Tislelizumab Holds PFS Benefit After 15 Months in Recurrent/Metastatic Nasopharyngeal Carcinoma


Updated results from the RATIONALE-309 study show that tislelizumab continues to prolong PFS extend PFS after the next line of therapy in patients with recurrent or metastatic nasopharyngeal carcinoma.

Li Zhang, MD

Li Zhang, MD

Tislelizumab (BGB-A3171) administered in combination with chemotherapy sustained a progression-free survival (PFS) benefit after 15.5 months of follow-up, further demonstrating a clinically meaningful improvement in patients with recurrent or metastatic nasopharyngeal carcinoma, according to updated findings from the RATIONALE-309 clinical trial (NCT03924986).1

“Globally, [nasopharyngeal carcinoma] accounts for approximately 133,000 new cases and 80,000 deaths per year. The prognosis of patients that have recurrent or metastatic nasopharyngeal carcinoma treated with first-line chemotherapy remain poor with [a] median PFS [of] 7 months and overall survival of 22 months,” said Prof Li Zhang, MD of the Sun Yat-Sen University Cancer Centre, during a presentation at the ASCO Plenary Series: April 2022 Session.

Results showed that the PFS benefit of the combination extended to PFS after the next line of treatment (PFS2), achieving a substantial improvement. Median PFS after a median of 15.5 months of follow-up was 9.6 months (95% CI, 7.6-11.7) with tislelizumab and chemotherapy compared with 7.4 months (95% CI, 5.7-7.6) with placebo plus chemotherapy (stratified HR, 0.50; 95% CI, 0.37-0.68). In terms of PFS2, the median number of months was not reached (NR) in the tislelizumab/chemotherapy arm (95% CI, 23.7-NR) vs 13.9 months (95% CI, 12.5-17.9) in the control arm (stratified HR, 0.38; 95% CI, 0.25-0.58).

Tislelizumab is a humanized anti-PD-1 IgG4 monoclonal antibody, which, in preclinical models, showed the ability to minimize binding to FcyR on macrophages. Its mechanism of action allows it to get rid of antibody-dependent cellular phagocytosis, which could otherwise lead to T-cell clearance and anti-PD-1 resistance.

The agent has previously demonstrated efficacy in multiple phase 2 and 3 trials in patients with nasopharyngeal carcinoma, esophageal cancer, hepatocellular carcinoma, non–small cell lung cancer, urothelial carcinoma, and microsatellite instability-high and mismatch repair deficient solid tumors. Also, the interim analysis of RATIONALE-309 showed that tislelizumab in combination with chemotherapy achieved a median PFS of 9.2 months vs. 7.4 months in the control arm, meeting the primary end point of the study.2

In RATIONALE-309, patients had histologically confirmed treatment-naïve recurrent or metastatic nasopharyngeal carcinoma. All patients were between the ages of 18 and 75 years old and had at least 1 measurable lesion and an ECOG performance status of 1 or lower.1

Patients with randomized 1:1 to receive either tislelizumab plus chemotherapy or placebo plus chemotherapy. In the experimental arm, patients received tislelizumab 200 mg via intravenous (IV) infusion on day 1, every 2 weeks plus gemcitabine 1 g/m2 IV on days 1 and 8 and cisplatin 80 mg/m2 on day 1, every 3 weeks for 4 to 6 cycles. In the control arm, patients received a matching placebo and chemotherapy. All treatment was administered until disease progression, intolerable toxicity, death, or withdrawal of patient consent.

The study’s protocol permitted patients in the experimental arm to receive tislelizumab monotherapy in the event that it was deemed clinical beneficial at the investigator’s discretion. Moreover, crossover to the tislelizumab-containing arm from the placebo/chemotherapy arm was allowed for patients if it is thought to be clinically beneficial by the study investigators.

Patients with recurrent/metastatic nasopharyngeal carcinoma in the study were stratified by genre and the presence of liver metastases to test the primary end point of PFS in the intention-to-treat (ITT) population by independent review committee. Secondary end points included overall survival (OS), investigator-assessed PFS2, and safety. Exploratory end points were also evaluated in the study, including biomarker analyses of features like PD-L1 expression and gene expression profiling.

