Tislelizumab/Chemo May Become Frontline SOC for Recurrent/Metastatic Nasopharyngeal Cancer


The combination of tislelizumab and gemcitabine/cisplatin continued to demonstrate a greater progression-free survival benefit than chemotherapy alone when used in the frontline treatment of patients with recurrent or metastatic nasopharyngeal cancer.

Li Zhang, MD

Li Zhang, MD

The combination of tislelizumab (BGB-A317) and gemcitabine/cisplatin continued to demonstrate a greater progression-free survival (PFS) benefit than chemotherapy alone when used in the frontline treatment of patients with recurrent or metastatic nasopharyngeal cancer, according to updated data from the phase 3 RATIONALE-309 trial (NCT03924986) presented during an ASCO Plenary Series session.1

At a median follow-up of 15.5 months, the median PFS with tislelizumab plus chemotherapy (n = 131) was 9.6 months (95% CI, 7.6-11.7) vs 7.4 months (95% CI, 5.7-7.6) with chemotherapy alone (n = 132), translating to a 50% reduction in the risk of disease progression or death (HR, 0.50; 95% CI, 0.37-0.68).

These findings were consistent with what had previously been reported in the interim data analysis of the trial, where at a median follow-up of 10.0 months, the median PFS in the investigative arm was 9.2 months (95% CI, 7.6-10.1) vs 7.4 months (95% CI, 5.6-7.5) in the control arm (HR, 0.52; 95% CI, 0.38-0.73; P < .0001).

The addition of tislelizumab to chemotherapy also resulted in a numerical overall survival (OS) benefit over chemotherapy alone, although final data remain immature. At a median follow-up of 15.4 months in the tislelizumab/chemotherapy arm, the median OS had not yet been reached (95% CI, 23.7–not reached [NR]) vs 23.0 months (95% CI, 19.8-NR) in the chemotherapy arm (HR, 0.60; 95% CI, 0.35-1.01).

Moreover, the tislelizumab combination substantially improved the time to second disease progression (PFS2) over chemotherapy alone, despite 49.2% of patients having crossed over to receive single-agent tislelizumab. The median PFS2 in the investigative arm was not yet reached (95% CI, 23.7-NR) vs 13.9 months (95% CI, 12.5-17.9) in the control arm (unstratified HR, 0.38; 95% CI, 0.25-0.58).

“This updated analysis of the RATIONALE-309 study indicates that tislelizumab in combination with chemotherapy may become a SOC first-line therapy for patients with recurrent or metastatic nasopharyngeal cancer,” Li Zhang, MD, lead study author and professor at the Collaborative Innovation Center for Cancer Medicine, State Key Laboratory of Oncology and Sun Yat-sen University Cancer Center, said in a presentation on the data.

A humanized, anti–PD-1 IgG4 monoclonal antibody, tislelizumab was designed to minimize binding to FcγRon macrophages to abrogate antibody-dependent cellular phagocytosis. The agent has been found to have activity in several cancers, including esophageal cancer, hepatocellular carcinoma, non–small cell lung cancer, urothelial carcinoma, and microsatellite instability–high/deficient mismatch repair solid tumors.

The double-blind, phase 3 RATIONALE-309 trial enrolled treatment-naïve patients with histologically or cytologically confirmed, recurrent or metastatic nasopharyngeal cancer who had at least 1 measurable lesion per RECIST v1.1 criteria, an ECOG performance status of 0 or 1, and who were between the ages of 18 years and 75 years.

A total of 263 participants were randomized 1:1 to receive tislelizumab at 200 mg on day 1 every 3 weeks or matching placebo. Patients on both arms were given gemcitabine at 1 g/m2 on days 1 and 8 plus cisplatin at 80 mg/m2 on day 1, every 3 weeks, for 4 to 6 cycles. Stratification factors included gender (male vs female) and the presence of liver metastases (yes vs no).

Treatment was administered until progressive disease, unacceptable toxicity, death, or withdrawn consent. Patients in the investigative arm were able to go on to receive single-agent tislelizumab at 200 mg every 3 weeks if a study investigator considered this to be clinically beneficial. Those in the control arm were permitted to crossover to receive tislelizumab monotherapy per investigator decision.

The primary end point of the trial was PFS per independent review committee (IRC) assessment in the intention-to-treat (ITT) population, and secondary end points comprised OS, investigator-assessed PFS2, and safety. Biomarker analyses, such as PD-L1 expression and gene expression profiling (GEP), served as exploratory end points.

At the time of the interim analysis, at a median follow-up of 10.0 months, the combination of tislelizumab and chemotherapy was found to result in a significant improvement in IRC-assessed PFS compared with chemotherapy alone, meeting the primary end point of the trial.

The data cutoff date for the updated analysis was September 30, 2021. All patients who underwent randomization (n = 263) provided baseline tumor tissue samples for biomarker assessment. Ninety-one percent (n = 240) of these patients were evaluable for PD-L1 expression, and 94% (n = 247) were evaluable for GEP.

The biomarker-evaluable population and the ITT population had similar baseline characteristics and efficacy outcomes, according to Zhang.

The PFS improvement achieved with tislelizumab plus chemotherapy over chemotherapy alone was noted in all patients, irrespective of PD-L1 expression.

The GEP analysis, which was conducted by utilizing gene signatures that were representative of immune and tumor cell characteristics and had unsupervised clustering, revealed 3 gene expression clusters as potential biomarkers for efficacy: cold, medium, and hot.

“A ‘hot’ tumor immune profile was characterized by the highest expression of immune cells, including dendritic cells, and was associated with a greater PFS benefit vs [a] ‘cold’ tumor [immune profile] for tislelizumab plus chemotherapy,” Zhang explained.

Moreover, the PFS benefit achieved with the tislelizumab combination was noted to be highest among those with an activated dendritic cell signature. “We further investigated the individual genes that composed the dendritic cell signature and found LAMP3, a dendritic cell activation marker that was associated with PFS benefit,” Zhang added. “These results advocated the use of dendritic cell signature as a potential biomarker tool.”

The toxicity profile observed with tislelizumab plus chemotherapy was noted to be consistent with what had been reported at the time of the interim analysis. “The safety profile [of the combination] was manageable…no new safety signals were identified,” Zhang noted.

The most common treatment-related adverse effects reported with the tislelizumab combination included decreased white blood cell count, anemia, decreased neutrophil count, neutropenia, decreased platelet count, and leukopenia.


  1. Zhang L, Yang Y, Pan J-J, 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. J Clin Oncol. 2022;40(suppl 36):384950
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