The addition of the checkpoint inhibitor tislelizumab to first-line chemotherapy significantly reduced the risk of disease progression or death by 50% and, despite a 49% crossover rate, numerically boosted overall survival in patients with recurrent or metastatic nasopharyngeal cancer, Zhang et al reported in an April 2022 session of the ASCO Plenary Series (Abstract 384950).
Li Zhang, MD
“This updated analysis of the RATIONALE-309 study indicates that tislelizumab plus chemotherapy may become a standard-of-care first-line therapy for patients with relapsed or metastatic nasopharyngeal cancer,” said first study author Li Zhang, MD, Professor and Director of the Department of Medical Oncology, Sun Yat-sen University Cancer Center, Guangzhou, China.
About Tislelizumab and RATIONALE-309
Tislelizumab is an anti–PD-1 monoclonal IgG4 antibody being developed in China. The drug was engineered to minimize binding to the Fcγ receptor on macrophages as a means of abrogating antibody-dependent cellular phagocytosis, a mechanism of T-cell clearance and potential anti–PD-1 resistance, Dr. Zhang explained.
Tislelizumab is one of several anti–PD-1 agents—all developed in China—that are being evaluated in nasopharyngeal cancer, which is more common in Asia than in Western countries. Its efficacy has been demonstrated in phase II and III trials across multiple tumor types, and it is approved in China for previously treated patients with relapsed or refractory classical Hodgkin lymphoma.
In the RATIONALE-309 study, 263 treatment-naive patients with relapsed or metastatic nasopharyngeal cancer were randomly assigned 1:1 to receive either tislelizumab at 200 mg intravenously in combination with gemcitabine at 1 g/m2 plus cisplatin at 80 mg/m2 every 3 weeks for four to six cycles or placebo and chemotherapy; this was followed by tislelizumab or placebo every 3 weeks until disease progression. After progression, patients could continue or cross over to tislelizumab monotherapy (200 mg every 3 weeks). The primary endpoint was progression-free survival by independent review.
Progression-Free and Overall Survival
After 15.5 months, median progression-free survival was 9.6 months with the combination vs 7.4 months with chemotherapy alone (hazard ratio [HR] = 0.50, 95% confidence interval [CI] = 0.37–0.68). In the previous interim analysis, which was conducted after a median follow-up of 10 months, it was 9.2 vs 7.4 months (HR = 0.52, P < .0001).
“The progression-free survival remained consistent with the interim data analysis and demonstrated a clinically meaningful improvement,” said Dr. Zhang. “And while the overall data are still immature, a numerical overall survival benefit was observed.”
Median overall survival was not reached with tislelizumab plus chemotherapy and was 23.0 months with chemotherapy alone (HR = 0.60, 95% CI = 0.35–1.01). At 12 months, 89.6% of patients were alive vs 86.4%, despite the fact that 49.2% of patients in the placebo arm crossed over to receive tislelizumab.
Other Outcomes
A substantial benefit was also observed in second progression-free survival (ie, time from randomization to objective disease progression on next line of therapy or death from any cause). Median time to second progression was not reached with the combination but was 13.9 months with chemotherapy alone (HR = 0.38, 95% CI = 0.25–0.58). “These results indicated that tislelizumab plus chemotherapy should be used in the first line to deliver the maximum clinical benefit,” Dr. Zhang commented.
The combination of tislelizumab with chemotherapy was generally well tolerated and had a comparable safety profile compared with placebo plus chemotherapy. The most frequent adverse events reported with the combination were leukopenia, neutropenia, anemia, and thrombocytopenia.
Exploratory Analyses
Biomarker assessments were performed on baseline tumor tissue, including PD-L1 immunohistochemistry, and gene-expression profiling was also performed (1,392 genes were included); investigators obtained biomarker data on more than 90% of patients in the intent-to-treat population.
By tumor cell PD-L1 expression, after a median follow-up of 15.5 months, an improvement in progression-free survival for tislelizumab plus chemotherapy was observed in all tumor cell PD-L1 expression subgroups, ie, < 1% or ≥ 1% and < 10% or ≥ 10%.
Gene-expression profiling identified signatures that could offer a potential biomarker for efficacy. Gene-expression analysis (representing both immune and tumor cell characteristics) with unsupervised clustering identified three gene-expression clusters that were classified as cold, medium, and hot. Greater progression-free survival benefit was observed in patients with a “hot” tumor microenvironment, which was characterized by the highest expression of T cells, natural killer cells, and dendritic cells, along with major histocompatibility complex and interferon-gamma signatures.
Enhanced efficacy was also observed in patients with a high activated dendritic cell signature, suggesting this too could be a potential biomarker tool, according to Dr. Zhang. The lowest rate of events among patients receiving the combination occurred in patients with a high signature (58.5%) vs low (64.4%). In the placebo arm, events were common (78.0% and 79.7%, respectively).
“We further investigated the individual genes that composed the dendritic cell signature and found LNMP3, a classic dendritic cell activation marker, was most significantly associated with progression-free survival benefit,” he said. “These results advocate the use of the dendritic cell signature as a potential biomarker.”
Disclosure: The manufacturer of tislelizumab, BeiGene, has partnered with Novartis for the clinical development and marketing of the drug in the United States, Europe, and Japan. This research was funded by BeiGene, Ltd. Dr. Li had personal financial disclosures for BeiGene, AstraZeneca, Innovent Biologics, Roche China, and HenRui. For full disclosures of the study authors, visit coi.asco.org.
