Tislelizumab Plus Chemo Sustains Survival Benefit at 3 Years in Metastatic NPC

The first-line combination of tislelizumab-jsgr (Tevimbra) and chemotherapy continued to generate a progression-free survival (PFS) benefit and a clinically meaningful improvement in overall survival (OS) compared with placebo plus chemotherapy in patients with recurrent or metastatic nasopharyngeal carcinoma (NPC), according to 3-year follow-up results from the phase 3 RATIONALE-309 trial (NCT03924986) published in JAMA Oncology.¹

At a median follow-up of 27.5 months (range, 0.1-53.0), the median PFS as assessed by an independent review committee (IRC) was 9.6 months (95% CI, 7.6-11.6) in the tislelizumab arm (n = 131) compared with 7.4 months (95% CI, 5.6-7.6) in the placebo arm (n = 132; HR, 0.53; 95% CI, 0.39-0.71). The median OS was 45.3 months (95% CI, 33.4-not estimable [NE]) with the investigational combination vs 31.8 months (95% CI, 25.0-NE) with the placebo combination (HR, 0.73; 95% CI, 0.51-1.05).

“The PFS benefit persisted…and was consistent with the interim analysis findings,” lead study authors Yunpeng Yang, MD, and Chia-Jui Yen, MD, and coauthors wrote in the paper. “With extended follow-up, [patients] receiving tislelizumab plus chemotherapy [experienced] a clinically meaningful improvement in OS…despite a high crossover rate [n = 69/132; 52.3%] in the placebo plus chemotherapy arm.”

Yang and Yen are affiliated with the State Key Laboratory of Oncology in South China, the Guangdong Key Laboratory of Nasopharyngeal Carcinoma Diagnosis and Therapy, and the Guangdong Provincial Clinical Research Center for Cancer at the Sun Yat-sen University Cancer Center in Guangzhou, China.

What was the design of the RATIONALE-309 trial?

This double-blind, placebo-controlled trial was conducted at 42 sites across Asia and randomly assigned adult patients with treatment-naive recurrent or metastatic NPC in a 1:1 ratio. Patients received either:

• Tislelizumab (200 mg every 3 weeks) intravenous plus gemcitabine and cisplatin for 4 to 6 cycles, or
• Placebo plus gemcitabine and cisplatin for 4 to 6 cycles

The primary end point was PFS by IRC. Secondary end points included OS, PFS after next-line therapy, and safety. Notably, the trial design allowed patients in the placebo arm to cross over to receive tislelizumab monotherapy upon IRC-confirmed disease progression.

What were the study population’s baseline characteristics?

A total of 263 patients were included, of whom 78.3% were male, with a median age of 50 years (range, 23-74). Most patients (94.3%) were from China. At baseline, 32.7% of patients had primary metastatic disease, whereas 62.7% of patients had recurrent disease following prior treatment for local disease. Baseline characteristics, including liver metastatic status and PD-L1 expression levels, were balanced between the 2 treatment arms.

What findings from RATIONALE-309 were previously reported?

Data from the interim analysis of the trial showed that at a median follow-up of 10.0 months (range, 0.1-23.3) and a data cutoff of March 26, 2021, the median IRC-assessed PFS was significantly longer in the tislelizumab arm vs the placebo arm, at 9.2 months (95% CI, 7.6-10.1) vs 7.4 months (95% CI, 5.6-7.5), respectively (HR, 0.52; 95% CI, 0.38-0.73; P < .0001).² The investigator-assessed PFS outcomes were consistent with these findings.

Furthermore, at an updated data cutoff of September 30, 2021, and a median follow-up of 15.5 months, the IRC-assessed PFS outcomes were consistent with those from the interim analysis, at 9.6 months (95% CI, 7.6-11.7) in the tislelizumab arm vs 7.4 months (95% CI, 5.7-7.6) in the placebo arm (HR, 0.50; 95% CI, 0.37-0.68; nominal P < .0001).

