advanced stages of gastric/GEJ and esophageal cancers are among the lowest of all cancer types despite recent advances, and new treatment options are needed,” said Professor Florian Lordick, MD, PhD, director and professor of Oncology at the University Cancer Center in Leipzig, Germany, stated in a news release. “The RATIONALE-305 and 306 trials showed that tislelizumab plus chemotherapy improved survival compared to treatment with placebo plus chemotherapy, highlighting its potential to deliver better outcomes for eligible patients.”

Reviewing RATIONALE-305: Population, Design, Additional Efficacy Data

A total of 997 patients with locally advanced unresectable or metastatic adenocarcinoma of the stomach or GEJ cancer who were at least 18 years of age, had at least 1 measurable or nonmeasurable lesion by RECIST 1.1 criteria, and an ECOG performance status of either 0 or 1 were enrolled to the randomized, double-blind, global, phase 3 study.² Patients had not received systemic treatment for advanced disease and did not have HER2-positive disease.

They were randomly assigned 1:1 to receive tislelizumab at 200 mg or placebo on day 1 every 3 weeks plus chemotherapy in the form of oxaliplatin at 130 mg/m² on day 1 every 3 weeks (Q3W) plus capecitabine at 1000 mg/m² twice daily for days 1 to 14 Q3W (XELOX) or cisplatin at 80 mg/m² on day 1 Q3W plus 5-fluorouracil (5-FU) at 800 mg/m² on days 1 to 5 Q3W. Patients received initial treatment with tislelizumab or placebo plus chemotherapy for up to 6 treatment cycles; for cycles 7 and beyond, they received tislelizumab or placebo. Capecitabine maintenance was optional, only for patients who received the XELOX regimen. Patients were stratified based on enrollment region, peritoneal metastases, PD-L1 score (≥ 5% vs < 5%), and investigator-selected chemotherapy regimen (XELOX vs cisplatin/5-FU).

The primary end point of the study was OS in the subset of patients with a PD-L1 score of at least 5% and in the intention-to-treat (ITT) population. Secondary end points included progression-free survival (PFS), objective response rate (ORR), duration of response (DOR), disease control rate (DCR), clinical benefit rate, health-related quality of life (HRQOL), and safety.

Additional efficacy data showed that the median PFS with tislelizumab/chemotherapy in the ITT population was 6.9 months (95% CI, 5.7-7.2) vs 6.2 months (95% CI, 5.6-6.9) with chemotherapy alone (HR, 0.78; 95% CI, 0.67-0.90). The respective ORRs achieved with these regimens were 47.3% (95% CI, 42.9%-51.8%) and 40.5% (95% CI, 36.2%-45.0%). The median DOR with tislelizumab was 8.6 months (95% CI, 7.9-11.1) vs 7.2 months (95% CI, 6.0-8.5) without.

Running Through RATIONALE-306: Eligibility, Treatment, Additional Efficacy Findings

The global, randomized, double-blind, parallel-arm, placebo-controlled, phase 3 study enrolled patients with unresectable, locally advanced, recurrent, or metastatic ESCC irrespective of PD-L1 expression who were at least 18 years of age, had measurable or evaluable disease by RECIST 1.1 criteria, and an ECOG performance status no greater than 1.³

Participants were randomized 1:1 to receive tislelizumab at 200 mg or placebo given every 3 weeks on day 1, plus investigator-selected chemotherapy in the form of cisplatin at 60 to 80 mg/m² on day 1 or oxaliplatin at 130 mg/m² on day 1 paired with fluorouracil at 750 mg/m² to 800 mg/m² on days 1 to 5 or capecitabine at 1000 mg/m² twice daily on days 1 to 14 or paclitaxel at 175 mg/m² on day 1. They were stratified by investigator-chosen chemotherapy (platinum plus fluoropyrimidine vs platinum plus paclitaxel), region (Asia excluding Japan vs Japan vs other regions), and whether they received previous definitive therapy (yes vs no).

The trial’s primary end point was OS, and key secondary end points comprised PFS, ORR, OS in the subset of patients with a PD-L1 score of at least 10%, DOR, safety, and HRQOL. Exploratory end points included DCR by investigator assessment; and independent review committee–assessed PFS, ORR, DOR, and DCR.

Additional findings indicated that the median PFS with tislelizumab/chemotherapy was 7.3 months (95% CI, 6.9-8.3) by investigator assessment vs 5.6 months (95% CI, 4.9-6.0) with chemotherapy alone (HR, 0.62; 95% CI, 0.52-0.75; P < .0001). The 12-month PFS rates in the respective arms were 30.0% (95% CI, 24.6%-35.6%) and 15.7% (95% CI, 11.5%-20.4%). Investigator-assessed ORRs with the respective regimens were 63% and 42% (odds ratio, 2.38; 95% CI, 1.73-3.27; P < .0001).

Safety Insights

Safety was examined in 1534 patients who received single-agent tislelizumab at the approved dosing regimen, as well as 1319 patients with gastric/GEJ cancer, ESCC, or non–small cell lung cancer who received tislelizumab at the approved dosing regimen plus chemotherapy. The most common grade 3 or 4 toxicities experienced with the agent when given with chemotherapy were neutropenia, thrombocytopenia, anemia, fatigue, hypokalemia, hyponatremia, pneumonia, reduced appetite, rash, lymphopenia, increased alanine and aspartate aminotransferase levels, diarrhea, pneumonitis, and hepatitis.¹

References

1. BeiGene receives positive CHMP opinions for TEVIMBRA as a first-line treatment for advanced/metastatic gastric or gastroesophageal junction cancer and esophageal squamous cell carcinoma. News release. BeiGene. October 21, 2024. Accessed October 21, 2024. https://ir.beigene.com/news/beigene-receives-positive-chmp-opinions-for-tevimbra-as-a-first-line-treatment-for-advanced-metastatic-gastric-or/ed86eb4d-f10f-4a73-8744-2f212a91d349/
2. Xu R-H, Oh D-Y, Kato K, et al. Tislelizumab (tis) plus chemotherapy (chemo) vs placebo (pbo) plus chemo as first-line (1L) treatment of advanced gastric or gastroesophageal junction adenocarcinoma (GC/GEJC): final analysis results of the RATIONALE-305 study. Ann Oncol. 2023;34(suppl 4):S1526-S1527. doi:10.1016/j.annonc.2023.10.274
3. Xu J, Kato K, Raymond E, et al. Tislelizumab plus chemotherapy versus placebo plus chemotherapy as first-line treatment for advanced or metastatic oesophageal squamous cell carcinoma (RATIONALE-306): a global, randomised, placebo-controlled, phase 3 study. Lancet Oncol. 2023;24(5):483-495. doi:10.1016/S1470-2045(23)00108-0