Efficacy, Safety, and Correlative Biomarkers of Toripalimab in Previously Treated Recurrent or Metastatic Nasopharyngeal Carcinoma: A Phase II Clinical Trial (POLARIS-02)

Abstract

Purpose: As yet, no checkpoint inhibitor has been approved to treat nasopharyngeal carcinoma (NPC). This study was aimed to evaluate the antitumor activity, safety, and biomarkers of toripalimab, a new programmed death-1 (PD-1) inhibitor for recurrent or metastatic NPC (RM-NPC) refractory to standard chemotherapy.

Patients and methods: In this single-arm, multicenter phase II study, patients with RM-NPC received 3 mg/kg toripalimab once every 2 weeks via intravenous infusion until confirmed disease progression or unacceptable toxicity. The primary end point was objective response rate (ORR). The secondary end points included safety, duration of response (DOR), progression-free survival (PFS), and overall survival (OS).

Results: Among all 190 patients, the ORR was 20.5% with median DOR 12.8 months, median PFS 1.9 months, and median OS 17.4 months. Among 92 patients who failed at least two lines of systemic chemotherapy, the ORR was 23.9%. The ORRs were 27.1% and 19.4% in PD-L1+ and PD-L1- patients, respectively (P = .31). Patients with ≥ 50% decrease of plasma Epstein-Barr virus (EBV) DNA copy number on day 28 had significantly better ORR than those with < 50% decrease, 48.3% versus 5.7% (P = .0001). Tumor mutational burden had a median value of 0.95 muts/mega-base in the cohort and had no predictive value for response. Whole-exome sequencing results from 174 patients revealed that the patients with genomic amplification in 11q13 region or ETV6 genomic alterations had poor responses to toripalimab.

Conclusion: The POLARIS-02 study demonstrated a manageable safety profile and durable clinical response of toripalimab in patients with chemorefractory metastatic NPC. An early decrease in plasma EBV DNA copy number correlated with favorable response.

Trial registration: ClinicalTrials.gov NCT02915432.

FIG 1.

Tumor responses of patients with nasopharyngeal carcinoma in this study cohort. (A) Maximal change of tumor size from baseline assessed by independent review committee (IRC) according to RECIST v1.1 for patients with at least one post-treatment radiographic evaluation. The length of the bar represents maximal decrease or minimal increase in target lesion(s). (B) Change of individual tumor burden over time from baseline assessed by IRC according to RECIST v1.1. Tumor response was assessed before treatment, once every 8 weeks in the first year and then once every 12 weeks from the second year until disease progression.

FIG 2.

Plasma EBV DNA copy number was measured from 148 patients at baseline and on day 28. The fold reduction of EBV titer from baseline to day 28 was shown in patients with objective response (n = 34), stable disease (n = 34), or progressive disease (n = 80). T-test was used to determine statistical significance between two groups. Significant differences were observed between CR + PR and stable disease groups and CR + PR and progressive disease groups. Fold reduction = (baseline EBV tier)/(day 28 EBV titer). CR, complete response; EBV, Epstein-Barr virus; PR, partial response.

FIG A1.

Consort diagram for the phase II study of toripalimab treating patients with recurrent or metastatic nasopharyngeal carcinoma refractory to standard therapy.

FIG A2.

Patient survival in relation to tumor PD-L1 expression. (A) Progression-free survival of PD-L1 > 25% versus PD-L1 ≤ 25% patients. (B) Overall survival of PD-L1 > 25% versus PD-L1 ≤ 25% patients. Percentages of survival patients are shown at indicated time points. Censored patients are marked with “┃” in the graph. Numbers of patients at risk at indicated time points are shown below the x-axis. PFS was defined as the time from first dosing to first recorded progression of disease or death because of any reason, whichever came first. Patients with no PFS event during follow-up will be censored at the last tumor evaluation. Patients with no postbaseline evaluation will be censored at the date of first dosing. Patients with death or progression after two or more consecutive missing tumor assessments were censored at the last postbaseline tumor evaluation before the missed visits. If patients did not have the postbaseline tumor evaluation before the missed visits, they were censored at the date of first dosing. OS was defined as the time from first dosing to death because of any cause. Patients with no OS events were censored on the last known survival date. PD-L1, programmed death ligand-1; PFS, progression-free survival.

FIG A3.

Genetic alternations, frequencies, and pathway alternations identified by whole-exome sequencing from 174 available patients with nasopharyngeal carcinoma. Patients were grouped by clinical responses. CR, complete response; EBV, Epstein-Barr virus; MSI, microsatellite instability; MSS, microsatellite stable; PR, partial response; PD, progressive disease; SD, stable disease; SWI/SNF: SWItch/Sucrose Non-Fermentable complexes.

FIG A4.

Patient survival in relation to tumor mutational burden. The tumor mutational burden (TMB) was calculated by summing up somatic mutations within the coding regions by whole-exome sequencing. Using top 10% TMB value of 2.9 mutations per Mb as a cutoff. (A) Progression-free survival of TMB ≥ 2.9 muts/Mb versus TMB < 2.9 muts/Mb patients. (B) Overall survival of TMB ≥ 2.9 muts/Mb versus TMB < 2.9 muts/Mb patients. Percentages of survival patients are shown at indicated time points. Censored patients are marked with “┃” in the graph. Numbers of patients at risk at indicated time points are shown below the x-axis.