达拉非尼联合曲美替尼在黑色素瘤治疗中致皮肤系统不良反应的文献分析

目的：分析达拉非尼联合曲美替尼治疗黑色素瘤致皮肤系统不良反应（ADR）的发生情况及临床特点,为临床安全用药提供参考。方法：检索Web of Science、PubMed、知网和万方数据库,收集国内外相关个案报道并进行分析总结。结果：共筛选出有效文献31篇,共38例次,患者年龄主要为31～80岁（89.47%）;ADR多发生在用药后90 d内（60.52%）;主要临床表现为痤疮样皮疹（18.42%）、肉芽肿性皮炎（13.16%）、脂膜炎（10.53%）、纹身并发症（10.53%）及结节性红斑病变（10.53%）;34例患者皮肤ADR痊愈或好转,其中2例永久停用了达拉非尼与曲美替尼,10例继续联合治疗,12例暂停联合治疗,其中11例患者好转或痊愈后重启联合治疗。在重启或继续使用联合治疗的患者中,10例再次出现ADR。结论：本研究中,达拉非尼联合曲美替尼致皮肤系统ADR表现出不同的发生率和特征,且免疫治疗后进行靶向治疗可能增加严重皮肤ADR发生风险。临床在联合使用时应加强用药监测,及时发现ADR并采取适当的防治措施,同时严密监测重启或继续用药所致ADR,确保用药安全。     

维莫非尼联合安罗替尼致心肌梗死1例

<正>1 病例介绍患者,男,63岁。2021年7月1日,患者因“胸闷间歇发作5 d, 加重1 d余”由急诊收治入院。2017年11月因无明显诱因下出现咳嗽气喘伴胸闷,胸片提示右侧胸腔积液,右肺门旁可疑结节。行胸腔穿刺抽积液,胸腔积液基因检测：表皮生长因子受体未检测到突变。诊断为肺恶性肿瘤cT1N1M1IV期;表皮生长因子受体(野生型)。2017年12月—2018年2月给予贝伐珠单抗+紫杉醇+卡铂方案治疗,4周期。     

呋喹替尼与瑞戈非尼作为转移性结直肠癌三线治疗的成本-效用分析

目的:从我国医疗卫生系统角度出发,比较呋喹替尼和瑞戈非尼三线治疗转移性结直肠癌(mCRC)的成本-效用。方法:基于两项Ⅲ期临床试验和一篇已发表的网状Meta分析,运用Markov模型模拟疾病进展状况,对两个用药方案进行药物成本效用分析。并采用单因素敏感性分析和概率敏感性分析对结果的不确定性进行评价。结果:基础分析结果显示,呋喹替尼组的总成本为121 056.88元,效用值为0.60 QALYs(质量调整生命年);瑞戈非尼组的总成本为159 426.06元,效用值为0.57 QALYs,增量成本效用比为负值。单因素敏感性分析显示总生存期(OS)风险比为最大影响因素。概率敏感性分析显示,呋喹替尼为优势方案的比例为100%。结论:与瑞戈非尼相比,呋喹替尼三线治疗mCRC更具成本效用优势。     

基于FAERS数据库的甲磺酸达拉非尼联合曲美替尼致药品不良事件信号挖掘

目的：探讨甲磺酸达拉非尼联合曲美替尼上市后的药品不良事件信号,为临床安全用药提供参考。方法：利用OpenVigil 2.1-MedDRA平台,收集美国食品药品监督管理局不良事件报告系统(FAERS)数据库中有关甲磺酸达拉非尼与曲美替尼联合应用的不良事件数据,截至2022年第2季度。采用比例失衡算法分析不良事件信号,分析不良事件上报的人群特征以及频数较高和新发的不良事件信息。结果：共获取甲磺酸达拉非尼与曲美替尼联合应用的不良事件报告9 712例,涉及男性患者4 555例(占46.90%),女性患者3 921例(占40.37%);18～<65岁患者较多(2 503例,占25.77%);上报数据主要源于美国(4 287例,占44.14%);严重的不良事件主要包括死亡(2 100例,占21.62%)、导致住院或住院时间延长(1 889例,占19.45%)。发生频数较高的不良事件主要有恶性肿瘤转移,发热和皮肤毒性等;新发的不良事件主要有吞咽困难、惊厥和脂膜炎等。结论：临床联合应用甲磺酸达拉非尼与曲美替尼时,应对发生频数较高以及新发的不良事件予以重视。在使用药物治疗前、治疗中及随访阶段,均应...     