The study was 82% powered to detect PFS improvement with a hazard ratio (HR) of 0.65 with a 1-sided P-value significance level of 0.025. To determine the results of the survival end points between the 2 treatment arms, a stratified log-rank test was utilized, and PFS rates were estimated using a Kaplan-Meier analysis. The data cutoff date for this 15.5-month follow-up analysis was September 30, 2021.

In terms of survival, the results showed a numeral OS benefit with tislelizumab plus chemotherapy compared with the placebo arm. However, final OS data were still immature, with a median follow-up of 15.4 months in the tislelizumab group and 15.8 in the placebo group. At 6 months, the OS rate with tislelizumab/chemotherapy was 95.3% (95% CI, 89.9%-97.9%) compared with 97.6% (95% CI, 92.9%-99.2%) with placebo/chemotherapy. By month 12, the OS rate in the tislelizumab/chemotherapy arm was 89.6% (95% CI, 82.8%-93.0%) vs 86.4% (95% CI, 78.8%-91.5%) with placebo/chemotherapy.

The 6-month PFS2 rate with the experimental combination was 95.3% (95% CI, 89.8%-97.9) vs 94.4% (95% CI, 88.6%-07.3%) in the placebo arm. The 12-month PFS2 rate with the tislelizumab combination was 83.4% (95% CI, 75.4%-88.9%) compared with 62.6% (95% CI, 53.1%-70.8%) with placebo.

“This result indicated that tislelizumab plus chemotherapy should be used in the first line to deliver the maximum clinical benefit,” Zhang stated.

The exploratory biomarker analysis was conducted for all 263 patients in the ITT population, based on tumor tissue provided at baseline. Ninety-one percent of patients were PD-L1 immunohistochemistry evaluable, and 94% were gene-expression profiling evaluable. The 2 biomarker testing groups had similar baseline characteristics and efficacy outcomes.

“The biomarker analysis that showed that PFS benefit of tislelizumab/chemotherapy was greatest in the hot tumor microenvironment cluster as defined by gene expression profiling,” explained Zhang. “Dendritic cell activation was positively correlated with PFS benefit and may serve as a potential biomarker for predicted effector, and further study is warranted,” he added.

Patients with recurrent/metastatic nasopharyngeal carcinoma in the study were also followed for a median of 10.0 months to assess safety. Treatment-emergent adverse events (TEAEs) occurred in all patients in the tislelizumab arm vs 99.2% of the placebo arm, and serious TEAEs occurred in 80.9% vs 81.8%, respectively. TEAEs led to death in 3.8% of the tislelizumab group vs 1.5% of the placebo group, and permanent discontinuations resulting from TEAEs occurred in 1.5% vs 2.3%, respectively.

Immune-mediated TEAEs that were grade 3 or higher occurred in 18.3% of patients who received tislelizumab and chemotherapy compared with no patients in the placebo group. The most common TEAEs observed in the study were white blood count decreased, anemia, neutrophil count decreased, neutropenia, platelet count decreased, and leukopenia.

Regarding safety, Zhang stated that the safety profile of tislelizumab was consistent with previous reports and no new safety signals were identified.

“The current data analysis indicated that tislelizumab plus chemotherapy may become our standard-of-care, first-line therapy for patients with recurrent and metastatic nasopharyngeal carcinoma,” said Zhang.


1. Yang Y, Pan J, Chen X, et al. RATIONALE-309: Updated progression-free survival (PFS), PFS after next line of treatment, and overall survival from a phase 3 double-blind trial of tislelizumab versus placebo, plus chemotherapy, as first-line treatment for recurrent/metastatic nasopharyngeal cancer. Presented at: ASCO Plenary Series: April 2022 Session; April 19, 2022. Abstract 384950. Virtual.

2. Yang Y, Pan J, Wang H, et al. 121O - RATIONALE 309: A randomized, global, double-blind, Phase 3 trial of tislelizumab (TIS) vs placebo, plus gemcitabine + cisplatin (GP), as 1L treatment for recurrent/metastatic nasopharyngeal cancer (RM-NPC). Ann Oncol. 2021;32(suppl 7): S1428-S1457. doi: 10.1016/annonc/annonc787

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