Toripalimab plus chemo a good 1st-line CHOICE for advanced NSCLC

The prespecified final analysis of the phase III CHOICE-01 trial of toripalimab in combination with chemotherapy shows significant improvement in overall survival (OS) in treatment-naïve patients with advanced non-small-cell lung cancer (NSCLC) without EGFR/ALK driver mutations.

CHOICE-01 was a randomized double-blind phase III trial of toripalimab, an anti–PD-1 monoclonal antibody, plus standard chemotherapy, which previously reported significant improvements in progression-free survival (PFS) and OS in treatment-naïve patients with advanced NSCLC. Of 465 enrolled patients, 309 were assigned to toripalimab plus standard first-line chemotherapy, while 156 patients received placebo plus standard first-line chemotherapy. In the placebo group, 51.9 percent of patients were switched to active crossover treatment following disease progression as assessed by the investigator. In total, 17.2 percent of toripalimab patients and 65.4 percent of placebo patients received subsequent anti–PD-1/PD-L1 therapy, including both active crossover and post-study treatments. [Signal Transduct Target Ther 2024;doi:10.1038/s41392-024-02087-6]

At a median survival follow-up of 21.2 months, a notable enhancement in OS was observed in the toripalimab vs placebo group (median OS, 23.8 vs 17.0 months; hazard ratio [HR], 0.69; 95 percent confidence interval [CI], 0.57–0.93; p_nominal=0.01). The respective 1-, 2-, and 3-year OS rates were 74.0 vs 72.8 percent, 49.8 vs 37.5 percent, and 32.5 vs 18.4 percent. Within subgroups based on PD-L1 expression (tumour cells [TC]: <1 percent [n=139], 1–49 percent [n=203], ≥50 percent [n=100], and not evaluable [n=23]), the HRs were 0.79 (95 percent CI, 0.52–1.24), 0.72 (95 percent CI, 0.51–1.03), 0.91 (95 percent CI, 0.49–1.80), and 0.40 (95 percent CI, 0.15–1.10), respectively.

Subgroup analyses revealed that the survival advantage was markedly more substantial in the non-squamous cell carcinoma (non-SCC) subgroup (median OS, 27.8 vs 15.9 months; HR, 0.49; 95 percent CI, 0.35–0.69; p<0.001), while there was no observed benefit in the SCC subgroup. “The lack of OS benefits in SCC in the current study may partly stem from immediate active crossover implementation,” commented the investigators. “[However,] the disparity in immunotherapy responses observed between SCC and non-SCC patients necessitates further exploration to elucidate the underlying mechanisms.”

No new safety concerns emerged following prolonged toripalimab exposure for up to 2 years. The incidence of grade ≥3 adverse events (AEs) was comparable between the two groups (78.9 vs 82.1 percent), as was the rate of serious AEs (46.4 vs 35.3 percent). AEs leading to treatment discontinuation were more frequent in the toripalimab group (15.3 vs 3.2 percent), as were investigator-assessed immune-related AEs (irAEs) (50.6 vs 21.2 percent) and grade ≥3 irAEs (16.9 vs 3.2 percent). All-grade increased alanine aminotransferase (6.5 vs 1.9 percent), hypo- (11.4 vs 1.3 percent) and hyperthyroidism (8.1 vs 1.9 percent), diarrhoea (1.3 vs 0 percent), and rash (10.7 vs 6.4 percent) were more frequently reported in the toripalimab group.

To further validate previous findings from tumour tissue profiling, the investigators extracted ctDNA from 460 pretreatment plasma samples and subjected it to deep panel-based sequencing (520-gene panel). Among them, 84.1 percent of patients tested positive for somatic alterations (ctDNA-positive). The absence of baseline ctDNA correlated with improved PFS and OS but did not predict a response to toripalimab treatment. “Notably, the overall mutational landscape of ctDNA greatly exhibited a striking resemblance to the results obtained from tissue-based analysis,” highlighted the investigators. Similarly, blood-based tumour mutation burden also exhibited a strong correlation with tissue-based TMB.