Frontline Tislelizumab/Chemo Bests Chemotherapy Alone in Recurrent or Metastatic Nasopharyngeal Cancer

Results of the phase 3 RATIONALE-309 trial demonstrate efficacy of tislelizumab added to chemotherapy for recurrent or metastatic nasopharyngeal carcinoma.

Updated data from the phase 3 RATIONALE-309 trial (NCT03924986) showed persistent progression-free survival (PFS) benefit of tislelizumab plus chemotherapy vs chemotherapy alone for the treatment of patients with recurrent or metastatic nasopharyngeal carcinoma, according to a presentation during the 2022 American Society of Clinical Oncology (ASCO) Annual Meeting.1

At a median follow-up of 15.5 months, the median PFS with the tislelizumab/chemotherapy combination was 9.6 months (95% CI, 7.6-11.7) compared with 7.4 months (95% CI, 5.7-7.6) in the chemotherapy alone arm (HR, 0.50; 95% CI, 0.37-0.68).

A positive trend in overall survival (OS) was also observed in the tislelizumab/chemotherapy arm vs the chemotherapy-alone arm. In the investigative arm, the median OS had not been reached (95% CI, 23.7–not evaluable [NE]) vs 23.0 months (95% CI, 19.8-NE), respectively (HR, 0.60; 95% CI, 0.35-1.01).

The RATIONALE-309 data are consistent with other phase 3 randomized, controlled trials of PD-1 inhibitors in nasopharyngeal carcinoma, according to Li Zhang, MD, lead study author and professor in the Collaborative Innovation Center for Cancer Medicine at State Key Laboratory of Oncology and Sun Yat-sen University Cancer Center. JUPITER-02 (NCT03581786) and CAPTAN-1st (NCT03707509) showed a PFS benefit with toripalimab and camrelizumab, respectively, in combination with standard chemotherapy for first-line treatment of patients with recurrent/metastatic nasopharyngeal carcinoma.2,3

“Combined, these 3 studies provide robust support for the use of a PD-1 inhibitor plus chemotherapy for first-line recurrent/metastatic nasopharyngeal carcinoma,” Zhang said in a presentation on the data.

The continued improvements in median PFS and OS occurred despite a 49.2% crossover rate from chemotherapy to tislelizumab monotherapy, per protocol, if the trial investigator considered a switch to be clinically beneficial, Zhang added. The tislelizumab/chemotherapy combination improved the time to second disease progression (PFS2) over chemotherapy alone. The median PFS2 in the investigative arm was not yet reached (95% CI, 23.7-NE) vs 13.9 months (95% CI, 12.5-17.9) in the control arm (HR, 0.38; 95% CI, 0.25-0.58).

“This is the first analysis of PFS2 in first-line recurrent/metastatic NPC, and the observed PFS2 benefit supports the use of tislelizumab plus chemotherapy first in the treatment sequence,” Zhang noted.

In the double-blind study, which was conducted in China, 263 treatment-naïve patients with histologically or cytologically confirmed, recurrent or metastatic nasopharyngeal carcinoma were randomized 1:1 to receive intravenous (IV) tislelizumab at 200 mg on day 1 every 3 weeks, or matching placebo. Patients in both arms received IV gemcitabine at 1 g/m2 on days 1 and 8, plus IV cisplatin at 80 mg/m2 on day 1, every 3 weeks, for 4 to 6 cycles.

Treatment was administered until progressive disease, unacceptable toxicity, death, or withdrawn consent. Patients in the investigative arm were able to go on to receive tislelizumab monotherapy 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 data cutoff date for the updated analysis was September 30, 2021. All patients who underwent randomization provided baseline tumor tissue samples for biomarker assessment. In the biomarker analysis, 3 unique gene expression clusters, representing immunologically hot and cold tumors, were identified. The hot cluster was characterized by a higher abundance of T cells, natural killer cells, active dendritic cells, and antigen presentation machinery I and II.

In addition, the activated dendritic cell activation marker LAMP3 was identified as a potential biomarker for efficacy of tislelizumab/chemotherapy.

“Further research is warranted to assess the biomarker potential of the activated dendritic cell signature found in this study,” Zhang concluded.


  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. doi:10.1200/JCO.2022.40.36_suppl.384950
  2. Mai H-Q, Chen QY, Chen D, et al. Toripalimab or placebo plus chemotherapy as first-line treatment in advanced nasopharyngeal carcinoma: a multicenter randomized phase 3 trial. 2021;27(9):1536-1543. doi:10.1038/s41591-021-01444-0
  3. Yang Y, Qu S, Li J, et al. Camrelizumab versus placebo in combination with gemcitabine and cisplatin as first-line treatment for recurrent or metastatic nasopharyngeal carcinoma (CAPTAIN-1st): a multicentre, randomised, double-blind, phase 3 trial. Lancet Oncol. 2021;22(8):1162-1174. doi:10.1016/S1470-2045(21)00302-8
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