Abstract
Immunotherapy by immune checkpoint inhibitors (ICIs) has showed outstanding efficacy in the treatment of advanced non-small cell lung cancer (NSCLC). The combination of immunotherapy with anti-angiogenic therapy exhibited enhanced efficacy in multiline treatment. However, the potential biomarkers for predicting and monitoring the therapeutic response of the combined therapy remain undefined. In this study, we performed a pilot study by prospectively recruiting 22 advanced NSCLC patients who failed to previous lines of chemotherapy, chemoradiotherapy, TKI therapy, surgery, or any combination of the therapies, and investigated the prognostic factors for patients who received anti-PD-1 (Camrelizumab) and anti-angiogenic (Apatinib) combined therapy. The objective response rate (ORR) assessed by an independent radiology review was 22.7%, and the median progression-free survival (PFS) was 5.25 months. We found that high concentration of circulating-free DNA (cfDNA) (HR = 27.75, P = 0.003), MIKI67 mutation (HR = 114.11, P = 0.009) and gene variations related to hyper-progressive disease (HPD) (HR = 36.85, P = 0.004) were independent risk factors and exhibited significant correlation with PFS. Circulating tumor DNA (ctDNA) mutational status was also a predicting indicator for PFS. In contrast, the blood tumor mutational burden (bTMB) could not stratify the clinical benefit in this combined therapy (HR = 0.81, P = 0.137). Furthermore, we found that the variant allele fraction (VAF) of mutations in ctDNA was sensitive indicators of therapeutic response and therefore can be used to monitor the tumor relief or progression. In conclusion, cfDNA concentration, MIKI67 mutations and HPD-related mutations were independent risk factors and PFS predictors for multiline combined anti-angiogenic/ICI combined therapy. ctDNA may be a novel monitoring biomarker for therapeutic response and predicting biomarker for prognosis in future combined therapy involving PD-1 blockade.
Highlights
Immune checkpoint inhibitors (ICIs), such as programmed death 1 (PD-1)/programmed death ligand 1 (PD-L1) inhibitors have made a significant breakthrough in lung cancer treatment [1,2,3]
Since the traditional biomarkers for immunotherapy, such as the PD-L1 expression and tumor mutation burden (TMB) appeared to have limited predicting values in several clinical trials using combined immunotherapy [11, 12, 22, 24, 25], we investigated the values of a few new biomarkers in predicting and monitoring the therapeutic response and prognosis in secondline or higher settings when ICI was combined with antiangiogenic therapy
We found that circulating-free DNA (cfDNA) concentration, MIKI67 mutations, and HPDrelated gene mutations and potentially Circulating tumor DNA (ctDNA) mutations, were independent risk factors for therapeutic response prediction, while age, gender, lung cancer subtypes, smoking history, and blood tumor mutational burden (bTMB) did not affect the response
Summary
Immune checkpoint inhibitors (ICIs), such as programmed death 1 (PD-1)/programmed death ligand 1 (PD-L1) inhibitors have made a significant breakthrough in lung cancer treatment [1,2,3]. Antibody blockade of the PD pathway rectifies immunodeficiency in tumor microenvironment, and empowers CD8+ T cells with the capability to kill tumor cells efficiently [4, 5]. Along with success in clinical trials of immunotherapy, many more therapeutic options have appeared for lung cancer patients [6,7,8,9,10,11,12]. In patients with previously treated lung cancer, especially patients with wild-type driver genes, ICIs have substantially improved clinical prognosis compared with chemotherapy, as evidenced by an improvement of overall survival (OS) from 9.6 to 13.8 months in OAK cohorts [13]. There is an urgent need to explore appropriate methods for improving the efficacy of immunotherapy and selecting patients potentially benefit from immunotherapy at multiline levels
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