miR-148b regulates radioresistance of lung cancer cells by modulating MLH1 expression level.
Background Apatinib, a highly selective VEGFR2 inhibitor, significantly improved efficacy versus placebo as a third- and later-line treatment for advanced gastric cancer in phase 2 and 3 trials. This prospective, single-arm, multicenter phase IV AHEAD study was conducted to verify the safety and efficacy of apatinib in patients with advanced or metastatic gastric or gastroesophageal adenocarcinoma after at least two lines of systematic therapy in clinical practice settings. Methods Patients with advanced gastric cancer who had previously failed at least two lines of chemotherapy received oral apatinib until disease progression, death or unacceptable toxicity. The primary endpoint was safety. The secondary endpoints included objective response rate (ORR), disease control rate (DCR), progression-free survival (PFS) and overall survival (OS). Adverse events were summarized by the incidence rate. Median OS and PFS were estimated using the Kaplan–Meier method. ORR, DCR, OS at 3 and 6 months, and PFS at 3 and 6 months were calculated, and their 95% CIs were estimated according to the Clopper-Pearson method. Results Between May 2015 and November 2019, a total of 2004 patients were enrolled, and 1999 patients who received at least one dose of apatinib were assessed for safety. In the safety population, 87.9% of patients experienced treatment-related adverse events (TRAEs), with the most common hypertension (45.2%), proteinuria (26.5%), and white blood cell count decreased (25.3%). Additionally, 51% of patients experienced grade ≥ 3 TRAEs. Fatal TRAEs occurred in 57 (2.9%) patients. No new safety concerns were reported. Among the 2004 patients included in the intention-to-treat population, the ORR was 4.4% (95% CI, 3.6–5.4%), and DCR was 35.8% (95% CI, 33.7–38.0%). The median PFS was 2.7 months (95% CI 2.2–2.8), and the median OS was 5.8 months (95% CI 5.4–6.1). Conclusions The findings in the AHEAD study confirmed the acceptable and manageable safety profile and clinical benefit of apatinib in patients with advanced gastric cancer as a third- or later-line of treatment. Trial registration This study was registered with ClinicalTrials.gov NCT02426034. Registration date was April 24, 2015.
In the present study, the IER3 expression was examined in tumor tissue from PHC patients to determine whether the IER3 expression is correlated with other clinicopathological parameters. Materials and Methods Sample selectionSixty-two pathologically conformed human HCC specimens without preoprative therapy, such as chemotherapy and radiotherapy, were collected at the pathology department of Zibo center hospital. All specimens were fixed in bufered 4% para formaldehyde, embedded in paraffin. The procedures were performed according to the national institutes of health guidelines regarding the use of human tissues and the study was approved from the review board of the ethics committee of Zibo center hospital. RNA isolation and cDNA conversionRNA was extracted from FFPE tissues using the Relia prep TM FFPE total RNA Miniprep system and based on the manufacturer's recommendation (Promega, 1002). Briefly, six shaving 10 μm thick from a paraffin block of tissue were deparaffinized by washing the tissue with xylene. Tissue was then digested in protease K and allowed to adhere to the RNA biding column.
