Toripalimab Confers Survival Benefit to Treatment Naïve Patients With NSCLC

Toripalimab led to significantly improved progression-free and overall survival (PFS; OS) in patients with non–small cell lung cancer (NSCLC) without EGFR nor ALK mutations according to findings from the CHOICE-1 study (NCT03856411), which were published in the Journal of Clinical Oncology.¹

In a PFS analysis, the combination of the immune checkpoint inhibitor and chemotherapy induced a median PFS of 8.4 months and placebo plus chemotherapy yielded a median PFS of 5.6 months (HR, 0.49; 95% CI, 0.39-0.61; P < .001). Toripalimab was also associated with improved OS—the median OS was not reached at the interim analysis in the experimental arm, compared with a median OS of 17.1 months in the placebo arm (HR, 0.69; 95% CI, 0.53-0.92; P = .0099).

A genomic analysis showed that patients with high tumor mutational burden achieved significantly better median PFS with toripalimab than with chemotherapy (13.1 months vs 5.5 months; P = .026). This benefit was more pronounced in patients who had mutations in the focal adhesion–PI3K-AKT signaling pathway (P < .001).

Additionally, the rates of grade 3 or higher adverse events (AEs) was similar between the 2 cohorts.

“Our results demonstrated that the addition of toripalimab to the standard first-line chemotherapy resulted in statistically significant and clinically meaningful improvements in both PFS and OS than chemotherapy alone, irrespective of PD-L1 expression,” wrote Zhijie Wang, MD, of Chinese Academy of Medical Sciences & Peking Union Medical College, in Beijing, China, and co-investigators in the findings.

Immune checkpoint inhibitors directed at PD-1 or PD-L1 antibodies have had a tremendous effect on the treatment landscape of NSCLC. Toripalimab, which is a humanized IgG4K monoclonal antibody specific for human PD-1, engages a different differential domain of PD-1 than nivolumab or pembrolizumab (Keytruda) and has demonstrated promising antitumor activity in preclinical studies and in early clinical trials.

CHOICE-01 was a randomized, double-blind, placebo-controlled, phase 3 trial designed to assess the efficacy and safety of toripalimab in combination with chemotherapy as frontline treatment for these patients. The trial randomly assigned 465 treatment naïve patients with advanced NSCLC and no EGFR or ALK mutations 2:1 to receive either toripalimab at a 240 mg dose (n = 309) or placebo (n = 156) every 3 weeks in combination with 4 to 6 cycles of chemotherapy, followed by maintenance with toripalimab or placebo once every 3 weeks in addition to standard care. PFS was the primary endpoint; OS and safety were the key secondary outcomes.

At an interim analysis with a median follow-up of 7.1 months, the combination therapy decreased the risk of disease progression or death by 42% compared with placebo (HR, 0.58; 95% CI, 0.44-0.77; P = .0001).

In the final analysis, the 1-year PFS rates between the 2 treatment arms were 36.7% and 17.2%, respectively. PFS reports were consistent between both blinded independent central review– and investigator–determined assessments.

At first interim analysis for OS, at a median follow-up of 16.2 months, the stratified HR for death within the intention-to-treat population was 0.69 (95% CI, 0.53-0.92; P = .0099).

At final analysis, among patients receiving toripalimab and placebo, the 1-year and 2-year OS rates were 74.0% and 72.8%, and 51.2% and 33.9%, respectively.

Notably, the median duration of treatment was slightly longer with toripalimab than with placebo (6.6 vs 5.0 months) and concomitant administration did not affect the completion of planned chemotherapy.

Investigators also completed a genomic analysis of patients using whole-exome sequencing. This revealed that patents with high tumor mutational burden (TMB) experience better objective response rates with toripalimab (72.7% vs 46.7%). In addition, although patients with low TMB achieved modest PFS benefit with toripalimab (8.3 vs 6.5 months), those with high TMB experienced a significant improvement (13.1 vs 5.5 months) in median PFS with toripalimab (HR, 0.34; 95% CI, 0.21-0.54; P = .026). In contrast, toripalimab yielded no significant difference in OS data across mutational burden cohorts.

The analyses also provided insight into gene mutations which demonstrated significant activity with the treatment, such as RB1, KEAP1, and SMARCA4. Of note, patients with SMARC4 mutations, experienced significantly better PFS with the experimental agent (9.9 months vs 2.9 months). However, RB1 mutations, corresponded with worse PFS with toripalimab (4.2 vs 8.2 months).

At the cutoff date, nearly all patients had experienced at least one treatment-emergent adverse event (TEAE). Although the rate of grade 3 TEAES were similar between the 2 arms, (78.6% vs 82.1%), fatal TEAEs (5.5% vs 2.6%), serious AEs (44.8% vs 35.5%), and infusion-related reactions (2.6% vs 1.3%), were more common in patients receiving immune-checkpoint inhibition compared with placebo. Moreover, more patients experienced a TEAE which called for treatment discontinuation following toripalimab (14.3% vs 3.2%).

The major AEs associated with toripalimab included thyroid disease, diarrhea, edema, pneumonitis, and rash. Immune-related AEs or irAEs, were also linked to toripalimab; 49% of patients experienced an irAE with toripalimab vs 21.2% with placebo. Ultimately, 15.6% of patients receiving toripalimab and 32% of patients receiving placebo, experienced grade 3 or worse irAEs.

Study authors noted that this trial was entirely based out of China. However, because prior trials have demonstrated similar treatment effects in both China and in the West for patients with NSCLC—KEYNOTE-189 (NCT02578680) and KEYNOTE-407 (NCT02775435)—and because checkpoint inhibitors are believed to effect similar responses in both Asian and non-Asian populations, study authors believe these results can be extrapolated to Western patients as well.

“The addition of toripalimab to chemotherapy in treatment-naïve patients with advanced NSCLC results in superior PFS and OS than chemotherapy alone [and has] a manageable safety profile,” study authors concluded. “These results support the use of toripalimab with chemotherapy as a first-line therapy for patients with advanced NSCLC without EGFR/ALK mutations.”

Reference

Wang Z, Wu L, Li B, et al. Toripalimab plus chemotherapy for patients with treatment-naive advanced non-small-cell lung cancer: a multicenter randomized phase III trial (CHOICE-01) J Clin Oncol. Published online October 7, 2022. doi:10.1200/JCO