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Sunvozertinib for patients in China with platinum-pretreated locally advanced or metastatic non-small-cell lung cancer and EGFR exon 20 insertion mutation (WU-KONG6): single-arm, open-label, multicentre, phase 2 trial.
Wang, M, Fan, Y, Sun, M, Wang, Y, Zhao, Y, Jin, B, Hu, Y, Han, Z, Song, X, Liu, A, et al
The Lancet. Respiratory medicine. 2024;(3):217-224
Abstract
BACKGROUND Sunvozertinib is an oral, irreversible, and selective tyrosine kinase inhibitor that has a favourable safety profile and encouraging antitumour activity, as shown in phase 1 studies of patients with heavily pretreated non-small cell lung cancer (NSCLC) with EGFR exon 20 insertion mutation (exon20ins). We aimed to assess the antitumour efficacy of sunvozertinib in patients with platinum-pretreated locally advanced or metastatic NSCLC with EGFR exon20ins. METHODS WU-KONG6 is a single-group, open-label, multicentre phase 2 trial of sunvozertinib monotherapy, conducted across 37 medical centres in China. We enrolled adult patients with pathologically or cytologically confirmed locally advanced or metastatic NSCLC whose tumour tissue carried an EGFR exon20ins mutation. All patients had received at least one line of previous systemic therapy, with at least one line containing platinum-based chemotherapy. The primary endpoint was objective response rate (ORR), as assessed by the independent review committee. The ORR was defined as the percentage of patients who achieved complete or partial response, confirmed by two separate assessments with at least 4-week time interval, until disease progression or initiation of any new anti-cancer therapy. Enrolled patients received sunvozertinib 300 mg once daily until meeting discontinuation criteria per the protocol. Patients who received at least one dose of treatment and were evaluable for efficacy analysis were included in the primary analysis, and all patients who received at least one dose of treatment were included in the safety analysis. This study is registered with ChinaDrugTrials.org, CTR20211009, and ClinicalTrials.gov, NCT05712902, and efficacy and safety follow-up are ongoing. FINDINGS Between July 19, 2021, and May 6, 2022, 104 patients were enrolled. At data cutoff (Oct 17, 2022), the last enrolled patient had been followed up for about 6 months. Among 97 patients evaluable for efficacy analysis, 59 (61%) patients achieved tumour response, with a confirmed ORR of 61% (95% CI 50-71). All tumour responses were partial responses. Tumour responses were observed irrespective of age, sex, smoking history, EGFR exon20ins subtypes, brain metastasis at baseline, previous lines of therapy, and history of onco-immunotherapy. In total, 19 death events occurred over a median follow-up period of 7·6 months (IQR 6·1-9·4). Sunvozertinib was well tolerated at 300 mg once daily. The most common grade 3 or worse treatment-related adverse events were blood creatine phosphokinase increased (18 [17%] of 104), diarrhoea (eight [8%]), and anaemia (six [6%]). The most common serious treatment-related adverse events were interstitial lung disease (five [5%] of 104), anaemia (three [3%]), vomiting (two [2%]), nausea (two [2%]) and pneumonia (two [2%]). INTERPRETATION In this phase 2 study, sunvozertinib demonstrated antitumour efficacy in patients with platinum-based chemotherapy pretreated NSCLC with EGFR exon20ins, with a manageable safety profile. A multinational randomised, phase 3 study of sunvozertinib versus platinum-doublet chemotherapy in EGFR exon20ins NSCLC is ongoing (NCT05668988). FUNDING Dizal Pharmaceutical.
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Safety, Efficacy, and Pharmacokinetics of Almonertinib (HS-10296) in Pretreated Patients With EGFR-Mutated Advanced NSCLC: A Multicenter, Open-label, Phase 1 Trial.
Yang, JC, Camidge, DR, Yang, CT, Zhou, J, Guo, R, Chiu, CH, Chang, GC, Shiah, HS, Chen, Y, Wang, CC, et al
Journal of thoracic oncology : official publication of the International Association for the Study of Lung Cancer. 2020;(12):1907-1918
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Abstract
INTRODUCTION Almonertinib (HS-10296) is a novel, third-generation EGFR tyrosine kinase inhibitor (EGFR TKI) that targets both EGFR-sensitizing and T790M resistance mutations. This first-in-human trial aimed to evaluate the safety, efficacy, and pharmacokinetics of almonertinib in patients with locally advanced or metastatic EGFR mutation-positive NSCLC that had progressed after pevious EGFR TKI therapy. METHODS This phase 1, open-label, multicenter clinical trial (NCT0298110) included dose-escalation (55, 110, 220, and 260 mg) and dose-expansion cohorts (55, 110, and 220 mg) with once daily oral administration of almonertinib. In each expansion cohort, tumor biopsies were obtained for the determination of EGFR T790M status. The safety, tolerability, antitumor activity, and pharmacokinetics of almonertinib were evaluated. RESULTS A total of 120 patients (26 patients in the dose-escalation cohort and 94 patients in the dose-expansion cohort) were enrolled. The maximum tolerated dose was not defined in the dose-escalation phase; the 260 mg regimen was not further evaluated in the dose-expansion phase owing to safety concerns and saturation of exposure. The most common treatment-related grade greater than or equal to 3 adverse events were increased blood creatine phosphokinase (10%) and increased alanine aminotransferase (3%). Among 94 patients with the EGFR T790M mutation in the dose-expansion cohort, the investigator-assessed objective response rate and disease control rate were 52% (95% confidence interval [CI]: 42-63) and 92% (95% CI: 84-96), respectively. Median progression-free survival was 11.0 months (95% CI: 9.5-not reached) months. CONCLUSIONS Almonertinib is safe, tolerable and effective for patients with locally advanced or metastatic NSCLC harboring the EGFR T790M mutation who were pretreated with EGFR TKIs.
