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Adding the PD-1 inhibitor tislelizumab to chemotherapy led to a progression-free survival (PFS) improvement for patients with recurrent or metastatic nasopharyngeal carcinoma (NPC), according to updated results from a phase III randomized trial.

Over a follow-up of 15.5 months, the median PFS was 9.6 months for patients randomized to tislelizumab plus gemcitabine-cisplatin chemotherapy compared with 7.4 months for those assigned to placebo plus chemotherapy (HR 0.50, 95% CI 0.37-0.68), reported Li Zhang, MD, of the Sun Yat-sen University Cancer Center in Guangzhou, China.

"This updated analysis of the RATIONALE-309 study indicates that tislelizumab plus chemotherapy may become standard-of-care first-line therapy for patients with recurrent or metastatic nasopharyngeal carcinoma," Zhang said during an .

As for secondary endpoints, PFS after the next line of treatment (PFS2) was not reached at the time of data cutoff for the tislelizumab arm, compared with 13.9 months for the placebo arm (HR 0.38, 95% CI 0.25-0.58), and median overall survival was not yet reached versus 23 months, respectively (HR 0.60, 95% CI 0.35-1.01).

Zhang and colleagues noted that this is the first report of a PFS2 benefit with an anti-PD-1 monoclonal antibody plus chemotherapy in the first-line setting for recurrent or metastatic NPC. "This result indicates that tislelizumab therapy should be used in the first line to deliver the maximum clinical benefit," Zhang said.

Tislelizumab is the third PD-1 inhibitor -- along with toripalimab (evaluated in the JUPITER-2 trial) and camrelizumab () -- to show a PFS benefit in recurrent/metastatic NPC, noted discussant Robert Haddad, MD, of Dana-Farber Cancer Institute and Harvard Medical School in Boston.

Across the three trials, the addition of a PD-1 inhibitor to chemotherapy reduced the risk of progression or death, with hazard ratios ranging from 0.50 to 0.54, Haddad pointed out. "The addition of a checkpoint inhibitor to gemcitabine-cisplatin clearly improves progression-free survival. We rarely -- if ever -- have ever seen this among phase III data in such a short time showing a similar signal. The signal is there. The benefit is clear."

"I believe gemcitabine-cisplatin plus a checkpoint inhibitor represents a reasonable option to treat patients with recurrent/metastatic NPC in that first-line setting," he added, suggesting that the next step would be to test PD-1 inhibition in the upfront setting as part of neoadjuvant and definitive therapy.

In RATIONALE-309, a total of 263 eligible patients with recurrent or metastatic NPC were randomly assigned 1:1 to tislelizumab 200 mg intravenously or placebo on day 1, plus gemcitabine 1 g/m² on days 1 and 8 and cisplatin 80 mg/m² on day 1, every 3 weeks for 4 to 6 cycles, followed by tislelizumab or placebo every 3 weeks until disease progression, unacceptable toxicity, or withdrawal. Upon disease progression, patients in the placebo arm could cross over to receive tislelizumab.

Zhang and colleagues also performed a biomarker analysis, and found that the improvement in PFS with the combination was observed regardless of PD-L1 status.

Gene expression profiling identified subgroups of patients with "cold," "medium," and "hot" tumor immune profiles. Patients with a hot tumor environment -- characterized by the highest expression of immune cells, including T cells, natural killer cells, dendritic cells, and antigen presentation machinery -- achieved the greatest PFS benefit with tislelizumab compared with the cold and medium subgroups, Zhang reported. "The difference between them may help to predict the effect of tislelizumab plus chemotherapy," he noted.

An enhanced PFS benefit was also observed in patients with high activated dendritic cell signatures, he added, suggesting that these signatures could be used as a potential biomarker.

Treatment-emergent adverse events (TEAEs) occurred in all patients in the tislelizumab arm and 99.2% of the placebo arm, while serious TEAEs occurred in 80.9% and 81.8%, respectively. The most common TEAEs were anemia, neutropenia, thrombocytopenia, and leukopenia.

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