Toripalimab plus chemotherapy as second-line treatment in previously EGFR-TKI treated patients with EGFR-mutant-advanced NSCLC: a multicenter phase-II trial

Tao Jiang, Pingyang Wang, Jie Zhang, Yanqiu Zhao, Jianying Zhou, Yun Fan, Yongqian Shu, Xiaoqing Liu, Helong Zhang, Jianxing He, Guanghui Gao, Xiaoqian Mu, Zhang Bao, Yanjun Xu, Renhua Guo, Hong Wang, Lin Deng, Ningqiang Ma, Yalei Zhang, Hui Feng, Sheng Yao, Jiarui Wu, Luonan Chen, Caicun Zhou, Shengxiang Ren, Tao Jiang, Pingyang Wang, Jie Zhang, Yanqiu Zhao, Jianying Zhou, Yun Fan, Yongqian Shu, Xiaoqing Liu, Helong Zhang, Jianxing He, Guanghui Gao, Xiaoqian Mu, Zhang Bao, Yanjun Xu, Renhua Guo, Hong Wang, Lin Deng, Ningqiang Ma, Yalei Zhang, Hui Feng, Sheng Yao, Jiarui Wu, Luonan Chen, Caicun Zhou, Shengxiang Ren

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).

Conflict of interest statement

Honoraria to Dr. Caicun Zhou: Lilly, Roche, Boehringer Ingelheim, MSD, Hengrui Therapeutics, and QiLu Pharmaceutical; Consulting or advisory role: AmoyDx, Hengrui Therapeutics, Inovent, and QiLu Pharmaceutical. Other authors declared no potential conflicts of interest.

© 2021. The Author(s).

Figures

Fig. 1
Fig. 1
CONSORT diagram for this phase-II study
Fig. 2
Fig. 2
Summary of treatment response, progression-free and overall survival. a Maximal change of tumor size from baseline assessed by the investigator per RECIST v1.1 (n = 38). The length of the bar represents maximal decrease or minimal increase in target lesion(s). # Unconfirmed partial response classified as stable disease. * Patient with target lesion(s) reduction over 30% but with new lesion(s) or progression of nontarget lesion(s). b Change of individual tumor burden over time from baseline assessed by the investigator per RECIST v1.1 (n = 38). c Progression-free survival by RECIST v1.1 of all 40 enrolled patients. d Overall survival by RECIST v1.1 of all 40 enrolled patients. No. number
Fig. 3
Fig. 3
Whole-exome sequencing. a Highlight mutated genes color-coded by the type of mutations in experimental samples. b According to the P value of PFS between groups, the top three combinations with different gene numbers were selected. The red line in the left panel shows the threshold of the filter. The white number on the barplot in the right panel represents the proportion of the corresponding sample in the total population. c Progression-free survival in patients with DSPP + TP53 comutation versus wild type (log-rank test). d Immune infiltration of DSPP + TP53 comutation versus wild type from EGFR-mutant samples obtained from TCGA (Wilcoxon signed-rank test). e Progression-free survival in patients with DSPP mutation versus wild type (log-rank test). f Immune infiltration of DSPP mutation versus wild type from EGFR mutant samples obtained from TCGA (Wilcoxon signed-rank test). PFS progression free survival; HR hazard ratio; *P < .05, **P < .01, ***P < .001, ****P < .0001
Fig. 4
Fig. 4
Integrated analysis of whole exome and transcriptome sequencing. a Sample correlation heat map based on expression matrix; different colors represent different correlation coefficients. b Volcano plot of eight upregulated and five downregulated differentially expressed genes between PR and non-PR group, each of them labeled the names of the first five genes. c Immune analysis of PR versus non-PR group from our cohort (Wilcoxon signed-rank test). d M1/M2 macrophage ratio of PR versus non-PR from our cohort (Wilcoxon signed-rank test). e M1/M2 macrophage ratio of DSPP-mutant versus wild-type tumors from EGFR-mutant samples obtained from TCGA (Wilcoxon signed-rank test). *P < 0.05, **P < 0.01, ***P < 0.001, ****P < 0.0001

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