medwireNews: Supplementing first-line chemotherapy with the PD-1 inhibitor toripalimab significantly improves the progression-free survival (PFS) and overall survival (OS) of patients with advanced non-small-cell lung cancer (NSCLC), suggest Chinese trial data.
The phase 3 study also evaluated “predictive biomarkers for survival,” providing “new perspectives on patient selection on the basis of tumor genetic alternations,” say the researchers in the Journal of Clinical Oncology.
The CHOICE-01 trial enrolled 465 individuals with treatment-naïve locally advanced or metastatic NSCLC lacking EGFR or ALK alterations and randomly assigned them to receive intravenous toripalimab 240 mg or placebo every 3 weeks alongside four to six cycles of chemotherapy, consisting of nab-paclitaxel plus carboplatin for squamous disease and pemetrexed plus cisplatin or carboplatin for nonsquamous disease. This was followed by maintenance treatment with toripalimab or placebo as per the random assignment, with nonsquamous NSCLC patients continuing with pemetrexed.
The final analysis for the primary endpoint of investigator-assessed PFS showed a significant improvement with the use of toripalimab (n=309) rather than placebo (n=156) alongside chemotherapy, with respective medians of 8.4 and 5.6 months, and a 51% reduction in the risk for progression or death with the anti-PD-1 agent.
At the 1-year mark, 36.7% of toripalimab-treated patients were alive and progression-free compared with 17.2% of placebo-treated patients.
OS was also significantly improved with toripalimab relative to placebo, with the second interim analysis for this endpoint – conducted at a median follow-up of 16.2 months – showing that the median durations were unreached and 17.1 months, respectively. The risk for death was a significant 31% lower with toripalimab than placebo, and the 1- and 2-year OS rates were 74.0% versus 72.8% and 51.2% versus 33.9%, respectively.
Jie Wang (Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing) and co-investigators highlight that the OS benefit of toripalimab “was mainly driven by the nonsquamous subpopulation.” Specifically, these patients had a significant 52% reduction in the mortality risk with toripalimab versus placebo, whereas there was no such significant difference among the squamous NSCLC subgroup.
The incidence of grade 3 or worse treatment-emergent adverse events (TEAEs) was comparable in the toripalimab and placebo groups (78.6 vs 82.1%), but higher rates were seen with toripalimab for serious AEs (44.8 vs 35.3%), discontinuations due to TEAEs (14.3 vs 3.2%), and fatal TEAEs (5.5 vs 2.6%).
Biomarker analysis showed that the PFS and OS advantage offered by toripalimab was independent of tumor PD-L1 expression. But the team observed “a positive interaction” between tumor mutational burden (TMB) and toripalimab treatment, such that TMB-high (≥10 mutations/Mb) patients derived a greater PFS benefit from the use of toripalimab instead of placebo than their TMB-low counterparts (hazard ratios=0.34 and 0.62, respectively).
“By contrast, similar OS benefits were observed in both TMB subgroups,” note the study authors.
Further genomic analysis revealed several gene mutations that were significantly associated with outcomes. For instance, both PFS and OS were significantly prolonged with the toripalimab combination versus chemotherapy alone for participants with versus without mutations in the focal adhesion-PI3K-Akt signaling pathway.
Wang and colleagues speculate that disruption of this pathway “may increase immune surveillance by overcoming the fibrotic and immunosuppressive tumor microenvironment and sensitize tumor to immunotherapy.”
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