First case report of ensartinib in a patient with metastatic ALK rearranged lung cancer with ALK I1171N mutation: a case report.

BACKGROUND: The acquired resistance to ALK tyrosine kinase inhibitors (TKIs) in ALK-rearranged NSCLC is associated with poor survival outcomes and poses distinct clinical challenges. It is essential to develop potential therapeutic strategies for overcoming resistance. CASE PRESENTATION: Here, we first report a female lung adenocarcinoma patient with an acquired ALK resistance mutation (ALK 11171N) who was treated with ensartinib. Her symptoms significantly improved after only 20 days, and with a side effect of mild rash. Follow-up images observed no further brain metastases after 3 months. CONCLUSIONS: This treatment may provide a new therapeutic strategy for ALK TKIs resistant patients, especially in position 1171 of ALK exon20.

EGFR-TKI Combined with Pemetrexed versus EGFR-TKI Monotherapy in Advanced EGFR-mutated NSCLC: A Prospective, Randomized, Exploratory Study.

PURPOSE: We aimed to evaluate whether the addition of pemetrexed is effective in improving progression-free survival (PFS) in epidermal growth factor receptor (EGFR)-mutated patients with or without concomitant alterations. Materials and Methods: This multicenter clinical trial was conducted in China from June 15, 2018, to May 31, 2019. A total of 92 non-small cell lung cancer (NSCLC) patients harboring EGFR-sensitive mutations were included and divided into concomitant and non-concomitant groups. Patients in each group were randomly treated with EGFR-tyrosine kinase inhibitor (TKI) monotherapy or EGFR-TKI combined with pemetrexed in a ratio of 1:1. PFS was recorded as the primary endpoint. RESULTS: The overall median PFS of this cohort was 10.1 months. There were no significant differences in PFS between patients with and without concomitant and between patients received TKI monotherapy and TKI combined with pemetrexed (p=0.210 and p=0.085, respectively). Stratification analysis indicated that patients received TKI monotherapy had a significantly longer PFS in non-concomitant group than that in concomitant group (p=0.002). In concomitant group, patients received TKI combined with pemetrexed had a significantly longer PFS than patients received TKI monotherapy (p=0.013). Molecular dynamic analysis showed rapidly emerging EGFR T790M in patients received TKI monotherapy. EGFR mutation abundance decreased in patients received TKI combined chemotherapy, which supports better efficacy for a TKI combined chemotherapy as compared to TKI monotherapy. A good correlation between therapeutic efficacy and a change in circulating tumor DNA (ctDNA) status was found in 66% of patients, supporting the guiding role of ctDNA minimal residual disease (MRD) in NSCLC treatment. CONCLUSION: EGFR-TKI monotherapy is applicable to EGFR-sensitive patients without concomitant alterations, while a TKI combined chemotherapy is applicable to EGFR-sensitive patients with concomitant alterations. CtDNA MRD may be a potential biomarker for predicting therapeutic efficacy.

A 12-hour rapid titration method for cancer pain: a randomized, controlled, open-label study.

BACKGROUND: Opioid titration is the best way to achieve a balance of pain relief and tolerable side effects for moderate-to-severe cancer pain. Rapid dose titration helps to achieve early analgesia. We explored the efficacy and safety of a 12-hour rapid dose titration in treating cancer pain. METHODS: Opioid-naïve patients with moderate-to-severe cancer pain were randomly divided into oxycodone group and morphine group. The medicines were adjusted to oxycodone sustained-release tablets after 12 hours, and the dose of oxycodone sustained-release tablets was adjusted every 12 hours. The analgesic efficacy and adverse reactions during the treatment were observed until the 72nd hour. RESULTS: A total of 106 patients were included in the analysis, with 51 patients in the oxycodone group and 55 in the morphine group. The pain control rate of all patients reached 96.2% 24 hours after treatment, and it was not significantly different between two groups (P=0.619). The proportion of Numeric Rating Scale (NRS) score that decreased by ≥50% was significantly higher in the oxycodone group than in the morphine group (P=0.013). In the first 12 hours and 24 hours, significantly lower proportions of patients in the oxycodone group experienced multiple episodes of breakthrough pain (BTP) than in the morphine group (P=0.032, P=0.021, respectively). The quality of life of the patients in the oxycodone group was significantly higher than that in the morphine group at the 24th hour (P=0.047), as was the degree to which the quality of life had improved (P<0.001). Only grade 1 or 2 adverse reactions were observed during the study period, and no significant difference between two groups. CONCLUSIONS: The 12-hour rapid dose titration method can achieve early analgesia, with mild adverse reactions. In particular, the rapid titration method with background sustained-release oxycodone can reduce BTP episodes and achieve significant early pain relief.