35 Background: A fine balance between maintaining efficacy and reducing toxicity is necessary for drug therapies in many cancers. This study seeks to review the data from phase IV clinical trial of Ahead-G201 to help elucidate the optimal initial dose of apatinib in advanced gastric cancer. Methods: Pts data from the Ahead-G201 study at cut-off date of Jul 10, 2017 were extracted to explore the correlation of apatinib initial dose (500 mg vs 850 mg) with safety and clinical efficacy. Results: 864 of eligible pts received apatinib at an initial dose of 500 mg, and 58 pts received at 850 mg. Dose interruption occurred in 258 pts (33.1%) at 500 mg and in 27 pts (46.5%) at 850 mg. For safety, the most common adverse events (AEs) were proteinuria, hypertension and leukocyte decrease in both groups. Moreover, the incidence of all AEs and grade 3-4 AEs in pts at 500 mg was significantly lower than pts at 850 mg (Table). For efficacy, pts at 500 mg achieved an objective response rate (ORR) of 10.8% and a disease control rate (DCR) of 70.6%, at best response, which were 10.3% and 55.2% in pts at 850 mg. Pts at 500 mg got a significantly longer median progression-free survival (mPFS) and median overall survival (mOS) than pts at 850 mg (PFS, 4.6 mos vs 2.2 mos; OS, 6.8 mos vs 4.0 mos). Multivariate analysis indicated that apatinib treatment at an initial dose of 500 mg was significantly associated with longer mOS in advanced gastric cancer pts (6.8 mos vs 4.0 mos: hazard ratio, 0.5; 95%CI, 0.3 to 0.8), compared to initial dose of 850 mg. Conclusions: Compared to receiving apatinib at initial dose of 850mg, oral administration of apatinib starting from 500 mg seemed to bring more clinical benefit for patients with advanced gastric cancer, whilst with lower toxicities. Clinical trial information: NCT02426034. [Table: see text]
142 Background: Apatinib, a small molecule VEGFR TKI, has been approved in the treatment of advanced gastric cancer in China. Due to toxicity, many pts underwent temporary interruptions during treatment. We analyzed the data from a phase IV clinical trial of Ahead-G201 to evaluate the relationship between dose interruption, drug safety and efficacy. Methods: At the cutoff date of Jul 10, 2017, Ahead-G201 study enrolled 1037 pts. The adverse events (AEs) and clinical efficacy were evaluated for pts with no, 1, 2 and ≥3 dose interruptions. Results: 336 of 1037 pts underwent dose interruptions during apatinib treatment: 1 interruption in 183 pts; 2 interruptions in 67 pts; and ≥3 interruptions in 86 pts. The toxicity and efficacy for them were listed in Table. For safety, pts with no interruption had the lowest incidence of all AEs (59.3%) and grade 3-4 AEs (30.0%). Pts with ≥3 interruptions had the highest objective response rate (ORR, 20.3%) and disease control rate (DCR, 82.6%). Moreover, these pts got median progression-free survival (mPFS) of 6.6 mos and median overall survival (mOS) of 9.4 mos, which were the longest among 4 groups. Furthermore, multivariate analysis revealed that ≥3 interruptions of apatinib bring much more efficacy benefit both in mPFS (6.6 vs 3.8 mos: hazard ratio, 0.5, 95%CI, 0.3 to 0.7) and mOS (9.4 vs 6.6 mos: hazard ratio, 0.5, 95%CI, 0.3 to 0.8) for pts, than those with no interruption. Conclusions: Current results indicated that dose interruptions are required to manage toxicity and it is necessary to explore an optimal dosing pattern of apatinib in advanced gastric cancer. Clinical trial information: NCT02426034. [Table: see text]
126 Background: Old age is a potential negative predictor, and thus is of interest. Data from the ongoing post-marketing Phase IV trial were collected to assess the effect of age on apatinib treatment in 2000+ patients (pts) with chemotherapy-refractory advanced or metastatic gastric cancer. Methods: This subgroup analysis was stratified by age (<65 or ≥65 yrs). Both incidence of adverse events (AEs) and clinical outcomes were compared. Results: 725 pts <65 yrs and 312 pts ≥65 yrs were enrolled (data cut-off 2017/7/10). Differences in gender, ECOG PS, BMI, disease duration and metastatic sites were observed. 