阿法替尼和吉非替尼一线治疗EGFR突变阳性非小细胞肺癌的成本效用分析

目的 从中国医疗保健支付者的角度,评价阿法替尼与吉非替尼在表皮生长因子受体（epidermal growth factor receptor,EGFR）突变阳性非小细胞肺癌一线治疗中的成本效用。方法 基于一项高质量、多中心的二期随机临床试验（LUNG7）,依据疾病发展进程建立三状态Markov模型（无进展生存状态、疾病进展状态、死亡状态）,模型各状态转移概率与不良反应发生率通过临床试验数据提取并计算,效用值取自研究文献中的中国人群效用值,直接医疗成本取自本地收费或相关文献。对总人群Markov模型进行为期10年的成本效用评估,并对模型分析结果的稳定性进行确定敏感性和概率敏感性分析。结果 在基础分析中,10年间阿法替尼组相对于吉非替尼组需多花费$16 499.77,但同时可多获得0.29个质量调整生命年（quality-adjusted life years,QALYs）,其增量成本效果比（incremental cost-effectiveness ratio,ICER）为$57 428.17/QALY。此时ICER值高于中国支付意愿阈值（willingness to pay,WTP）$26 331/QALY,表明阿法替尼目前相对于吉非替尼不具经济优势。一维敏感性分析结果显示疾病进展阶段的效用值、吉非替尼和阿法替尼的价格以及无进展生存期效用值对结果的稳定性影响较大,但除吉非替尼价格外,其他变量均不能使ICER值降至WTP之下,表明模型结果稳定。结论 对于中国EFGR突变阳性非小细胞肺癌患者,阿法替尼在一线治疗中相对于吉非替尼当前没有表现出经济性。     

奥希替尼一线治疗EGFR突变阳性的局部晚期或转移性非小细胞肺癌的成本-效用分析

目的:评价奥希替尼对比第1代表皮生长因子受体酪氨酸激酶抑制(EGFR-TKIs)一线治疗表皮生长因子受体(EGFR)编码基因突变阳性的局部晚期或转移性非小细胞肺癌(NSCLC)的经济性,为我国医疗卫生决策提供循证依据.方法:从卫生体系角度出发,利用FLAURA研究中的患者生存数据和已发表的文献数据建立马尔科夫模型,模拟...     

达可替尼对比吉非替尼一线治疗表皮生长因子受体突变晚期非小细胞肺癌的成本-效果分析

目的:从我国卫生体系的角度出发,在新版医保目录实施的背景下,评估降价后的达可替尼对比吉非替尼一线治疗EGFR突变的NSCLC的经济性。方法:基于一项三期临床试验的数据构建Markov模型,以增量成本-效果比(ICER)为指标评价达可替尼对比吉非替尼的经济性,并对结果进行敏感性分析。结果:模型运行结果显示,达可替尼相比吉非替尼的ICER为12 976 3.86元/QALY,小于3倍的我国人均GDP,达可替尼具有成本-效果优势。敏感性分析结果显示,无进展状态的效用值和达可替尼的成本对结果的影响最大;在WTP为3倍的我国人均GDP时,达可替尼具有成本-效果优势的概率为83.04%。结论:加入医保目录降价后的达可替尼对比吉非替尼一线治疗EGFR突变的NSCLC更具有经济性。     

大剂量伊马替尼、达沙替尼和尼洛替尼治疗慢性髓性白血病的成本效用分析

目的：分析大剂量伊马替尼、达沙替尼和尼洛替尼治疗对标准剂量伊马替尼耐药的慢性髓性白血病患者的成本效用。方法：计算三种治疗方案下患者的效用和花费的成本,在马尔可夫模型（Markov）中以3个月为周期进行5年的模拟并对结果做成本效用比较。结果：尼洛替尼治疗方案累计成本为1 595 289.10元,健康效用为1.276 4质量调整生命年（QALYs）,相比于尼洛替尼,大剂量伊马替尼组的增量成本效用比（ICUR）为-22 759 433.08（￥/QALYs）,达沙替尼组为-30 960 469.51（￥/QALYs）。结论：尼洛替尼方案累计成本最低且获得最多的QALYs,为绝对优势方案。     

