FDA Approves Tislelizumab Plus Chemo for PD-L1+ Unresectable or Metastatic Gastric/GEJ Cancer

The FDA has approved tislelizumab-jsgr (Tevimbra) in combination with platinum- and fluoropyrimidine-based chemotherapy for the first-line treatment of patients with unresectable or metastatic, HER2-negative gastric or gastroesophageal junction (GEJ) adenocarcinoma whose tumors express PD-L1 (≥1).1,2

The regulatory decision was supported by data from the phase 3 RATIONALE-305 trial (NCT03777657), which showed that treatment with tislelizumab plus chemotherapy led to a statistically significant and clinically meaningful improvement in overall survival (OS) compared with placebo plus chemotherapy (HR, 0.80; 95% CI, 0.70-0.92; P = .0011).1 Patients treated with tislelizumab plus chemotherapy experienced a median OS of 15.0 months vs 12.9 months for those treated with placebo plus chemotherapy.

“Today’s FDA approval of [tislelizumab] for the treatment of gastric or GEJ cancers in PD-L1–positive adult patients marks a significant step forward in our mission to deliver transformative therapies to patients with cancer,” Mark Lanasa, MD, PhD, chief medical officer, Solid Tumors at BeiGene, stated in a news release.1 “This is the second U.S. 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.”

The randomized, multicenter, placebo-controlled, double-blind RATIONALE-305 trial enrolled patients with HER2-negative, previously untreated unresectable or metastatic G/GEJ adenocarcinoma.2 Enrollment was allowed irrespective of PD-L1 expression level. PD-L1 expression was evaluated prospectively via central laboratory using the VENTANA PD-L1(SP263) assay that identified PD-L1 staining on both tumor and tumor-associated immune cells (TAP score); combined positive score (CPS) was evaluated retrospectively.

Patients were excluded if they had active leptomeningeal disease or uncontrolled brain metastasis; active autoimmune disease or history of autoimmune diseases; or a medical condition requiring systemic corticosteroids or immunosuppressants.

Patients were randomly assigned to receive tislelizumab at 200 mg once every 3 weeks or placebo once every 3 weeks in combination with investigator’s choice of chemotherapy in 21-day cycles. Treatment with tislelizumab or placebo continued until disease progression or unacceptable toxicity.

The chemotherapy regimens in both arms included CAPOX, which consisted of oxaliplatin at 130 mg/m2 on day 1 for up to 6 cycles plus capecitabine at 1000 mg/m2 twice per day for 14 consecutive days (capecitabine could continue beyond 6 cycles); or cisplatin at 80 mg/m2 on day 1 and 5-FU at 800 mg/m2 per day on days 1 to 5 for up to 6 cycles.

OS in the intention-to-treat and TAP score of at least 5% populations served as the trial's primary end point. Secondary end points included investigator-assessed progression-free survival (PFS), objective response rate (ORR), and duration of response (DOR) per RECIST 1.1 criteria.

Additional Efficacy and Safety Data

Findings from RATIONALE-305 showed that in patients with a TAP score of at least 1%, tislelizumab plus chemotherapy (n = 432) elicited a median OS of 15.0 months (95% CI, 13.3-16.7) compared with 12.8 months (95% CI, 12.1-14.1) for placebo plus chemotherapy (n = 453; HR, 0.78; 95% CI, 0.67-0.90). The median PFS was 6.9 months (95% CI, 5.7-7.2) vs 5.9 months (95% CI, 5.6-6.9), respectively (HR, 0.78; 95% CI, 0.67-0.91).

In the TAP score of at least 1% population, the ORR was 48% (95% CI, 43%-53%) for tislelizumab plus chemotherapy vs 41% (95% CI, 37%-46%) for placebo plus chemotherapy. The median DOR was 8.6 months (95% CI, 7.8-10.4) vs 7.2 months (95% CI, 5.8-8.3), respectively.

Pooled safety data showed that most common grade 3 or 4 adverse effects for tislelizumab in combination with chemotherapy included neutropenia, thrombocytopenia, anemia, fatigue, hypokalemia, hyponatremia, pneumonia, decreased appetite, rash, lymphopenia, increased alanine aminotransferase levels, increased aspartate aminotransferase levels, diarrhea, pneumonitis, and hepatitis.1

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://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/
2. Tevimbra. Prescribing information. December 2024. Accessed December 27, 2024. https://www.beigene.com/PDF/TEVIMBRAUSPI.pdf