68.6% and 39.7% of pts aged ≥65 yrs experienced AEs of any grade and grade ≥3, which were not different with 70.2% and 40.0% of pts aged <65 yrs. The common AE profile was similar, but elderly pts had a higher incidence of hypertension, diarrhea and bilirubin increase (Table). Pts ≥65 yrs showed a higher objective response rate (12.2% vs. 9.9%) and longer overall survival (7.82 vs. 6.05 mos); however, there was no statistical difference. The disease control rate (79.6% vs. 65.4%; p=0.002) and progression free survival (PFS) (5.71 vs. 3.22 mos; p<0.001) of pts ≥65 yrs were significantly superior to pts <65 yrs. Multivariate Cox regression model confirmed that age ≥65 yr was a positive prognostic factor for PFS independent of baseline and treatment characteristics (HR: 0.67 [95%CI, 0.50–0.88]). Conclusions: Pts ≥65 yr is not at increased risk of overall AEs, but hypertension, diarrhea and bilirubin increase should be closely monitored. The PFS benefit in elderly pts will be validated. Clinical trial information: NCT02426034. [Table: see text]
19 Background: Easily detectable and reliable prognostic factors for apatinib response in gastric cancer are of great interest. In this study, 42 characteristics were test for their prognostic value. Methods: Data were collected from the ongoing single-arm phase IV trial in patents (pts) with advanced or metastatic adenocarcinoma of the stomach or gastroesophageal junction after failure of ≥2 lines of chemotherapy. Kaplan–Meier and multivariable Cox analysis were conducted. Results: As of 2017/7/10, 1037 pts were enrolled. 820 were evaluable for survival. The median progression free survival (PFS) and overall survival (OS) was 4.60 and 6.57 m. Age, metastatic lesions, region, treatment interruption, leucocyte decrease and adverse events (AEs) occurrence were independent prognostic factors for PFS, while ECOG PS, disease duration, metastatic lesions, region, developed city, initial dose, treatment interruption, BMI, AST abnormal, hand-foot-skin reaction (HFSR), leucocyte decrease and AE occurrence for OS (Table). Conclusions: Multiple demographics, baseline clinical and laboratory indexes, treatment related indicators and occurrence of AEs can predict the efficacy of apatinib in gastric cancer. Updated results will be reported to guide the clinical application of apatinib. Clinical trial information: NCT02426034. [Table: see text]
103 Background: The clinical benefit and safety profile of apatinib in advanced gastric cancer have been established in the randomised controlled phase III clinical trial (J Clin Oncol. 34(13):1448-54). A post-marketing study to confirm the safety and efficacy of apatinib is ongoing in a broad range of patients (pts). Methods: This is a single-arm, open-label, multi-center, Phase IV trial with the target sample size of 2000+ (ClinicalTrials.gov Identifier: NCT02426034). Pts were recruited to receive oral apatinib until disease progression, death or unacceptable toxicity. The primary objective was safety, and the secondary objectives included overall response rate (ORR), disease control rate (DCR), progression free survival (PFS) and overall survival (OS). Results: Herein, we report the preliminary data as documented in the EDC System. As of Jul 10, 2017, 1037 pts were enrolled from 138 hospitals across China. Pts characteristics were: median age 59 yrs, male/female 72.0/28.0%, ECOG PS 0/1/≥2 16.6/66.2/17.2%, stage IV 91.0%. 336 (32.4%) pts interrupted treatment and dose modification occurred in 172 (16.6%) pts (reduction 132/12.7%; rise 87/8.4%). Eventually, the mean dosage was 526.2 mg/d. 652 (62.9%) pts had 4407 drug-related adverse events (DRAEs). Grade ≥3 DRAEs occurred in 300 (28.9%) pts. Severe AEs were reported by 221 (21.3%) pts. The most common DRAEs were proteinuria (19.3%), hypertension (18.8%), leukocyte decrease (16.4%), fatigue (14.2%), platelet decrease (13.6%), hand-foot-skin reaction (11.1%) and neutrophil decrease (10.1%). 820 pts were evaluable for efficacy analysis. The best ORR and DCR were 10.7% and 70.0%, respectively. The median PFS and OS were 4.60 (95%CI, 3.25–4.73) and 6.57 (95%CI, 5.78–7.59) months, respectively. Conclusions: Apatinib monotherapy is effective and has a favorable toxicity profile in real-world clinical setting. The preliminary results of this Phase IV study confirmed the safety and efficacy of apatinib demonstrated in the Phase II and III trials. Updated results will be discussed. Clinical trial information: NCT02426034.
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