The FDA has accepted for review a biologics license application seeking the approval of tislelizumab for use in the frontline treatment of patients with unresectable, recurrent, locally advanced or metastatic esophageal squamous cell carcinoma.
The FDA has accepted for review a biologics license application (BLA) seeking the approval of tislelizumab (Tevimbra) for use in the frontline treatment of patients with unresectable, recurrent, locally advanced or metastatic esophageal squamous cell carcinoma (ESCC).1
The application is supported by findings from the phase 3 RATIONALE 306 (NCT03783442) in which the addition of tislelizumab to chemotherapy (n = 326) resulted in improved overall survival (OS) vs placebo plus chemotherapy (n = 323), at a median of 17.2 months (95% CI, 15.8-20.1) vs 10.6 months (95% CI, 9.3-12.1), respectively (stratified HR, 0.66; 95% CI, 0.54-0.80; P < .0001).2 The 12-month OS rates in the investigative and control arms were 65.0% (95% CI, 59.4%-70.0%) and 44.9% (95% CI, 39.2%-50.3%), respectively; the 18-month rates were 48.6% (95% CI, 42.9%-54.0%) and 34.5% (95% CI, 29.2%-39.8%), respectively.
Under the Prescription Drug User Fee Act, the regulatory agency has assigned a target action date in the second half of 2024.1
“We are excited to announce the European Commission approval and the FDA filing acceptance for tislelizumab, having recently regained full global rights to this important medicine,” Mark Lanasa, MD, PhD, chief medical officer of Solid Tumors at BeiGene, Ltd., stated in a press release. “These significant milestones for people with advanced or metastatic ESCC, as tislelizumab has been shown to deliver clinically meaningful survival benefit as monotherapy and in combination with chemotherapy in patients worldwide.”
The double-blind, parallel-arm, placebo-controlled, phase 3 trial enrolled patients with histologically confirmed, unresectable, locally advanced, recurrent, or metastatic esophageal carcinoma who are at least 18 years of age and who have not received prior systemic treatment for advanced disease.2 Patients needed to have measurable disease by RECIST v1.1 criteria and an ECOG performance status of 0 or 1. They were enrolled irrespective of PD-L1 status.
If they had brain or leptomeningeal metastases that were symptomatic and needed treatment or had evidence of complete esophageal obstruction that was not able to receive treatment, they were excluded. Other exclusion criteria included having evidence of fistula, active autoimmune diseases, or medical conditions that needed treatment with corticosteroids or immunosuppressants. They could not have previously received PD-1, PD-L1 or PD-L1 inhibitors.
Study participants were randomly assigned 1:1 to receive tislelizumab or placebo plus investigator’s choice of a chemotherapy doublet. Tislelizumab was given at a dose of 200 mg every 3 weeks on day 1 of 21-day cycles. Chemotherapy options included cisplatin at 60 mg/m2 to 80 mg/m2 on day 1 or oxaliplatin at 130 mg/m2 on day 1 plus 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.
Stratification factors included the chemotherapy (platinum plus fluoropyrimidine vs platinum plus paclitaxel), region (Asia excluding Japan vs Japan vs other regions), and receipt or prior definitive therapy (yes vs no).
OS served as the trial’s primary end point, and secondary end points included progression-free survival (PFS), OS in the subset of patients with a PD-L1 tumor area positivity (TAP) score of at least 10%, duration of response (DOR), safety, and health-related quality of life. Exploratory end points included disease control rate (DCR) by investigator assessment, PFS by blinded independent review committee assessment, overall response rate, DOR, and DCR.
The median age across the investigative and control arms was 64.5 years (range, 58-70) with 46% and 50% of patients, respectively, aged 65 years and older. Most patients were male (87% vs 87%), from Asia (75% vs 75%), had an ECOG performance status of 1 (67% vs 68%), and were current or former smokers (76% vs 72%).
Moreover, most patients had metastatic disease at the time of study entry (86% vs 87%) with almost half of patients having 1 metastatic site (44% vs 44%). Almost all patients (>99% vs 100%) had squamous cell carcinoma and more than half (56% vs 56%) had not previously received definitive treatment. Regarding PD-L1 expression, of those in the tislelizumab arm, 36% had a TAP score of 10% or higher, 46% had a score of less than 10^, and 18% had status; these rates were 33%, 52%, and 15%, respectively, in the placebo arm.
The data cutoff date was February 28, 2022, and the median follow-up in the tislelizumab and placebo arms was 16.3 months (interquartile range [IQR], 8.6-21.8) and 9.8 months (IQR, 5.8-19.0), respectively.
Additional data showed that in those with a PD-L1 TAP score of 10% or higher who received tislelizumab plus chemotherapy (n = 116), the median OS was 16.6 months (95% CI, 15.3-24.4) vs 10.0 months (95% CI, 8.6-13.3) with placebo plus chemotherapy (n = 107; HR, 0.62; 95% CI, 0.44-0.87; P = .0029). The 18-month OS rates were 46.9% (95% CI, 37.5%-55.8%) and 34.8% (95% CI, 25.7%-44.0%), respectively.
In those with a PD-L1 TAP score of less than 10%, those given tislelizumab (n = 151) experienced a median OS of 15.8 months (95% CI, 12.3-19.6) vs 10.4 months (95% CI, 9.0-13.6) with placebo (n = 168; HR, 0.77; 95% CI, 0.59-1.01). The 18-month OS rates were 45.8% (95% CI, 37.6%-53.6%) and 33.7% (95% CI, 26.5%-41.0%), respectively.
The median investigator-assessed PFS was 7.3 months (95% CI, 6.9-8.3) with tislelizumab plus chemotherapy 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 were 30.0% (95% CI, 24.6%-35.6%) vs 15.7% (95% CI, 11.5%-20.4%), respectively.
Regarding safety, 97% of those in the tislelizumab arm and 96% of those in the placebo arm experienced at least 1 treatment-related toxicity; these effects were grade 3 or higher in 67% and 64% of patients, respectively. The most frequently experienced grade 3 or 4 effects included decreased neutrophil count (31% vs 33%), decreased white blood cell count (11% vs 16%), and anemia (15% vs 13%).
Serious treatment-related adverse effects (TRAEs) occurred in 29% of those in the tislelizumab arm vs 19% of those in the placebo arm, and the most common were pneumonia (2% vs 2%) and neutropenia (<1% vs 2%). These effects resulted in discontinuation for 70% vs 63% of patients, respectively. TRAEs led to death in 5% of patients in both arms.