Abstract
This multicenter phase-II trial aimed to investigate the efficacy, safety, and predictive biomarkers of toripalimab plus chemotherapy as second-line treatment in patients with EGFR-mutant-advanced NSCLC. Patients who failed from first-line EGFR-TKIs and did not harbor T790M mutation were enrolled. Toripalimab plus carboplatin and pemetrexed were administrated every three weeks for up to six cycles, followed by the maintenance of toripalimab and pemetrexed. The primary endpoint was objective-response rate (ORR). Integrated biomarker analysis of PD-L1 expression, tumor mutational burden (TMB), CD8 + tumor-infiltrating lymphocyte (TIL) density, whole-exome, and transcriptome sequencing on tumor biopsies were also conducted. Forty patients were enrolled with an overall ORR of 50.0% and disease-control rate (DCR) of 87.5%. The median progression free survival (PFS) and overall survival were 7.0 and 23.5 months, respectively. The most common treatment-related adverse effects were leukopenia, neutropenia, anemia, ALT/AST elevation, and nausea. Biomarker analysis showed that none of PD-L1 expression, TMB level, and CD8 + TIL density could serve as a predictive biomarker. Integrated analysis of whole-exome and transcriptome sequencing data revealed that patients with DSPP mutation had a decreased M2 macrophage infiltration and associated with longer PFS than those of wild type. Toripalimab plus chemotherapy showed a promising anti-tumor activity with acceptable safety profiles as the second-line setting in patients with EGFR-mutant NSCLC. DSPP mutation might serve as a potential biomarker for this combination. A phase-III trial to compare toripalimab versus placebo in combination with chemotherapy in this setting is ongoing (NCT03924050).
Highlights
ECOG Eastern Cooperative Oncology Group, TNM Tumor, node, metastasis staging system, LDH Lactate dehydrogenase **Positive defined as ≥1% of tumor cells expressing PD-L1 by JS311 IHC staininge received gefitinib as first-line treatment, whereas 16 (40.0%) received icotinib and 4 (10.0%) received erlotinib
After 1000 times independent random grouping experiments on our data set, we found that five of the six test samples can be grouped correctly 985 times with the predictor mentioned above, and 951 of them can be grouped into all pairs
We found that mitogen-activated protein kinase (MAPK) signaling pathway gene set was significantly downregulated (ES = -0.309) in the DSPP-mutant group (Supplementary Fig. S5b)
Summary
The therapeutic landscape has dramatically shifted during the past decade for advanced non-small-cell lung cancer (NSCLC) patients with EGFR-sensitizing mutations.[1,2] First-line setting with EGFR-TKIs, such as erlotinib, gefitinib, icotinib, afatinib, dacomitinib, and osimertinib, has resulted in significantly longer progression-free survival (PFS) than the previous standard of care.[3,4,5,6,7,8,9] after failure of first-line EGFR-TKI therapy, PFS with second or subsequent lines of treatment is disappointing with 4.4–5.4 months in EGFR T790M-negative group that received chemotherapy.[10,11,12] Even though those with EGFR T790M mutations received osimertinib, resistance is inevitable and subsequent treatments often show very limited clinical efficacy.[1,13] a novel strategy is urgently needed to further improve the prognosis of these patients after failure to EGFR-TKIs.Currently, immune-checkpoint inhibitors (ICIs) targeting the PD-. In order to evaluate the efficacy and safety of toripalimab plus carboplatin and pemetrexed in previously EGFR-TKI-treated patients with EGFR-mutant NSCLC, we conducted this open-label, single-arm phase-II trial and enrolled 40 patients from eight medical centers in China.
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