Molecular gene mutation profiles, TMB and the impact of prognosis in Caucasians and east Asian patients with lung adenocarcinoma.

BACKGROUND: The difference in molecular gene mutation profile, tumor mutational burden (TMB) and their prognostic effects in lung adenocarcinoma between different ethnic groups are still unknown. A retrospective analysis was used to investigate the differences in lung adenocarcinoma driver gene mutations, TMB, and their impact on prognosis across different ethnic groups. METHODS: The incidence of epidermal growth factor receptor (EGFR) mutations and follow-up data of 647 Chinese lung adenocarcinoma patients were compared with the data from 522 Caucasian patients in The Cancer Genome Atlas (TCGA) database. Moreover, a comprehensive analysis was performed to compare the differences in gene mutation frequency, signaling pathway variation, and TMB using the whole-exome sequencing (WES) data of Chinese patients with that of Caucasian patients. RESULTS: A comparison of tumor signaling pathways and gene mutation profiles between Caucasians and Chinese revealed ethnic variations in the incidence of mutations in TGF-ß and RTK-RAS signaling pathways, with P values of 0.012 and 0.016, respectively. In the Caucasian population, the mutations in 5 signaling pathways and 18 genes were all significantly correlated with TMB, whereas in the Chinese population, only mutations in the Notch pathway and 6 genes were found to be associated with TMB-high. EGFR mutations showed a better prognosis in Chinese patients with lung adenocarcinoma, while the opposite was found in Caucasians patients. CONCLUSIONS: Variations in the incidence of mutations in signaling pathways involved in lung adenocarcinoma and the correlation of the signaling pathways with TMB may exist across different ethnic groups.

Efficacy and safety of apatinib as third- or further-line therapy for patients with advanced NSCLC: a retrospective study.

BACKGROUND: Apatinib, an oral small-molecule angiogenesis inhibitor, selectively inhibits vascular endothelial growth factor receptor 2 (VEGFR-2), which inhibits vascular endothelial growth factor (VEGF) stimulated endothelial cell migration and proliferation and decreases tumour growth and metastasis. Recently, the efficacy of multi-target angiogenic drugs has been demonstrated for many cancers, including non-small-cell lung cancer (NSCLC). The aim of this retrospective study was to evaluate the clinical efficacy of apatinib in patients with advanced NSCLC. PATIENTS AND METHODS: We conducted a retrospective analysis of 70 patients with advanced NSCLC who received second-line and later treatment from November 2015 to July 2017 with poor results. Out of the 70 patients, 36 patients received apatinib treatment after second-line or later treatment, whereas 34 patients in the control group did not receive further treatment. The patients were treated with oral apatinib 500 mg once a day every day for 4 weeks per cycle. Treatment was continued in responding and stable patients until disease progression or intolerable toxicity. The objective response rate (ORR), disease control rate (DCR), progression-free survival (PFS), overall survival (OS), and side effects of the drug were recorded and reviewed. RESULTS: ORR, DCR, PFS, and OS were evaluated in 36 patients receiving apatinib and 34 patients in the control group. The ORR and DCR in patients receiving apatinib therapy were 22.2% and 77.8%, respectively. The median PFS and OS in the treatment group were 5.6 and 9.6 months, respectively. The median OS in the apatinib group was significantly longer than that in the control group (9.6 versus 3.8 months; p < 0.0001). In contrast, there were no differences in adverse reactions between the patients in the treatment and control groups. CONCLUSION: Apatinib showed favourable efficacy and safety and can thus be used as a treatment option for patients with advanced NSCLC.

Multiple-line Chemotherapy and Tyrosine Kinase Inhibitor Treatment in Patients with Advanced Lung Cancer.

