Toripalimab Plus Chemotherapy for Recurrent or Metastatic Nasopharyngeal Carcinoma: The JUPITER-02 Randomized Clinical Trial

Abstract

Importance: There are currently no therapies approved by the US Food and Drug Administration for nasopharyngeal carcinoma (NPC). Gemcitabine-cisplatin is the current standard of care for the first-line treatment of recurrent or metastatic NPC (RM-NPC).

Objective: To determine whether toripalimab in combination with gemcitabine-cisplatin will significantly improve progression-free survival and overall survival as first-line treatment for RM-NPC, compared with gemcitabine-cisplatin alone.

Design, setting, and participants: JUPITER-02 is an international, multicenter, randomized, double-blind phase 3 study conducted in NPC-endemic regions, including mainland China, Taiwan, and Singapore. From November 10, 2018, to October 20, 2019, 289 patients with RM-NPC with no prior systemic chemotherapy in the RM setting were enrolled from 35 participating centers.

Interventions: Patients were randomized (1:1) to receive toripalimab (240 mg [n = 146]) or placebo (n = 143) in combination with gemcitabine-cisplatin for up to 6 cycles, followed by maintenance with toripalimab or placebo until disease progression, intolerable toxicity, or completion of 2 years of treatment.

Main outcome: Progression-free survival as assessed by a blinded independent central review. Secondary end points included objective response rate, overall survival, progression-free survival assessed by investigator, duration of response, and safety.

Results: Among the 289 patients enrolled (median age, 46 [IQR, 38-53 years; 17% female), at the final progression-free survival analysis, toripalimab treatment had a significantly longer progression-free survival than placebo (median, 21.4 vs 8.2 months; HR, 0.52 [95% CI, 0.37-0.73]). With a median survival follow-up of 36.0 months, a significant improvement in overall survival was identified with toripalimab over placebo (hazard ratio [HR], 0.63 [95% CI, 0.45-0.89]; 2-sided P = .008). The median overall survival was not reached in the toripalimab group, while it was 33.7 months in the placebo group. A consistent effect on overall survival, favoring toripalimab, was found in subgroups with high and low PD-L1 (programmed death-ligand 1) expression. The incidence of all adverse events, grade 3 or greater adverse events, and fatal adverse events were similar between the 2 groups. However, adverse events leading to discontinuation of toripalimab or placebo (11.6% vs 4.9%), immune-related adverse events (54.1% vs 21.7%), and grade 3 or greater immune-related adverse events (9.6% vs 1.4%) were more frequent in the toripalimab group.

Conclusions and relevance: The addition of toripalimab to chemotherapy as first-line treatment for RM-NPC provided statistically significant and clinically meaningful progression-free survival and overall survival benefits compared with chemotherapy alone, with a manageable safety profile. These findings support the use of toripalimab plus gemcitabine-cisplatin as the new standard of care for this patient population.

Trial registration: ClinicalTrials.gov Identifier: NCT03581786.

Figure 1.. Screening, Randomization, and Flow of Patients in a Trial of Toripalimab for Nasopharyngeal Carcinoma

^aSee eTable 2 in Supplement 3 for details about not meeting eligibility criteria. ^bPatients were randomized in a 1:1 ratio, stratified by baseline Eastern Cooperative Oncology Group performance status score (0 vs 1) and baseline disease stage (recurrent vs primary metastatic). Primary metastatic disease was defined as de novo metastatic disease at the initial diagnosis. ^cA prespecified interim analysis of progression-free survival was conducted by the data cutoff date of May 30, 2020. Because the interim progression-free survival results showed a significant improvement of progression-free survival in the toripalimab group, the independent data-monitoring committee recommended to unblind the study. Patients in the toripalimab group continued to receive toripalimab treatment, whereas patients in the placebo group (n = 31) discontinued placebo and concluded the study.

Figure 2.. Final Progression-Free Survival and Overall Survival Analyses in the Intention-to-Treat Population

A, Estimated progression-free survival as assessed by blinded independent central review according to RECIST (Response Evaluation Criteria in Solid Tumors) version 1.1. Median progression-free survival was 21.4 (IQR, 7.1 to not estimable) months in the toripalimab group and was 8.2 (IQR, 5.7 to not estimable) months in the placebo group. B, The median overall survival was not reached (IQR, 27.6 months to not estimable) in the toripalimab group and was 33.7 (IQR, 17.8 to not estimable) months in the placebo group. Vertical ticks on curves indicate censored patients. Hazard ratios were stratified by baseline Eastern Cooperative Oncology Group performance status score (0 vs 1) and baseline disease stage (recurrent vs primary metastatic).