The Real-world Therapeutic Analysis of First-line Immunotherapy in Chinese Patients with Drive Gene Positive for Advanced Non-Small Cell Lung Cancer.

Background: Immune checkpoint inhibitors (ICIs) are widely used for treating advanced non-small cell lung cancer (NSCLC). However, some studies indicate that patients with genetic mutations do not benefit from immunotherapy. Hence, this study explored the efficacy of anti-programmed death-1 (PD-1) and anti-programmed death-ligand 1 (PD-L1) antibodies in the first-line treatment of advanced NSCLC with driver gene mutations in real-world settings. Methods: We retrospective analyzed patients with advanced NSCLC who treated with first-line anti-PD-1/PD-L1 antibodies at Shandong Provincial Hospital between May 2019 and October 2020. The patient's driver gene mutation status was identified using amplification refractory mutation system PCR (ARMS-PCR). The basic clinical characteristics, objective response rate (ORR), progression free survival (PFS), and other clinical data of patients were collected to evaluate the clinical efficacy and potential prognostic factors of treatment for patients with driver gene mutations. Results: A total of 430 patients' information was counted during this period, finally, 89 patients with NSCLC were enrolled in the study. The main pathological subtype of patients was adenocarcinoma (62.9%). The overall mutation rate was 44.9% (n = 40) and included following mutations: KRAS (n = 20), TP53 (n = 18), EGFR (n = 6), BRAF (n = 3), Her-2 (n = 3), MET (n = 3), ROS1 (n = 1), and NRAS (n = 1). The overall ORR was 44.30% and the disease control rate (DCR) was 82.23%. At the time of follow-up cut-off, the median PFS of all patients was 8.2 month. In NSCLC patients treated with ICI, median PFS was longer in mutation-negative patients than in mutation-positive patients (8.98 vs 7.07 months, P < 0.05). Survival benefit varied across mutational subgroups: KRAS patients could benefit from first-line immunotherapy (10.1 months, P < 0.05), patients with EGFR mutations have poor first-line immunotherapy outcomes, with a median PFS of only 3.0 months (P < 0.01), and patients with other mutation types having no significant difference in response from mutation-negative patients. In most mutation subgroups, immune combination therapy had longer PFS than immune monotherapy, and PD-L1 expression levels were positively correlated with clinical benefit in patients. Conclusion: In the real world, patients with KRAS mutations benefit from first-line immunotherapy, immune-combination modalities are more effective, and immune efficacy is positively correlated with PD-L1 expression; Patients with other driver mutations (BRAF, NRAS, Her2, MET, ROS1) benefit similarly to mutation-negative patients in first-line immunotherapy, and immunotherapy is recommended for first-line therapy; Immunotherapy is worse effective in patients with EGFR mutations, immunotherapy is not recommended in first-line therapy even patients with high PD-L1 expression.

Response to Pralsetinib in Multi-Drug-Resistant Breast Cancer With CCDC6-RET Mutation.

Triple-negative breast cancers (TNBC) represent a pathological subtype of breast cancer, which are characterized by strong invasiveness, high metastasis rate, low survival rate, and poor prognosis, especially in patients who have developed resistance to multiline treatments. Here, we present a female patient with advanced TNBC who progressed despite multiple lines of treatments; next-generation sequencing (NGS) was used to find drug mutation targets, which revealed a coiled-coil domain-containing protein 6 (CCDC6)-rearranged during transfection (RET) gene fusion mutation. The patient was then given pralsetinib, and after one treatment cycle, a CT scan revealed partial remission and adequate tolerance to therapy. Pralsetinib (BLU-667) is a RET-selective protein tyrosine kinase inhibitor that can inhibit the phosphorylation of RET and downstream molecules as well as the proliferation of cells expressing RET gene mutations. This is the first case in the literature of metastatic TNBC with CCDC6-RET fusion treated with pralsetinib, an RET-specific antagonist. This case demonstrates the potential efficacy of pralsetinib in cases of TNBC with RET fusion mutations and suggests that NGS may reveal new opportunities and bring new therapeutic interventions to patients with refractory TNBC.

HER2-positive breast cancer progresses rapidly after pyrotinib resistance: acquired RET gene fusion and TP53 gene mutation are potential reasons.