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Fasting serum CGRP levels are related to calcium concentrations, but cannot be elevated by short-term calcium/vitamin D supplementation.
Hu, F, Chen, L, Che, H, Fang, J, Lv, F, Li, H, Zhang, S, Guo, C, Yin, H, Zhang, S, et al
Neuropeptides. 2015;:37-45
Abstract
Calcitonin gene-related peptide (CGRP) is an important cardioprotective neuropeptide. Few studies have shown that calcium supplementation may increase CGRP levels transiently. However, the relationship between CGRP and calcium is poorly known. This study was to explore the correlation between serum calcium and CGRP in coronary artery disease (CAD), and observe whether short-term calcium/vitamin D supplementation would increase fasting serum CGRP. A randomized, placebo-controlled and double-blind clinical trial, and a supplementary study for further analysis of the correlations were conducted. The results showed that the correlation between serum calcium and CGRP was positive in CAD without myocardial infarction (MI) (r = 0.487, P = 0.029), but negative in acute and healing MI (r = -0.382, P = 0.003). Moreover, we found a positive correlation between lg (amino-terminal pro-B-type natriuretic peptide, NT-proBNP) and CGRP (r = 0.312, P = 0.027), but a negative correlation between lg (NT-proBNP) and serum calcium (r = -0.316, P = 0.025) in acute and healing MI. As to the clinical trial, participants subjected to CAD but without evolving or acute MI, together with blood calcium ≤ 2.4 mmol/L, were randomized into three groups. Among the groups of placebo, caltrate (600 mg elemental calcium; 125 IU vitamin D3, per tablet) 1 tablet/d and caltrate 2 tablets/d, there were no significant differences in baseline characteristics. After short-term (5 days) treatments, the results indicated that the effect of grouping was not statistically significant (P = 0.915). In conclusion, the correlations between serum calcium and CGRP in different types of CAD are inconsistent, and the main reason may be associated with elevated natriuretic peptides after acute MI. Further, our study shows that short-term calcium/vitamin D supplementation cannot significantly increase fasting serum CGRP levels.
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A pilot observational study to assess the safety and efficacy of Menoprogen for the management of menopausal symptoms in Chinese women.
Liu, D, Lu, Y, Ma, H, Wei, RC, Li, J, Fang, J, Mahady, GB
Journal of alternative and complementary medicine (New York, N.Y.). 2009;(1):79-85
Abstract
OBJECTIVE Over the past 5 years, the interest in alternative therapies for menopause has increased dramatically due to the findings of the Women's Health Initiative (U.S. National Institutes of Health). Menoprogen, a traditional Chinese medicine formulation is an herbal remedy that has been used in China for the management of menopause-related symptoms. An observational pilot study was performed to assess the effects of Menoprogen in the management of menopausal symptoms in perimenopausal and postmenopausal women. DESIGN, SUBJECTS, AND SETTING A multicenter prospective study was conducted at four clinical centers in China. Female subjects were eligible if they had menopausal diagnosis for at least 3 months and wished to use an alternative to hormone replacement therapy (HRT). INTERVENTION Subjects received two capsules of Menoprogen (a combination product containing 0.2 g extracts of five herbs per capsule) orally, twice daily. MAIN OUTCOME MEASURES The primary outcome measured was an improvement of Kupperman Menopausal Index (KMI) from baseline. Secondary outcomes measured included hormone levels and the status of the endometrial and vaginal cytology after completion of treatment. RESULTS After treatment with Menoprogen, a significant reduction in the KMI was observed (mean of paired difference = -14.875; p < 0.01) as compared with baseline. Endogenous estrogen levels were significantly increased with Menoprogen (mean of paired difference = -3.145; p < 0.01). Progesterone levels increased with Menoprogen (mean of paired difference = -10.003; p < 0.01). Both follicle stimulating hormone (FSH) and luteinizing hormone (LH) levels showed significant before-and-after treatment difference (mean of paired difference = 6.125 mIU/mL for FSH and 4.938 mIU/mL for LH; p < 0.01). No significant endometrial hyperplasia was observed post-treatment with Menoprogen. Most of the postmenopausal women exhibited a vaginal cell proliferation degree of 2-3, suggesting a possible estrogenic effect. CONCLUSIONS The present pilot study found that Menoprogen reduced symptoms associated with perimenopausal and postmenopausal complaints. Therefore, the rationale for a randomized, placebo-controlled clinical trial is supported.
