The National Medical Products Administration of China has granted approval to tislelizumab in combination with fluoropyrimidine and platinum chemotherapy in the frontline treatment of patients with locally advanced unresectable or metastatic gastric or gastroesophageal junction adenocarcinoma with a high PD-L1 expression.
The National Medical Products Administration (NMPA) of China has granted approval to tislelizumab (BGB-A317) for use in combination with fluoropyrimidine and platinum chemotherapy in the frontline treatment of patients with locally advanced unresectable or metastatic gastric or gastroesophageal junction (GEJ) adenocarcinoma with a high PD-L1 expression.1
The regulatory decision was supported by findings from an interim analysis of the phase 3 RATIONALE-305 trial (NCT03777657), in which the addition of tislelizumab to chemotherapy (n = 274) significantly improved median overall survival (OS) over chemotherapy alone (n = 272), at 17.2 months (95% CI, 13.9-21.3) and 12.6 months (95% CI, 12.0-14.4), respectively, in the overall population; this translated to a 24% relative reduction in the risk of disease (HR, 0.74; 95% CI, 0.59-0.94; P = .0056).2
In the subset of patients with PD-L1–positive disease who received tislelizumab/chemotherapy, the median PFS was 7.2 months (95% CI, 5.8-8.4) vs 5.9 months (95% CI, 5.6-7.0) in those who received chemotherapy alone (HR, 0.67; 95% CI, 0.55-0.83).
“The prognosis for patients with advanced gastric/GEJ adenocarcinoma was poor with traditional chemotherapy treatment and we undertook the global phase 3 RATIONALE 305 trial with the aim to improve outcomes,” Xu Ruihua, MD, PhD, director of Cancer Control Center of Sun Yat-sen University, and global principal investigator of the trial, stated in a press release.
“With approval from the NMPA, we now have another option four our patients and I expect tislelizumab plus chemotherapy will soon become the new standard of care in this treatment setting in China.”
RATIONALE 305 enrolled patients with histologically confirmed gastric or GEJ cancer who did not previously receive treatment for unresectable, locally advanced or metastatic disease. Those with HER2-positive tumors were excluded.
Study participants were randomly assigned 1:1 to receive tislelizumab at 200 mg intravenously every 3 weeks or placebo plus chemotherapy in the form 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). Patients received maintenance treatment until intolerable toxicity or progressive disease.
Patients were stratified based on region of enrollment, peritoneal metastases, PD-L1 score (≥5% vs <5%), and investigator’s choice of chemotherapy.
The primary end points of the trial were OS in the PD-L1–positive population and the intention-to-treat population. Key secondary end points comprised progression-free survival, objective response rate (ORR), duration of response (DOR), disease control rate (DCR), clinical benefit rate, time to response, health-related quality of life, and safety.
The median age of those in the tislelizumab arm was 61.0 years (range, 23.0-83.0) vs 62.0 years (range, 30.0-84.0) in the placebo arm. Most patients were male (70.4% vs 73.9%, respectively), from East Asia (73.7% vs 73.9%), am ECOG performance status of 1 (64.2% vs 68.4%), and metastatic disease (98.5% vs 98.5%).
In the tislelizumab arm, 81.4% had their primary tumor in the stomach and 18.6% had GEJ adenocarcinoma; these rates were 18.6% and 21.3%, respectively, in the placebo arm. The investigator-chosen chemotherapy regimen in the tislelizumab was XELOX in 92.7% of patients and FP in 7.3% of patients; in the placebo arm, these rates were 93.4% and 6.6%, respectively. In the investigative and control arms, 13.5% and 14.0% of patients, respectively, received previous adjuvant or neoadjuvant treatment.
Additional data presented at the 2023 Gastrointestinal Cancers Symposium showed that an improvement in OS was observed with the addition of tislelizumab across all prespecified subgroups.
Tislelizumab plus chemotherapy elicited an ORR of 50.4% (95% CI, 44.3%-56.4%) vs 43.0% (95% CI, 37.1%-49.1%) with chemotherapy alone. Of those who responded in the investigative arm, the complete response rate was 3.3% and the partial response rate was 47.1%; 38.0% achieved stable disease and 4.4% had disease progression. The median DOR in the investigative arm was 9.0 months (95% CI, 8.2-19.4) vs 7.1 months (95% CI, 5.7-8.3) in the control arm. Moreover, the DCR with tislelizumab/chemotherapy was 88.3% (95% CI, 83.9%-91.9%) vs 83.1% (95% CI, 78.1%-87.3%) with chemotherapy alone.
The median duration of treatment with tislelizumab was 28.9 weeks (range, 0.6-135.3) vs 24.4 weeks (range, 2.3-128.6) with placebo. The safety profile of tislelizumab plus chemotherapy proved to be consistent with the known profile of each agent. No new signals were observed.
Any-grade treatment-emergent adverse effects (TEAEs) were experienced by 99.6% of those in the investigative arm and 97.8% of t hose in the control arm; these effects were treatment related in 97.1% and 96.0% of patients, respectively.
Grade 3 or higher TEAEs were reported in 64.7% and 62.9% of patients, respectively; they were treatment related in 97.1% and 96.0% of patients, respectively. Serious TEAEs were experienced by 42.3% and 36.8% of patients, respectively; they were treated related in 25.7% and 16.5% of cases, respectively.
The most common TEAEs reported in at least 20% of patients were 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.
TEAEs resulted in treatment discontinuation for 22.4% of those in the tislelizumab arm vs 12.1% of those in the placebo arm. TEAEs led to death in 8.8% and 7.7% of patients, respectively; these deaths were determined to be related to treatment in 2.2% and 0.7% of cases, respectively.