Toripalimab Plus Chemotherapy for Patients With Treatment-Naive Advanced Non-Small-Cell Lung Cancer: A Multicenter Randomized Phase III Trial (CHOICE-01)

Abstract

Purpose: The CHOICE-01 study investigated the efficacy and safety of toripalimab in combination with chemotherapy as a first-line treatment for advanced non-small-cell lung cancer (NSCLC).

Patients and methods: Patients (N = 465) with treatment-naive, advanced NSCLC without EGFR/ALK mutations were randomly assigned 2:1 to receive toripalimab 240 mg (n = 309) or placebo (n = 156) once every 3 weeks in combination with chemotherapy for 4-6 cycles, followed by the maintenance of toripalimab or placebo once every 3 weeks plus standard care. Stratification factors included programmed death ligand-1 expression status, histology, and smoking status. The primary end point was progression-free survival (PFS) by investigator per RECIST v1.1. Secondary end points included overall survival and safety.

Results: At the final PFS analysis, PFS was significantly longer in the toripalimab arm than in the placebo arm (median PFS, 8.4 v 5.6 months, hazard ratio = 0.49; 95% CI, 0.39 to 0.61; two-sided P < .0001). At the interim OS analysis, the toripalimab arm had a significantly longer OS than the placebo arm (median OS not reached v 17.1 months, hazard ratio = 0.69; 95% CI, 0.53 to 0.92; two-sided P = .0099). The incidence of grade ≥ 3 adverse events was similar between the two arms. Treatment effects were similar regardless of programmed death ligand-1 status. Genomic analysis using whole-exome sequencing from 394 available tumor samples revealed that patients with high tumor mutational burden were associated with significantly better PFS in the toripalimab arm (median PFS 13.1 v 5.5 months, interaction P = .026). Notably, patients with mutations in the focal adhesion-PI3K-Akt signaling pathway achieved significantly better PFS and OS in the toripalimab arm (interaction P values ≤ .001).

Conclusion: Toripalimab plus chemotherapy significantly improves PFS and OS in patients with treatment-naive advanced NSCLC while having a manageable safety profile. Subgroup analysis showed the OS benefit was mainly driven by the nonsquamous subpopulation.

Trial registration: ClinicalTrials.gov NCT03856411.

FIG 1.

CONSORT diagram of the CHOICE-01 study. From April 2, 2019, to August 5, 2020, a total of 835 patients were screened. Of these, 370/835 patients (44.3%) failed screening, mainly because of inclusion/exclusion criteria not met (305/370; 82.4%) or withdrawal of the informed consent (57/370; 15.4%). A total of 465 patients were successfully screened and randomly assigned 2:1 to the toripalimab plus chemotherapy arm (n = 309) or placebo plus chemotherapy arm (n = 156), stratified by PD-L1 expression status, histology (squamous v nonsquamous), and smoking status. By the cutoff date, 55 (17.8%) patients in the toripalimab arm and 23 (14.7%) in the placebo arm remained on the study treatment. ITT, intention-to-treat; PD-L1, programmed death ligand-1; PPS, per protocol set; SS, safety set.

FIG 2.

(A) Kaplan-Meier-estimated PFS curves as assessed by the investigator according to RECIST v1.1 in the intention-to-treat population on the data cutoff date October 31, 2021, are shown to compare the toripalimab plus chemotherapy arm with the placebo plus chemotherapy arm as first-line treatment for patients with advanced NSCLC. Censored patients are marked with “┃” in the graph. Numbers of patients at risk at indicated time points shown below x-axis. Number of events, median PFS, 1-year PFS rates, and stratified HR for PFS are shown to the right of Kaplan-Meier curves. (B) PFS in key subgroups. All HRs were computed using the Cox proportional hazards model. All P values were two-sided with no adjustment of multiplicity. The P values of comparing the Kaplan-Meier curves were computed using the log-rank test stratified by the baseline PD-L1 expression status, histology, and smoking status. The P values of testing the interaction of the subgroup variables with the treatment (B) were computed using the Cox proportional hazards regression model with the treatment arm, the subgroup variable, and their interaction as the covariates. ^aP values were stratified by the factors used for randomization except the subgroup variable itself. ^bNA,not applicable due to overlapping metastases to liver and bone. HR, hazard ratio; NA, not available; NSCLC, non–small-cell lung cancer; PD-L1, programmed death ligand-1; PFS, progression-free survival.

FIG 3.

(A) OS in the intention-to-treat population. Kaplan-Meier estimates of OS in the intention-to-treat population on the data cutoff date October 31, 2021, are shown to compare the toripalimab plus chemotherapy arm with the placebo plus chemotherapy arm as first-line treatment for patients with advanced NSCLC. Censored patients are marked with “┃” in the graph. Numbers of patients at risk at indicated time points are shown below the x-axis. Number of events, median OS, 1-year and 2-year OS rates, and stratified HR for death are shown to the right of Kaplan-Meier curves. (B) Overall survival in key subgroups. All HRs were computed using the Cox proportional hazards model. All P values were two-sided with no adjustment of multiplicity. The P values of comparing the Kaplan-Meier curves were computed using the log-rank test stratified by the baseline PD-L1 expression status, histology, and smoking status. The P values of testing the interaction of the subgroup variables with the treatment (B) were computed using the Cox proportional hazards regression model with the treatment arm, the subgroup variable, and their interaction as the covariates. ^aP values were stratified by the factors used for randomization except the subgroup variable itself. ^bNA, not applicable due to overlapping metastases to liver and bone. HR, hazard ratio; NA, not available; NE, not evaluable; NSCLC, non–small-cell lung cancer; OS, overall survival; PD-L1, programmed death ligand-1.