奥希替尼和吉非替尼/厄洛替尼一线治疗EGFR突变阳性非小细胞肺癌的成本-效果分析

目的从中国医疗保健支付者的角度,评价奥希替尼和吉非替尼/厄洛替尼在表皮生长因子受体(EGFR)突变阳性非小细胞肺癌一线治疗中的成本-效果。方法基于一项高质量、多中心的三期随机临床试验(FLAURA),依据疾病发展进程建立三状态Markov模型,模型各状态转移概率与不良反应发生率通过临床试验数据提取并计算,效用值取自研究文献中的中国人群效用值,直接医疗成本取自本地收费或相关文献。对总人群、中枢神经系统(CNS)转移患者进行为期10年的成本-效果评估,并对模型分析结果的稳定性进行确定敏感性和概率敏感性分析。结果在基础分析中,奥希替尼组相对吉非替尼/厄洛替尼组可多获得0.41个质量调整生命年(QALYs)。奥希替尼方案和吉非替尼/厄洛替尼方案在总人群及CNS转移亚组人群的增量成本效果比(ICER)分别为340 645.44元/QALY、246 175.55元/QALY。两组人群的ICER值均高于中国支付意愿阈值198 018.0元/QALY,表明奥希替尼相对吉非替尼/厄洛替尼经济性不足。敏感性分析结果显示药品价格、疾病进展阶段的效用值以及进展后治疗成本对结果的稳定性影响较大。结论奥希替尼能延...     

Future of combination therapy with dabrafenib and trametinib in metastatic melanoma

Introduction: Combination therapy with BRAF and MEK inhibitors is a recommended treatment strategy for metastatic melanoma patients with BRAF^V600 mutations. This treatment provides significant response rates and little added toxicity, with relatively improved survival outcomes compared to RAF/MEK inhibitor monotherapy and chemotherapy.

Areas covered: This review covers the pharmacology, efficacy, and toxicity data derived from clinical studies of dabrafenib, trametinib, and the combination thereof. The major downfall of combiDT is the limited durability of response, which is largely due to acquired resistance in the MAPK pathway.

Expert opinion: Future directions of combiDT concentrate on further combinations with immunotherapy or other targeted inhibitors, referred to triple-agent therapy, which may be essential to improving durability of responses and overcoming resistance.     

The safety and efficacy of dabrafenib and trametinib for the treatment of melanoma

Introduction: The introduction of BRAF and MEK inhibitors into clinical practice improved the prognosis of metastatic melanoma patients. The combination of BRAF inhibitor dabrafenib with MEK inhibitor trametinib has shown its superiority to single agent therapy and is characterized by a tolerable spectrum of adverse events which shows a decrease in incidence over time on treatment.

Areas covered: The current scientific literature on safety and adverse events (AEs) related to BRAF and MEK-inhibition has been investigated with special focus on the large phase 3 studies (COMBI-v, COMBI-d and CoBRIM) as well as recent updates presented at oncology and melanoma meetings. Additionally, published case series/case reports were screened for information on AEs.

Expert opinion: Even though almost every patient (98%) under combination therapy with dabrafenib and trametinib experiences at least one adverse event, these are generally mild to moderate, reversible and can be managed with dose reductions or interruptions. However, due to an increased life expectancy, there is a substantial need to prevent and treat also mild adverse events, as they play a central role for the quality of life of patients. Ongoing clinical trials will have to demonstrate the efficacy as well as safety of triple combination with anti-PD-1/anti-PD-L1 antibodies.     

BRAF and MEK inhibition for the treatment of advanced BRAF mutant melanoma

Introduction: BRAF inhibition alone has achieved unprecedented efficacy results in patients affected by BRAF-mutated advanced melanoma. Since these findings, it was postulated that dual inhibition of BRAF and other components of the RAS/RAF/MEK/ERK MAPK pathway (such as MEK) would be superior to BRAF inhibition as monotherapy. A series of recent clinical trials have confirmed this hypothesis.

Areas covered: In this article, the biological rationale for both single and concomitant inhibitions of the MAPK pathway in BRAF mutant melanoma is provided. Moreover, available clinical data on the efficacy and toxicity of BRAF and MEK inhibition as single agents and in combination are extensively reviewed.

Expert opinion: Dual BRAF and MEK inhibition in advanced BRAF-mutated melanoma is superior to single inhibition in terms of efficacy without significant increase in toxicity. Therefore, BRAF plus MEK inhibition is expected to supersede single-agent BRAF inhibition in these patients in the near future.     

Combination dabrafenib and trametinib in the management of advanced melanoma with BRAFV600 mutations

Introduction: In the 40–50% of advanced melanoma patients with tumors harboring BRAF V600E and V600 K mutations, BRAF inhibitors such as dabrafenib are a highly effective treatment. However, most patients develop resistance after several months on treatment. The addition of a MEK inhibitor, such as trametinib, to BRAF inhibition mitigates one key pathway of resistance, further increasing response rates and improving survival.