Approximately 15-20% of the patients with breast cancer overexpress human epidermal growth factor receptor 2 ( HER2 ). HER2 -positive breast cancer is highly aggressive and has a high relapse rate, suggesting that it is prone to and progresses rapidly after drug resistance. Pyrotinib resistance and changes in patients' conditions after drug resistance are challenging clinical issues and require medical attention. Recently, there are few clinical reports on changes in patients' conditions after pyrotinib resistance. We report a case of a 46-year-old patient with HER2 -positive breast cancer who developed resistance to pyrotinib and rapidly progressed to uncontrolled liver failure in less than a week. To elucidate the cause of the rapid progression, we collected samples of the patient's ascites and performed next-generation sequencing (NGS). On the basis of the NGS results, we speculated that the rapid progression after pyrotinib resistance might be due to RET gene fusion and TP53 gene mutations. Therefore, this case report aims to alert oncologists that patients with HER2 -positive breast cancer, who are resistant to pyrotinib or other targeted drugs, could experience rapid or even flare-up progression and that RET gene fusion and TP53 gene mutations might be potential causes.

Clinical characteristics and prognostic factors of patients with non-small cell lung cancer having HER2 alterations.

PURPOSE: Human epidermal growth factor 2 (HER2) alterations are found in approximately 2%-5% of non-small cell lung cancer (NSCLC). This study aimed to evaluate the clinical characteristics of patients with NSCLC having HER2 alterations in China and the differences compared with Western counterparts and also perform a prognostic analysis. MATERIAL AND METHODS: A total of 1300 patients diagnosed with NSCLC from January 2017 to December 2020 were included. Their clinical characteristics were retrospectively recorded. The gene expression profiles and clinical information of 20 patients having altered HER2 were downloaded from the Cancer Genome Atlas database and compared, and the prognostic factors affecting the Chinese population were analyzed. If tissues were sufficient, the overexpression was assessed by immunohistochemical staining. RESULTS: Among 39 (3.0%) patients with HER2 alterations, 31 patients (79.5%) had HER2 mutations. HER2 insertion mutation in exon 20 was the most common type (A775_G776 ins YVMA). Seven patients (17.9%) had amplification, and one had both. The HER2 kinase domain was most commonly mutated. A majority of patients in the study were young-aged with no smoking history; 66.7% had stage III/IV adenocarcinoma. Compared with Chinese patients, HER2 alterations in Western counterparts were mostly associated with old age, previous smoking, and stages I and II at diagnosis. The most common type of HER2 alteration was HER2 amplification; one patient had coexistence of HER2 gene amplification and fusion. The furin-like cysteine-rich region was most commonly mutated. The median overall survival (OS) of the Chinese patients was 41 months. The univariate analysis showed that age > 60 years, no surgical treatment, no liver or renal cysts on imaging, and maximum tumor diameter ≥ 4.25 cm were significantly associated with poor OS. The multivariate analysis showed that age, presence of surgery, and no hepatic or renal cysts were independent prognostic factors for OS. Chemotherapy achieved better outcomes, and HER2 mutations were not associated with HER2 amplification and overexpression. CONCLUSIONS: This study was novel in comprehensively investigating the clinical and molecular characteristics of patients in Chinese and Western populations, and in analyzing the factors affecting the prognosis of Chinese patients. It provided critical data for future therapies against HER2-altered NSCLC.

Potential mechanism of pyrotinib-induced diarrhea was explored by gut microbiome and ileum metabolomics.

