Toripalimab versus Placebo in Combination with First-Line Chemotherapy for Advanced NSCLC without EGFR/ALK Mutations: CHOICE-01 Phase 3 Study

Toripalimab, a novel anti–PD-1 humanized IgG4 monoclonal antibody, has shown manageable safety and antitumor activity in patients with advanced non–small-cell lung cancer (NSCLC).¹ In combination with chemotherapy, toripalimab showed significant improvement in progression-free survival (PFS) and overall survival (OS) in the first-line treatment of advanced NSCLC regardless of tumor PD-L1 expression. In this study, whole-exome sequencing (WES) was performed to identify correlative biomarkers for survival.²

The study enrolled 465 patients with treatment-naïve, advanced NSCLC without EGFR/ALK mutations. Patients were randomized 2:1 to receive toripalimab 240 mg (n = 309) or placebo (n = 156) in combination with chemotherapy (pemetrexed plus platinum for nonsquamous and nab-paclitaxel plus carboplatin for squamous) for 4 to 6 cycles, followed by maintenance of toripalimab or placebo plus standard of care until disease progression, toxicity, or 2 years of treatment. The results were stratified based on PD-L1 expression status, histology, and smoking status.²

The primary end point was PFS determined by the investigator per RECIST version 1.1. Secondary end points included PFS by a blinded independent review committee (BIRC), OS, and safety.²

At the prespecified final PFS analysis (cutoff date October 31, 2021), a significant improvement in PFS was observed for patients in the toripalimab arm compared with the placebo arm: median PFS 8.4 months versus 5.6 months (hazard ratio [HR], 0.49; 95% confidence interval [CI], 0.39-0.61; 2-sided P <.0001). The 1-year PFS rates were 36.7% versus 17.2%, respectively, in the toripalimab plus chemotherapy and placebo plus chemotherapy arms. As assessed by BIRC, PFS was also significantly longer in the toripalimab arm. The improvements in PFS were observed among all key subgroups, including histology and PD-L1 expression. At the interim OS analysis, patients in the toripalimab group had a significantly longer OS than the placebo arm: median OS not reached versus 17.1 months (HR, 0.69; 95% CI, 0.52-0.92; 2-sided P = .0099). The observed benefits in OS in the toripalimab group were independent of PD-L1 expression level, but were not observed in PD-L1–negative patients. However, WES sequencing revealed that patients with high tumor mutational burden (TMB ≥10 muts/Mbp) in the toripalimab group achieved better PFS.

The incidence of grade ≥3 adverse events (AEs) (78.6% vs 82.1%) was similar between the 2 groups. AEs leading to discontinuation of toripalimab/chemo compared with placebo/chemo (14.3% vs 3.2%) and fatal AEs (5.5% vs 2.6%) were more frequent in the toripalimab group.²

WES results from 394 available patients showed that high TMB (≥10 muts/Mbp) was associated with significantly better PFS in the toripalimab arm over the placebo arm (median PFS, 13.1 vs 5.5 months) (interaction P = .026). In addition, patients with mutations in the FAK-PI3K-Akt or IL-7 signaling pathways demonstrated greater PFS and OS in the toripalimab plus chemotherapy regimen (P ≤.01).²

The investigators concluded that the combination of toripalimab plus chemotherapy in patients with advanced NSCLC resulted in superior PFS and OS compared with chemotherapy alone and had a manageable safety profile. These findings establish toripalimab with chemotherapy as a first-line treatment option for patients with advanced NSCLC without EGFR/ALK mutations.

References

1. Zhao ZR, Yang CP, Chen S, et al. Phase 2 trial of neoadjuvant toripalimab with chemotherapy for resectable stage III non-small-cell lung cancer. Oncoimmunology. 2021;10:1996000.
2. Wang J, Wang Z, Wu L, et al. Final progression-free survival, interim overall survival, and biomarker analyses of CHOICE-01: a phase 3 study of toripalimab versus placebo in combination with first-line chemotherapy for advanced NSCLC without EGFR/ALK mutations. Presented at: 2022 American Society of Clinical Oncology Annual Meeting; June 3-7, 2022; Chicago, IL. Abstract 9028.