2 Clarke Drive
Cranbury, NJ 08512
© 2022 MJH Life Sciences™ and OncLive - Clinical Oncology News, Cancer Expert Insights. All rights reserved.
Tislelizumab in combination with chemotherapy significantly improved overall survival vs chemotherapy alone when used in the frontline treatment of patients with locally advanced, unresectable or metastatic gastric or gastroesophageal junction adenocarcinoma whose tumors expressed PD-L1, meeting the primary end point of the phase 3 RATIONALE 305 trial.
Tislelizumab (BGB-A317) in combination with chemotherapy significantly improved overall survival (OS) vs chemotherapy alone when used in the frontline treatment of patients with locally advanced, unresectable or metastatic gastric or gastroesophageal junction (GEJ) adenocarcinoma whose tumors expressed PD-L1, meeting the primary end point of the phase 3 RATIONALE 305 trial (NCT037777657).1
Moreover, the safety profile of tislelizumab was found to be consistent with what has previously been observed in other clinical trials. Notably, no new safety signals were observed with the addition of chemotherapy.
Although the data from the interim analysis were positive, additional follow-up is needed to evaluate the OS benefits of the combination in the intention-to-treat population, according to the press release issued by BeiGene.
“The addition of tislelizumab to chemotherapy significantly extended the OS for previously untreated patients with advanced or metastatic gastric or GEJ adenocarcinoma whose tumor expressed PD-L1,” Yong (Ben) Ben, MD, chief medical officer of Solid Tumors at BeiGene, stated in a press release.
For patients with locally advanced or metastatic gastric GEJ adenocarcinoma, standard options include irinotecan, taxane, fluoropyrimidine, and platinum-based combination chemotherapy regimens.2 Immune checkpoint inhibitors have showcased encouraging activity across several malignancies, including gastric/GEJ adenocarcinoma.
In GI cancer cell lines, it was found that PD-L1 expression increases following treatment with 5-fluorouracil, which may indicate that the PD-1/PD-L1 axis could play a role in chemotherapy resistance. The monoclonal antibody tislelizumab has been shown to have a higher affinity to PD-1 than other immunotherapy agents like pembrolizumab (Keytruda) or nivolumab (Opdivo); this is because tislelizumab possesses a different binding orientation to PD-1. Although the binding surface on PD-1 partially overlaps with that of pembrolizumab, it significantly differs from that of nivolumab.
The agent was designed to minimize binding to FcyR on macrophages to repeal antibody-dependent phagocytosis. Data from earlier studies (NCT02407990; NCT03469557) showed that when the agent was used as a monotherapy or in combination with chemotherapy in this population, it was found to have favorable tolerability and promising antitumor activity.
The double-blind, global, placebo-controlled, phase 3 trial enrolled adult patients with histologically confirmed unresectable or metastatic gastric/GEJ adenocarcinoma, an ECOG performance status of 0 or 1, acceptable organ function, and at least 1 measurable lesion per RECIST v1.1 criteria. They needed to be able to provide either a fresh or archival tumor tissue sample for PD-L1 assessment.
Patients could not have received prior systemic therapy for locally advanced, unresectable or metastatic disease, and they could not have squamous cell, undifferentiated, or other histological type of gastric cancer or a diagnosis of HER2-positive gastric/GEJ adenocarcinoma, they were excluded.
Other exclusion criteria included having a history of gastrointestinal perforation and/or fistulae within 6 months before randomization, clinically significant bowel obstruction, any other active malignancy 2 years or less prior to randomization, or if they received prior therapy with a drug targeting T-cell co-stimulation or checkpoint pathways.
A total of 997 participants were randomized 1:1 to arm A, where they received intravenous (IV) tislelizumab at 200 mg every 3 weeks plus oxaliplatin and capecitabine or tislelizumab and cisplatin/5-fluorouracil (5-FU), or arm B, where they received placebo and oxaliplatin/capecitabine or placebo plus cisplatin/5-FU.
Investigators selected which of the following 2 chemotherapy regimens patients would receive: IV oxaliplatin was given at a dose of 130 mg/m2 every 3 weeks on day 1 of each 21-day cycle plus oral capecitabine at 1000 mg/m2 twice daily on days 1 through 15 of every cycle; or cisplatin at 80 mg/m2 every 3 weeks on day 1 of each cycle plus 5-FU at 800 mg/m2 continuously for 24 hours on days 1 through 5 of every cycle.
Treatment with tislelizumab or placebo was continued until intolerable toxicity, progressive disease, withdrawn consent, or until other treatment discontinuation criteria were met. Chemotherapy was given for up to 6 treatment cycles.
The primary end point of the trial is OS. Key secondary end points include progression-free survival (PFS), overall response rate (ORR), duration of response (DOR) per blinded independent review committee assessment and RECIST v1.1 criteria, quality-of-life outcome measures, and safety/tolerability.
Exploratory end points include disease control rate (DCR) per independent review, clinical benefit rate (CBR), and time to response (TTR), as well as investigator-assessed PFS, ORR, DOR, DCR, CBR, and TTR.
“We will continue to follow up to determine OS benefits across the patient population in the trial,” Ben added in the release.