What additional efficacy findings were observed with the combination at 3 years of follow-up?

Beyond the primary results of the 3-year analysis, the median PFS after next-line therapy was significantly improved in the tislelizumab group at 45.3 months (95% CI, 31.5-NE) compared with 20.5 months (95% CI, 13.9-27.2) in the placebo group (unstratified HR, 0.51; 95% CI, 0.34-0.75).¹ Two different supportive analyses adjusting for crossover effect indicated more pronounced OS benefits with tislelizumab, with adjusted HRs of 0.56 (95% CI, 0.27-1.19) and 0.62 (95% CI, 0.40-0.97), respectively. The investigators noted that although the PFS improvement with tislelizumab-based therapy appeared modest, the sustained OS advantage highlights the unique mechanism of immunotherapy in establishing long-term disease control.

What was the safety profile of tislelizumab plus chemotherapy in patients with recurrent or metastatic NPC?

The long-term safety profile of the investigational combination was consistent with the known risks, with no new safety signals identified. Treatment-emergent adverse effects (TEAEs) occurred in 100% of patients in the tislelizumab group and 99.2% of those in the placebo group. Rates of grade 3 or higher TEAEs were comparable between the arms, occurring in 85.0% and 85.4% of patients, respectively. The most frequent TEAEs reported in these arms were anemia, decreased neutrophil count, and decreased white blood cell count.

Immune-mediated AEs were more common with tislelizumab (53.4%) than with placebo (37.7%), although most were grade 1 or 2. The most common of these were skin adverse reactions and hypothyroidism. Permanent discontinuation of study treatment due to TEAEs occurred in 16.5% of patients in the tislelizumab arm and 10.8% of those in the placebo arm.

What were the findings of the exploratory biomarker analysis from RATIONALE-309?

Exploratory gene expression profiling indicated that patients with activated immune signatures, particularly those with high B-cell signature expression, derived a more pronounced OS benefit from tislelizumab than those with low B-cell signature expression. In the high B-cell signature subgroup, the OS HR was 0.41 (95% CI, 0.23-0.74), whereas the low B-cell subgroup showed an OS HR of 1.14 (95% CI, 0.69-1.90). High expression of specific B-cell marker genes, including CD19, MS4A1, CD79B, and CXCR5, was also associated with clinically meaningful improvements in OS. Furthermore, benefit was observed in both hot and cold tumor microenvironments (TMEs), though the effect was more pronounced in the hot TME subgroup. The study investigators noted that these findings support the potential of high B-cell signature expression as a response biomarker.

What were the limitations of RATIONALE-309?

The RATIONALE-309 investigators noted several limitations of the trial, including its exclusive conduct in Asian regions, which may limit generalizability to areas where keratinizing carcinoma is more common. The high crossover rate in the control arm (52.3%) also limited the ability to conduct a precise between-arm comparison of OS, though supportive adjusted analyses were performed to address this. Additionally, results for certain patient subgroups, such as patients aged 65 and older, were based on small sample sizes and should be interpreted cautiously. Finally, the supportive statistical models used to adjust for crossover have inherent constraints and assumptions.

“These long-term efficacy and safety findings further support tislelizumab plus chemotherapy as an effective first-line recurrent or metastatic NPC treatment,” the authors concluded.

References

1. Yang Y, Yen CJ, Pan J, et al. First-line tislelizumab plus chemotherapy for recurrent or metastatic nasopharyngeal cancer: three-year follow-up of the phase 3 RATIONALE-309 randomized clinical trial. JAMA Oncol. Published online February 26, 2026. doi:10.1001/jamaoncol.2026.0020
2. Yang Y, Pan J, Wang H, et al. Tislelizumab plus chemotherapy as first-line treatment for recurrent or metastatic nasopharyngeal cancer: a multicenter phase 3 trial (RATIONALE-309). Cancer Cell. 2023;41(6):1061-1072.e4. doi:10.1016/j.ccell.2023.04.014