Camrelizumab, an Anti-PD-1 Monoclonal Antibody, Plus Carboplatin and Nab-Paclitaxel as First-Line Setting for Extensive-Stage Small-Cell Lung Cancer: A Phase 2 Trial and Biomarker Analysis

Abstract

This study aimed to investigate the efficacy, safety, and predictors of camrelizumab combined with carboplatin and nab-paclitaxel as first-line setting for patients with extensive-stage small-cell lung cancer (ES-SCLC). Camrelizumab plus carboplatin and nab-paclitaxel were administrated every 3 weeks for four to six cycles, followed by maintenance camrelizumab until intolerable toxicity or disease progression. The primary endpoint was 6-month progression-free survival (PFS) rate and secondary endpoints were objective response rate (ORR), disease control rate (DCR), PFS, overall survival (OS), and safety. We conducted the whole-exome and transcriptomic sequencing on available tumor samples to explore the potential predictive biomarkers. A total of 60 patients were included. Primary endpoint was met with 6-month PFS rate of 52.2%. The median PFS and OS were 7.1 and 18.1 months, respectively. The confirmed ORR and DCR were 73.3% and 93.3%, respectively. No unexpected adverse events were observed. Exploratory analysis showed that MUC17 alterations or high NEUROG1 expression were correlated with markedly shorter PFS and OS. Deeper investigation of transcriptomic data reveals two subsets with distinct immune features and therapeutic vulnerabilities. Collectively, this trial suggested that camrelizumab plus carboplatin and nab-paclitaxel might be an alternative first-line setting for ES-SCLC. Integration of multiomic data could highlight the complex mechanisms underlying chemo-immunotherapy responses.

Keywords: ES‐SCLC; biomarker; camrelizumab; immunotherapy; nab‐paclitaxel.

FIGURE 1

Flow diagram of this study. (a) Patients’ selection. (b) Sample collection and biomarker analysis.

FIGURE 2

Treatment outcomes of all eligible patients. (a) Kaplan–Meier curves for PFS in all patients (median PFS: 7.1 months, 95% CI: 5.5–9.7 months). (b) Kaplan–Meier curves for OS in all patients (median OS: 18.1 months, 95% CI: 12.9 months–not reached). (c) Best percentage change from baseline in target lesion. (d) Duration of response; the asterisks indicated unconfirmed responses; the pound key indicated this patient had disease progression due to new target lesion at assessment. CI, confidence interval; NR, not reached; OS, overall survival; PFS, progression‐free survival.

FIGURE 3

Whole‐exome sequencing data analysis. (a) Mutational landscape of all patients. (b) p value of top 20 frequent gene alterations or their combinations associated with treatment outcomes. (c) PFS comparison between patients with MUC17 alterations and wild type (median PFS: 4.1 vs. 5.7 months, p = 0.015). (d) OS comparison between patients with MUC17 alterations and wild type (median OS: 10.2 vs. NR months, p = 0.026). (e) Comparison of immune infiltrates estimated by CIBERSORT between patients with MUC17 alterations and wild type. HR, hazard ratio; NR, not reached; OS, overall survival; PFS, progression‐free survival; WT, wild type.

FIGURE 4

Whole transcriptomic sequencing data analysis. (a) Comparison of immune infiltrates estimated by CIBERSORT between CR+PR and SD+PD groups. (b) Volcano plot of 17 upregulated and 11 downregulated differentially expressed genes between CR+PR and SD+PD groups, all of them labeled the gene names. (c) Forest plots depicting the significance of dramatically differentially expressed genes in predicting PFS. (d) Forest plots depicting the significance of dramatically differentially expressed genes in predicting OS. (e) PFS comparison between patients with high and low NEUROG1 expression (median PFS: 6.3 vs. 4.5 months, p = 0.019). (f) OS comparison between patients with high and low NEUROG1 expression (median OS: NR vs. 10.8 months, p = 0.011). CI, confidence interval; HR, hazard ratio; NR, not reached; OS, overall survival; PFS, progression‐free survival.

FIGURE 5

De novo non‐negative matrix factorization (NMF) transcriptomic sequencing data and their associated treatment outcomes. (a) Composition of 22 immune cells in each sample. (b) Two clusters were well‐defined (named TME1 and TME2) by using NMF. (c) PFS comparison between patients in TME1 and TME2 (median PFS: 5.8 vs. 4.7 months, p = 0.010). (d) OS comparison between patients in TME1 and TME2 (median OS: 18.1 vs. 10.0 months, p = 0.160). (e) Comparison of immune infiltrates estimated by CIBERSORT between TME1 and TME2. NR, not reached; OS, overall survival; PFS, progression‐free survival.