Shengguang Wang

The safety and efficacy of combination of gefitinib with chemotherapy and bevacizumab in treatment patients with epidermal growth factor receptor (EGFR) mutations are currently unknown. This study was designed to evaluate the safety and preliminary efficacy of a combination therapy consisting of gefitinib, bevacizumab, pemetrexed, and carboplatin in patients with advanced non-squamous non–small cell lung cancer (NSCLC) harboring EGFR mutations. Eligible patients with EGFR-mutated advanced non-squamous NSCLC were recruited and received gefitinib combination with bevacizumab plus pemetrexed and carboplatin treatment. The primary endpoints were safety and progression-free survival (PFS). Secondary endpoints included objective response rate (ORR), disease control rate (DCR), duration of response (DOR), and overall survival (OS). From June 2019 to June 2021, 20 patients were enrolled in this study. The median follow-up was 33.8 months (95% CI, 31.0-36.6). Grade ≥ 3 adverse events was 65%, including neutropenia (30%), thrombocytopenia (20%), nausea (20%), skin rash (20%), bleeding (10%), and increased ALT (10%). There was no death related to toxicity occurred. The median PFS was 28 months (95% CI, 20.4–35.6). the ORR was 95% (95% CI, 75.1-99.9%), the DCR was 100% (95% CI, 83.2-100%), and the median DOR was 26.4 months (95% CI, 18.9–33.9). The median OS has not been reached. The results of this study demonstrate that the four-drug combination regimen, led by gefitinib, is manageable and tolerated and effective for patients with EGFR-mutated advanced non-squamous NSCLC.

Background: Despite the improved survival observed in PD-1/PD-L1 blockade therapy, a substantial proportion of cancer patients, including those with non-small cell lung cancer (NSCLC), still lack a response. Methods: Transcriptomic profiling was conducted on a discovery cohort comprising 100 whole blood samples, as collected multiple times from 48 healthy controls (including 43 published data) and 31 NSCLC patients that under treatment with a combination of anti-PD-1 Tislelizumab and chemotherapy. Differentially expressed genes (DEGs), simulated immune cell subsets, and germline DNA mutational markers were identified from patients achieved a pathological complete response during the early treatment cycles. The predictive values of mutational markers were further validated in an independent immunotherapy cohort of 1661 subjects, and then confirmed in genetically matched lung cancer cell lines by a co-culturing model. Results: The gene expression of hundreds of DEGs (FDR p < 0.05, fold change < -2 or > 2) distinguished responders from healthy controls, indicating the potential to stratify patients utilizing early on-treatment features from blood. PD-1-mediated cell abundance changes in memory CD4 + and regulatory T cell subset were more significant or exclusively observed in responders. A panel of top-ranked genetic alterations showed significant associations with improved survival (p < 0.05) and heightened responsiveness to anti-PD-1 treatment in patient cohort and co-cultured cell lines. Conclusion: This study discovered and validated peripheral blood-based biomarkers with evident predictive efficacy for early therapy response and patient stratification before treatment for neoadjuvant PD-1 blockade in NSCLC patients.

Background: Despite the improved survival observed in PD-1/PD-L1 blockade therapy, there still is a lack of response to the anti-PD1 therapy for a large proportion of cancer patients across multiple indications, including non-small cell lung cancer (NSCLC) Methods: Transcriptomic profiling was performed on 57 whole blood samples from 31 NSCLC patients and 5 healthy donors, including both responders and non-responders received anti-PD-1 Tislelizumab plus chemotherapy, to characterize differentially expressed genes (DEGs), signature pathways, and immune cell subsets regulated during treatment. Mutations of oncogenic drivers were identified and associated with therapeutic outcomes in a validation cohort with 1661 cancer patients. These multi-level biomarkers were validated and compared across different methods, external datasets and multiple computational tools. Results: NSCLC patients examined and achieved pathological complete response (pCR) were considered as responders or non-responders otherwise. Expression of hundreds DEGs (FDR p2) was changed in blood during neoadjuvant anti-PD-1 treatment, as well as in lung cancer tissue as compared to normal samples. Enriched PD-1-mediated pathways and elevated cell abundances of CD8 T cells and regulatory T cells were exclusively observed in responder blood samples. In an independent validation cohort of 1661 pan-cancer patients, a panel of 4 top ranked genetic alterations (PTCH1, DNMT3A, PTPRS, JAK2) identified from responders in discovery cohort were found positively associated with the overall survival (p<0.05). Conclusion: These findings suggest peripheral blood-based biomarkers and cell subsets could be utilized to define the response to neoadjuvant PD-1 blockade in NSCLC patients and a set of novel gene mutations is strongly associated with the therapeutic outcome of cancer immunotherapy.