Tislelizumab regimen confers clinically meaningful PFS benefit in nasopharyngeal cancer
The addition of tislelizumab to chemotherapy conferred a clinically meaningful PFS benefit among patients with recurrent or metastatic nasopharyngeal cancer, according to updated results of the randomized phase 3 RATIONALE-309 study.
The combination also showed a numerical OS benefit and substantial improvement in median PFS after next line of treatment (PFS2) compared with placebo and chemotherapy, findings presented during an ASCO Plenary Session showed.
Background and methodology
Patients with recurrent or metastatic nasopharyngeal cancer treated with first-line chemotherapy have a poor prognosis, with median PFS of 7 months and median OS of 22.1 months, according to Li Zhang, MD, professor of medical oncology and director of the department of medical oncology at Sun Yat-Sen University Cancer Center in Guangzhou, China.
“This highlights the unmet medical need for patients in this setting,” Zhang said during a presentation.
Tislelizumab (BGB-A317, BeiGene) is a humanized immunoglobulin G4 monoclonal antibody designed to minimize binding to Fc gamma receptors on macrophages, which may result in anti-PD-1 resistance. The treatment has shown efficacy in several tumor types in phase 2 and 3 trials.
The current double-blind study included 263 adults (median age, 50 years) with treatment-naive recurrent or metastatic nasopharyngeal cancer. Researchers randomly assigned patients to 200 mg tislelizumab via IV or placebo on day 1, plus 1 g/m2 gemcitabine on day 1 and day 8, and 80 mg/m2 cisplatin on day 1 every 3 weeks for four to six cycles, then tislelizumab or placebo every 3 weeks until disease progression, intolerable toxicity or withdrawal. Study protocol allowed patients in the placebo group to cross over to tislelizumab monotherapy following disease progression.
Independent review committee-assessed PFS among the intent-to-treat population served as the primary endpoint. Secondary endpoints included OS, investigator-assessed PFS2 and safety, with biomarker analyses as exploratory endpoints.
The study met the primary endpoint of improved PFS at interim analysis with median follow-up of 10 months. Median follow-up for the updated analysis was 15.5 months, with data cutoff Sept. 30, 2021.
Key findings
Results showed a consistent PFS benefit with the tislelizumab regimen (median, 9.6 months vs. 7.4 months; HR = 0.5; 95% CI, 0.37-0.68).
About half of patients (49%) crossed over to tislelizumab monotherapy. Despite the high crossover rate, researchers observed a numerical OS benefit with tislelizumab vs. placebo (median, not reached vs. 23 months; HR = 0.6; 95% CI, 0.35-1.01), although OS data remained immature. The tislelizumab group also showed substantial improvement in PFS2 vs. the placebo group (median, not reached vs. 13.9 months; HR = 0.38; 95% CI, 0.25-0.58).
Biomarker analysis of baseline tumor tissue showed a PFS benefit with the tislelizumab regimen regardless of PD-L1 expression. Gene expression profiling revealed three clusters — cold, medium and hot — in the tumor microenvironment as possible biomarkers for efficacy. Those with a hot tumor immune profile, characterized by greatest expression of immune cells, including dendritic cells, had the largest PFS benefit with tislelizumab, as did those with a high activated dendritic cell signature.
“This result advocated the use of dendritic cell signature as a potential biomarker,” Zhang said.
The tislelizumab regimen had a manageable safety profile consistent with prior reports. The most common adverse events included leukopenia, neutropenia, anemia and thrombocytopenia, Zhang said.
Similar proportions of patients in the tislelizumab and placebo groups experienced grade 3 or higher treatment-related adverse events (80.9% vs. 81.8%) and serious grade 3 or higher treatment-related adverse events (22.9% vs. 26.5%). Five patients in the tislelizumab group and two in the placebo group died of treatment-related adverse events.
“The current data analysis indicated that tislelizumab plus chemotherapy may become a standard-of-care first-line therapy for patients with recurrent and metastatic nasopharyngeal carcinoma,” Zhang said.
Implications
Discussant Robert I. Haddad, MD, chief of the division of head and neck oncology and McGraw chair in head and neck oncology at Dana-Farber Cancer Institute and professor of medicine at Harvard Medical School, noted common themes among RATIONALE-309 and two other phase 3 trials that evaluated the addition of a PD-1 inhibitor to cisplatin and gemcitabine: JUPITER-02, which involved toripalimab (Junshi Biosciences), and CAPTAIN-1st, which involved camrelizumab (SHR-1210, Jiangsu Hengrui Medicine Co). Those themes included similar HRs for PFS, OS trends that favored adding checkpoint blockade to chemotherapy, and benefit regardless of PD-L1 status.
“I believe that gemcitabine-cisplatin plus a checkpoint inhibitor represents a reasonable option to treat patients with recurrent or metastatic [nasopharyngeal carcinoma] in that first-line setting,” Haddad said. “The next step obviously would be to try to move these agents early on in the disease spectrum, and test them in an induction chemotherapy setting, which is currently the standard of care ... to test the notion of adding a checkpoint inhibitor to this platform for patients with curable nasopharyngeal carcinoma.”
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Zhang L, et al. Abstract 384950. Presented at: ASCO Plenary Series; April 19, 2022.