Areas covered: This article summarizes the mechanism of action of the combination of dabrafenib and trametinib, its evolution through Phase I, II and III clinical trials and discusses its current use in the management of patients with advanced melanoma.

Expert opinion: Combination therapy with dabrafenib and trametinib improves response rate, progression-free survival and overall survival when compared to dabrafenib or vemurafenib alone. The addition of trametinib to dabrafenib changes the adverse event profile, making hyperkeratosis and cutaneous squamous cell carcinomas less common but side effects such as fever and nausea more common. How dabrafenib/trametinib is best sequenced with other effective treatments such as immune checkpoint blockade remains uncertain.     

Dabrafenib for the treatment of BRAF V600-positive melanoma: a safety evaluation

Introduction: V-raf murine sarcoma viral oncogene homolog B1 (BRAF) inhibitors are emerging as the standard of care for treating advanced melanomas harboring the BRAF V600 oncogenic mutation. Dabrafenib is the second approved selective BRAF inhibitor (after vemurafenib) for the treatment of unresectable or metastatic BRAF V600-positive melanoma.

Areas covered: This review covers the current data on the efficacy and safety of the selective BRAF inhibitor dabrafenib in patients with metastatic BRAF V600 positive melanoma. The pharmacological, safety and efficacy data are discussed from Phase I, II, and III studies of dabrafenib monotherapy as well as in combination with the MEK inhibitor trametinib.

Expert opinion: Dabrafenib has demonstrated comparable efficacy to vemurafenib in BRAF V600E mutant melanoma patients. Dabrafenib is well tolerated in patients with metastatic melanoma, including patients with brain metastases. Nevertheless side effects are common, but usually manageable. In the Phase III study testing dabrafenib, 53% of patients reported grade 2 or higher adverse events (AEs). Toxicities were similar to those seen in the early-phase trials, with the most common being cutaneous manifestations (hyperkeratosis, papillomas, palmar-plantar erythrodysesthesia), pyrexia, fatigue, headache, and arthralgia. Combining a BRAF inhibitor with a MEK inhibitor, which may block paradoxical MAPK activation in BRAF wild type (skin) cells, may lower the incidence of squamoproliferative eruptions.     

BRAF and MEK inhibition in melanoma

Introduction: Selective inhibition of the MAPK pathway with either BRAF or MEK inhibition has emerged as a key component for the treatment of BRAF-mutant metastatic melanoma. New evidence suggests that the combination of BRAF and MEK inhibitors improves tumor response rate and progression-free survival, while potentially attenuating some of the serious adverse events observed with monotherapy.

Areas covered: This review covers the current data on the efficacy and safety of the selective BRAF (vemurafenib and dabrafenib) and MEK (trametinib) inhibitors as well as the available data on BRAF inhibitor + MEK inhibitor combination therapy (dabrafenib + trametinib and vemurafenib + cobimetinib). The efficacy, safety and toxicity data are discussed from Phase I, Phase II and Phase III trials of these drugs.

Expert opinion: Combination therapy with the BRAF and MEK inhibitors improves response rates and progression-free survival in patients with BRAF-mutant metastatic melanoma. Some of the serious adverse events, in particular, the incidence of cutaneous squamous cell carcinoma, are attenuated with combination therapy, whereas milder side effects such as pyrexia can be more common with combination therapy. Although dose reductions and dose interruptions are slightly more common with combination therapy, overall data supports the notion that combination therapy is safe and improves the outcomes for patients compared to single agent BRAF inhibitors.     

Update on BRAF and MEK inhibition for treatment of melanoma in metastatic,unresectable, and adjuvant settings

Introduction: Selective inhibition of the MAPK pathway with BRAF and MEK inhibitors has emerged as a key component of the treatment of BRAF-mutant unresectable/locally advanced metastatic melanoma.

Areas covered: Current data are presented on the efficacy and safety of BRAFi + MEKi combination therapy (dabrafenib/trametinib, vemurafenib/cobimetinib, and encorafenib/binimetinib) from phase I, II, and III trials in the unresectable/locally advanced metastatic setting, as well as neoadjuvant and adjuvant applications. The theoretical basis, pre-clinical findings, clinical trial results and current ongoing clinical studies of combined BRAF/MEK inhibition with immunotherapy, also known as ‘triplet therapy,’ are also explored.