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All-trans retinoic acid/As2O3 combination yields a high quality remission and survival in newly diagnosed acute promyelocytic leukemia.
Shen, ZX, Shi, ZZ, Fang, J, Gu, BW, Li, JM, Zhu, YM, Shi, JY, Zheng, PZ, Yan, H, Liu, YF, et al
Proceedings of the National Academy of Sciences of the United States of America. 2004;(15):5328-35
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Abstract
Both all-trans retinoic acid (ATRA) and arsenic trioxide (As(2)O(3)) have proven to be very effective in obtaining high clinical complete remission (CR) rates in acute promyelocytic leukemia (APL), but they had not been used jointly in an integrated treatment protocol for remission induction or maintenance among newly diagnosed APL patients. In this study, 61 newly diagnosed APL subjects were randomized into three treatment groups, namely by ATRA, As(2)O(3), and the combination of the two drugs. CR was determined by hematological analysis, tumor burden was examined with real-time quantitative RT-PCR of the PML-RAR alpha (promyelocytic leukemia-retinoic acid receptor alpha) fusion transcripts, and side effects were evaluated by means of clinical examinations. Mechanisms possibly involved were also investigated with cellular and molecular biology methods. Although CR rates in three groups were all high (> or =90%), the time to achieve CR differed significantly, with that of the combination group being the shortest one. Earlier recovery of platelet count was also found in this group. The disease burden as reflected by fold change of PML-RAR alpha transcripts at CR decreased more significantly in combined therapy as compared with ATRA or As(2)O(3) mono-therapy (P < 0.01). This difference persisted after consolidation (P < 0.05). Importantly, all 20 cases in the combination group remained in CR whereas 7 of 37 cases treated with mono-therapy relapsed (P < 0.05) after a follow-up of 8-30 months (median: 18 months). Synergism of ATRA and As(2)O(3) on apoptosis and degradation of PML-RAR alpha oncoprotein might provide a plausible explanation for superior efficacy of combination therapy in clinic. In conclusion, the ATRA/As(2)O(3) combination for remission/maintenance therapy of APL brings much better results than either of the two drugs used alone in terms of the quality of CR and the status of the disease-free survival.
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[Effects of Salvia miltiorrhiza compound injection on serum endothelin, prostaglandin I2/thromboxane A2 ratio alteration following myocardial ischemia-reperfusion in patients undergoing intracardiac surgery].
Shi, X, Xia, Z, Fang, J
Zhongguo Zhong xi yi jie he za zhi Zhongguo Zhongxiyi jiehe zazhi = Chinese journal of integrated traditional and Western medicine. 2000;(12):896-8
Abstract
OBJECTIVE To investigate the effects of Salvia miltiorrhiza compound injection (SMCI) on serum endothelin (ET), prostaglandin I2(PGI2), thromboxane A2(TXA2), and PGI2/TXA2 ratio following myocardial ischemia-reperfusion in patients undergoing intracardiac surgery. METHODS Twenty patients, scheduled for selective surgery, were randomly divided into the SMCI group (group A, 10 cases) and the control group (group B, 10 cases). SMCI 200 mg/kg was given intravenously in group A before starting the operation and at the time of rewarming respectively, and equivalent volumes of normal saline were administered to group B. The central venous blood samples were collected to measure the serum concentration of ET, PGI2, TXA2, and PGI2/TXA2 ratio. RESULTS ET significantly reduced, while PGI2 and TXA2 obviously raised in both groups at the beginning (T1) of extracorporeal cardiopulmonary bypass (CPB) (P < 0.05). After cardiac ischemia-reperfusion, ET in group B increased rapidly and significantly (P < 0.05) and evidently higher than the corresponding value in group A 30 min after reperfusion (T3) till 24 hrs after reperfusion (T5). During reperfusion, PGI2 and TXA2 in group A decreased more rapidly than that of group B, while group A maintained higher PGI2/TXA2 ratio than that of group B. At T5, PGI2 and TXA2 in group A were significantly lower than those in group B, while PGI2/TXA2 ratio was higher than that in group B (P < 0.05). The serum ET level was obviously negatively correlated to PGI2/TXA2 ratio. The postoperative cardiac function recovered much better in group A than in that group B. CONCLUSION SMCI can significantly reduce serum ET level, raise PGI2/TXA2 ratio, thus facilitate the postoperative cardiac function recovery following intracardiac surgery under CPB.