AIM: To analyse the clinical outcomes of patients with lung cancer treated with first and multiple-line chemotherapy and tyrosine kinase inhibitor (TKI). PATIENTS & METHODS: The present study included a total of 89 patients of whom lung cancer was histologically confirmed between July 2016 and September 2017. Patients' demographics, chemotherapy/TKI treatment details and clinical outcomes were retrieved. The progression-free survivals (PFS) after first-line and multiple-line treatments were evaluated using Kaplan-Meier analysis with log-rank test. Risk factors for progressive disease (PD) were identified using Cox multivariate regression model. RESULTS: A total of 50 males and 39 females were enrolled. About 90% of the tumors were histologically classified as adenocarcinoma, and 77/89 cases (86.5%) were at TNM stage IV. The median PFS for the first-line treatment was 6.17 months. After first-line treatment, more favourable PFS was observed in patients who had prior surgery of lung cancer (P = 0.002). Multivariate analysis showed that patients who had received no prior surgical treatment for lung cancer were at higher risk of PD (OR, 4.311; 95% CI, 1.836 to 10.120; P = 0.0008). Besides, in patients with driver mutations, those who received no TKI treatment were under higher risk of PD compared to those who had been treated with TKI (OR, 4.876; 95% CI, 1.877 to 12.666; P = 0.0011). The median PFS for the multiple-line treatment was 24.67 months. After multiple-line treatments, favourable PFS was associated with tumor histological types of adenocarcinoma (P = 0.041), genetic lesions at exon 19 of EGFR (P = 0.001) and fourth-line treatment (P = 0.001). Risk factors for PD after multiple-line treatments were no prior surgery for lung cancer (OR, 3.335; 95% CI, 1.158 to 9.605; P = 0.0256), no TKI use in multiple-line treatment (OR, 10.095; 95% CI, 2.405 to 42.378; P = 0.0016), and being treated by first-line treatment alone (OR, 30.421; 95% CI, 4.813 to 192.269; P = 0.0003). CONCLUSION: The present study demonstrated the benefits of TKI in patients with advanced lung cancer, providing insights into the refinement of the management strategy.

Comparison of the SuperARMS and Droplet Digital PCR for Detecting EGFR Mutation in ctDNA From NSCLC Patients.

BACKGROUND: Liquid biopsy is emerging as an important approach for tumor genotyping in non-small cell lung cancer, ddPCR and SuperARMS are both methods with high sensitivity and specificity for detecting EGFR mutation in plasma. We aimed to compare ddPCR and SuperARMS to detect plasma EGFR status in a cohort of advanced NSCLC patients. METHOD: A total of 79 tumor tissues and paired plasma samples were collected. The EGFR mutation status in tissue was tested by ADx-ARMS, matched plasma was detected by ddPCR and SuperARMS, respectively. RESULTS: The EGFR mutation rates were identified as 64.6% (tissue, ARMS), 55.7% (plasma, ddPCR), and 49.4% (plasma, Super ARMS), respectively. The sensitivity of ddPCR was similar with Super-ARMS in plasma EGFR detection (80.4% vs 76.5%), as well as the specificity (89.3% vs 100%). And the McNemar's test showed there was no significant difference (P = .125). The concordance rate between SuperARMS and ddPCR was 91.1%. A significant interaction was observed between cfDNA EGFR mutation status and EGFR-TKIs treatment tested by both methods. CONCLUSION: Super-ARMS and ddPCR share the similar accuracy for EGFR mutation detection in plasma biopsy; both methods predicted well the efficacy of EGFR-TKIs by detecting plasma EGFR status.

The concentration of erlotinib in the cerebrospinal fluid of patients with brain metastasis from non-small-cell lung cancer.

It has been demonstrated that erlotinib is effective in treating patients with brain metastasis from non-small-cell lung cancer. However, the number of studies determining the erlotinib concentration in these patients is limited. The purpose of this study was to measure the concentration of erlotinib in the cerebrospinal fluid of patients with brain metastasis from non-small-cell lung carcinoma. Six patients were treated with the standard recommended daily dose of erlotinib (150 mg) for 4 weeks. All the patients had previously received chemotherapy, but no brain radiotherapy. At the end of the treatment period, blood plasma and cerebrospinal fluid samples were collected and the erlotinib concentration was determined by high-performance liquid chromatography-tandem mass spectrometry (HPLC-MS/MS). The average erlotinib concentration in the blood plasma and the cerebrospinal fluid was 717.7±459.7 and 23.7±13.4 ng/ml, respectively. The blood-brain barrier permeation rate of erlotinib was found to be 4.4±3.2%. In patients with partial response (PR), stable disease (SD) and progressive disease (PD), the average concentrations of erlotinib in the cerebrospinal fluid were 35.5±19.0, 19.1±8.7 and 16.4±5.9 ng/ml, respectively. In addition, the efficacy rate of erlotinib for metastatic brain lesions was 33.3%, increasing to 50% in patients with EGFR mutations. However, erlotinib appeared to be ineffective in cases with wild-type EGFR. In conclusion, a relatively high concentration of erlotinib was detected in the cerebrospinal fluid of patients with brain metastases from non-small-cell lung cancer. Thus, erlotinib may be considered as a treatment option for this patient population.