Expert opinion: Combination therapy with BRAF and MEK inhibitors dramatically improves response rates, progression-free survival and overall survival in patients with BRAF-mutant metastatic melanoma compared to historical treatments such as chemotherapy. Some serious adverse effects, including cutaneous squamous cell carcinoma, are attenuated with combination therapy, while less severe and reversible effects including pyrexia, left ventricular dysfunction, and ocular events can be more common with combination therapy. Existing data are insufficient to recommend triplet therapy, or a particular treatment sequence, with respect to BRAF and MEK inhibitors and immune therapies, though results from multiple ongoing trials are anticipated.     

The discovery of vemurafenib for the treatment of BRAF-mutated metastatic melanoma

ABSTRACT

Introduction: In the era of precision medicine and sophisticated modern genetics, the discovery of the BRAF^V600 inhibitor, vemurafenib, quickly became the model for targeted therapy in melanomas. As early as 2002, the majority of metastatic melanomas were described to harbor the BRAF^V600 mutation, setting the stage for an explosion of interest for targeting this protein as a novel therapeutic strategy. The highly selective BRAF^V600 inhibitor, vemurafenib, was identified initially through a large-scale drug screen.

Areas covered: Here we examine vemurafenib’s journey from discovery to clinical use in metastatic melanoma. Topics covered include preclinical data, single agent Phase 1,2 and 3 clinical trials, resistance issues and mechanisms, adverse effects including the development of squamous cell cancers, and combination trials.

Expert opinion: Due to its tolerance, low toxicity profile, rapid tumor response, and improved outcomes in melanoma patients with BRAF^V600 mutations, vemurafenib was advanced rapidly through clinical trials to receive FDA approval in 2011. While its efficacy is well documented, durability has become an issue for most patients who experience therapeutic resistance in approximately 6–8 months. In addition, a concerning toxicity observed in patients taking the drug include development of localized cutaneous squamous cell carcinomas (SCCs). It is hypothesized that drug resistance and SCC development result from a similar paradoxical activation of protein signaling pathways, specifically MAPK. Identification of these mechanisms has led to additional treatment strategies involving new combination therapies.     

MicroRNA expression in BRAF-mutated and wild-type metastatic melanoma and its correlation with response duration to BRAF inhibitors

Objective: Currently, the treatment of BRAF V600-mutated metastatic melanoma with BRAF inhibitors gives a response rate of ～ 50% with a progression-free survival of ～ 6 – 7 months. In order to identify predictive biomarkers capable of stratifying BRAF-mutated patients at high risk of shorter response duration to anti-BRAF therapy, the authors analyzed the expression of 15 microRNAs (miRNAs) targeting crucial genes involved in melanoma biology and drug response.

Research design and methods: A total of 15 miRNAs and target gene expression were investigated in 43 patients (30 BRAF-mutated, and 13 BRAF wild-type). Moreover, 20 BRAF-mutated patients treated with vemurafenib were analyzed for miRNA expression in respect to time-to-progression.

Results: All miRNAs except miR-192 showed low expression in BRAF-mutated as compared with BRAF wild-type patients. In particular, miR-101, miR-221, miR-21, miR-338-3p and miR-191 resulted in significant downregulation in BRAF-mutated patients. Moreover, high expression of miR-192 and miR-193b* and low expression of miR-132 resulted in significant association with shorter progression.

Conclusion: Three miRNAs were significantly associated with clinical outcome in metastatic melanoma patients. An increased understanding of the molecular assessment of BRAF-mutated melanomas could allow development of specific molecular tests able to predict response duration.     

Cobimetinib and vemurafenib for the treatment of melanoma

Introduction: Cobimetinib combined with vemurafenib is a new approved MEK inhibitor for first line treatment of metastatic melanoma patients with BRAF V600 mutations. It improves tumor response rates and progression free survival compared to vemurafenib alone, while decreasing toxicities due to the paradoxical activation of the MAPK signaling pathway.

Areas covered: This review covers the pharmacology, efficacy, and toxicity data derived from clinical and preclinical studies on cobimetinib. It also reports ongoing trials evaluating cobimetinib to better understand future developments for this drug.

Expert opinion: The combination of cobimetinib and vemurafenib seems to be more toxic than the combination therapy dabrafenib and trametinib even if these four drugs have never been compared in a randomized trial. The future of this combination depends on its capacity to be combined simultaneously or sequentially with immune based therapies to improve the durability of responses.