First-Line Tislelizumab Plus Chemotherapy Could Become SOC in Nasopharyngeal Cancer

Investigators of the phase 3 RATIONALE-309 trial found an improvement in progression-free survival for patients with recurrent or metastatic nasopharyngeal cancer treated with tislelizumab plus chemotherapy vs chemotherapy alone.

Tislelizumab plus chemotherapy compared with chemotherapy alone improved progression-free survival (PFS) for patients with recurrent or metastatic nasopharyngeal cancer, according to findings from the phase 3 RATIONALE-309 trial (NCT03924986) presented at the 2022 American Society of Clinical Oncology Plenary Session.1,2

The updated analysis had a median follow-up of 15.5 months. The median PFS in the tislelizumab arm was 9.6 months vs 7.4 months in the placebo arm (HR, 0.50; 95% CI, 0.37-0.68), and a 50% lower risk of disease progression. For patients in the tislelizumab arm, the median PFS after next line of treatment (PFS2) and overall survival (OS) was not reached vs 13.9 months (HR, 0.38; 95% CI, 0.25-0.58) and 23.0 months in the placebo group (HR, 0.60; 95% CI, 0.35-1.01), respectively.

“These findings support the use of tislelizumab in combination with chemotherapy as a potential standard-of-care as first-line therapy in recurrent or metastatic nasopharyngeal cancer,” lead principal investigator Li Zhang, MD, professor at the Collaborative Innovation Center for Cancer Medicine, State Key Laboratory of Oncology in South China and Sun Yat-sen University Cancer, said in a press release.2

The trial enrolled 263 patients who were randomized 1:1 to receive either tislelizumab plus chemotherapy (arm A) or a placebo with chemotherapy (arm B). In arm A, patients received 200 mg of tislelizumab intravenously on day 1 every 3 weeks, gemcitabine at 1 g/m2 on day 1, and cisplatin at 80 mg/m2 intravenously on day 1 every 3 weeks for 4 to 6 cycles. Treatment continued until disease progression, toxicity, or withdrawal; this was followed by tislelizumab monotherapy at 200 mg if it was considered clinically beneficial. In arm B patients received the placebo at a dose of 200 mg plus the chemotherapy backbone. Patients in this arm were allowed to crossover to tislelizumab monotherapy if it was considered clinically beneficial.

In the tislelizumab and placebo groups, respectively, the OS rate at 6 months was 95.3% (95% CI, 89.9%-97.9%) vs 97.6% (95% CI, 92.9%-99.2%), at 9 months it was 94.5% (95% CI, 88.8%-97.3%) vs 92.6% (95% CI, 86.3%-96.1%), and at 12 months it was 89.6% (95% CI, 82.8%-93.8%) vs 86.4% (95% CI, 78.8%-91.5%).

The PFS2 rate at 6 months was 95.3% (95% CI, 89.8%-97.9%) vs 94.4% (95% CI, 88.6%-97.3%), 93.6% (95% CI, 87.7%-96.8%) vs 82.4% (95% CI, 74.3%-88.2%) at 9 months, and 83.4% (95% CI, 75.4%-88.9%) vs 62.6% (95% CI, 53.1%-70.8%) at 12 months in the tislelizumab and placebo groups, respectively.

A biomarker analysis was performed that included 240 patients who were PD-L1 immunohistochemistry evaluable and 247 were gene expression profiling (GEP) evaluable. Both the biomarker evaluable populations and intent to treat population were reported to have similarities in baseline characteristics and treatment outcomes. Investigators reported a PFS benefit regardless of PD-L1 expression among patients who received the experimental regimen.

Investigators reported that they were able to identify 3 gene expression clusters via GEP that could serve as potential efficacy biomarkers. The analysis was conducted using GEP signatures with unsupervised clustering and led to the identification of gene expression clusters that were cold, medium, and hot. In particular, patients who had a hot tumor microenvironment tended to have a greater PFS benefit. The hot tumor immune profile was defined as having a high expression of immune cells such as dendritic cells. Additionally, those with a high activated dendritic cell signature who received tislelizumab and chemotherapy experienced a robust PFS benefit, pointing to the marker as a potential predictor of outcomes.

The safety analysis was consistent with previous reports. At a median follow-up of 10.0 months, grade 3 or higher adverse effects (AEs) occurred in 80.9% of patients in the tislelizumab group and 81.8% in the placebo group. Serious treatment-emergent AEs (TEAEs) of grade 3 or higher were observed in 22.9% vs 26.5%, TEAEs leading to death occurred in 3.8% vs 1.5%, and TEAEs leading to permanent discontinuation occurred in 1.5% vs 2.3% of patients in the tislelizumab and placebo groups, respectively.

Immune-mediated TEAE of grade 3 or higher were observed in 2.3% of patients in the tislelizumab group and none in the placebo group. Additionally, 13.7% of patients in the tislelizumab group died vs 12.1% in the placebo group. The most common TEAEs of grade 3 or higher included white blood cell decrease, anemia, neutrophil count decrease, neutropenia, platelet count decrease, and leukopenia across both groups.

References

  1. Zhang L, Yang Y, Pan J, et al. RATIONALE-309: updated PFS, PFS2, and OS from a phase 3 double-blind trial of tislelizumab versus placebo, plus chemotherapy as first-line treatment for recurrent/metastatic nasopharyngeal cancer. American Society of Clinical Oncology Plenary Series: April 2022 Session. April 19, 2022. Accessed April 19, 2022.
  2. Adding tislelizumab to chemotherapy showed improved PFS in nasopharyngeal cancer in phase III study. News Release. ASCO. April 18, 2022. Accessed April 19, 2022. https://bit.ly/3xIIS9s