Pyrotinib is a novel epidermal growth factor receptor/human epidermal growth factor receptor-2 (HER2) tyrosine kinase inhibitor that exhibited clinical efficacy in patients with HER2-positive breast cancer and HER2-mutant/amplified lung cancer. However, severe diarrhea adverse responses preclude its practical use. At present, the mechanism of pyrotinib-induced diarrhea is unknown and needs further study. First, to develop a suitable and reproducible animal model, we compared the effects of different doses of pyrotinib (20, 40, 60 and 80 mg/kg) in Wistar rats. Second, we used this model to examine the intestinal toxicity of pyrotinib. Finally, the mechanism underlying pyrotinib-induced diarrhea was fully studied using gut microbiome and host intestinal tissue metabolomics profiling. Reproducible diarrhea occurred in rats when they were given an 80 mg/kg daily dose of pyrotinib. Using the pyrotinib-induced model, we observed that Lachnospiraceae and Acidaminococcaceae decreased in the pyrotinib groups, whereas Enterobacteriaceae, Helicobacteraceae and Clostridiaceae increased at the family level by 16S rRNA gene sequence. Multiple bioinformatics methods revealed that glycocholic acid, ursodeoxycholic acid and cyclic AMP increased in the pyrotinib groups, whereas kynurenic acid decreased, which may be related to the pathogenesis of pyrotinib-induced diarrhea. Additionally, pyrotinib-induced diarrhea may be associated with a number of metabolic changes mediated by the gut microbiome, such as Primary bile acid biosynthesis. We reported the establishment of a reproducible pyrotinib-induced animal model for the first time. Furthermore, we concluded from this experiment that gut microbiome imbalance and changes in related metabolites are significant contributors to pyrotinib-induced diarrhea.

Effects of Shenling Baizhu powder on pyrotinib-induced diarrhea: analysis of gut microbiota, metabonomics, and network pharmacology.

BACKGROUND: Shenling Baizhu Powder (SBP) is a traditional Chinese medicine (TCM) prescription, which has the good efficacy on gastrointestinal toxicity. In this study, we used gut microbiota analysis, metabonomics and network pharmacology to investigate the therapeutic effect of SBP on pyrotinib-induced diarrhea. METHODS: 24 Rats were randomly divided into 4 groups: control group, SBP group (3.6 g/kg /bid SBP for 10 days), pyrotinib model group (80 mg/kg/qd pyrotinib) and pyrotinib + SBP treatment group. A 16S rRNA sequencing was used to detect the microbiome of rat fecal bowel. Metabolic profiles were collected by non-targeted metabolomics and key metabolic pathways were identified using MetaboAnalyst 5.0. The antitumor effect of SBP on cells treated with pyrotinib was measured using a CCK-8 assay. Network pharmacology was used to predict the target and action pathway of SBP in treating pyrotinib-related diarrhea. RESULTS: In vivo study indicated that SBP could significantly alleviate pyrotinib-induced diarrhea, reaching a therapeutic effect of 66.7%. SBP could regulate pyrotinib-induced microbiota disorder. LEfSe research revealed that the SBP could potentially decrease the relative abundance of Escherichia, Helicobacter and Enterobacteriaceae and increase the relative abundance of Lachnospiraceae, Bacilli, Lactobacillales etc. In addition, 25-Hydroxycholesterol, Guanidinosuccinic acid, 5-Hydroxyindolepyruvate and cAMP were selected as potential biomarkers of SBP for pyrotinib-induced diarrhea. Moreover, Spearman's analysis showed a correlation between gut microbiota and metabolite: the decreased 25-hydroxycholesterol in the pyrotinib + SBP treatment group was negatively correlated with Lachnospiraceae while positively correlated with Escherichia and Helicobacter. Meanwhile, SBP did not affect the inhibitory effect of pyrotinib on BT-474 cells and Calu-3 cells in vitro. Also, the network analysis further revealed that SBP treated pyrotinib-induced diarrhea through multiple pathways, including inflammatory bowel disease, IL-17 signaling pathway, pathogenic Escherichia coli infection and cAMP signaling pathway. CONCLUSIONS: SBP could effectively relieve pyrotinib-induced diarrhea, revealing that intestinal flora and its metabolites may be involved in this process.

Opportunities and challenges of immune checkpoint inhibitors for extensive-stage small-cell lung cancer.

Small-cell lung cancer (SCLC) accounts for 15%-20% of primary lung cancers, and it is characterized by low differentiation, rapid proliferation, and early metastasis. At least two-thirds of SCLC patients present with the extensive stage (ES) at the time of initial clinical diagnosis. Over the last 2 decades, platinum-based combination chemotherapy has remained the standard first-line treatment for SCLC. With the introduction of the immunotherapy era, immunotherapy plus chemotherapy has replaced conventional chemotherapy as the first-line treatment option for ES-SCLC and is recommended by National Comprehensive Cancer Network clinical guidelines. Therefore, in this review, we present the latest research advances in SCLC treatment, predictive biomarkers, and other topics of high interest to provide options for patients with SCLC.