Safety of pembrolizumab for the treatment of melanoma

Introduction: The immune checkpoint inhibitor pembrolizumab is the first anti-programmed-death-1 (PD-1) drug licensed by the FDA. It has been approved for the treatment of advanced melanoma, thanks to its positive results in terms of efficacy and its favorable toxicity profile. However, it is not exempt from side effects. In general, these are usually mild and easily manageable but there are pembrolizumab-induced immune-related adverse events (irAEs) that can be severe. Therefore, the understanding, diagnosis and management of those side effects are essential for the optimal care of patients treated with pembrolizumab.

Areas covered: In this article, the safety and efficacy of pembrolizumab in melanoma are extensively reviewed as well as its mechanism of action and the role of the PD-1 pathway in cancer. Also, its profile of side effects is compared with other immune checkpoint inhibitors such as ipilimumab and nivolumab.

Expert opinion: Pembrolizumab is generally a well-tolerated drug but irAEs are not infrequent. However, these are usually mild and easily manageable in most cases. Early diagnosis and correct management of side effects induced by immune checkpoint inhibitors such as pembrolizumab should be areas of further work in forthcoming years.     

Safety evaluation of pembrolizumab for treating recurrent head and neck squamous cell carcinoma

ABSTRACT

Introduction

Programmed death 1 (PD-1) blockade has changed the therapeutic landscape of recurrent or metastatic head and neck squamous cell carcinoma (R/M HNSCC) with convincing overall response rates and overall survival benefits when compared to chemotherapy alone. The toxicity profile of pembrolizumab appears to be similar to that of other PD-1 or PD-L1 inhibitors, with frequent diarrhea, hypothyroidism or cutaneous rash cases, and rare cases of grade 3 to 5 pneumonitis.     

The safety and efficacy of pembrolizumab for the treatment of non-small cell lung cancer

ABSTRACT

Introduction: Lung cancer is the leading cancer-related cause of death worldwide. The introduction of immune checkpoint inhibitors (ICIs) for the treatment of lung cancer has significantly improved the outcome of these patients. Pembrolizumab, a monoclonal IgG4-kappa antibody against programmed-death-1 (PD-1) protein, nowadays represents a standard of care for NSCLC patients. Although it has a favorable toxicity profile, some immune-related adverse events (irAEs) can be life-threatening, therefore its knowledge may help to optimize the care of these patients.

Areas covered: The authors review data regarding the efficacy and safety of pembrolizumab from the most relevant clinical trials as well as toxicities reported in the clinical use. Special considerations of use in special populations will be noted. Finally, its toxicity profile will be compared with other ICIs used in NSCLC.

Expert opinion: In the scenario of NSCLC, pembrolizumab shows a favorable safety profile with less than 10% serious immune-related adverse events (irAEs) when used in monotherapy and without adding relevant extra-toxicity to chemotherapy when used in combination. Monotherapy with pembrolizumab is associated with better health-related quality of life than chemotherapy. Early recognition and appropriate treatment of irAEs is of prime importance as most are reversible if correctly managed. Rechallenge with pembrolizumab is frequently feasible.     

Pembrolizumab for the treatment of melanoma

The immune system plays a vital role in regulating tumor growth, and the oncology community has witnessed an exciting resurgence in clinical research to develop effective immunotherapeutic strategies. The utility of these strategies in advanced melanoma has been at the forefront of these developments. In particular, blockade of programmed cell death protein 1 (PD-1) in advanced melanoma has proven to be a most promising new anticancer strategy. Pembrolizumab is a humanized IgG4 anti-PD-1 antibody that exerts its anti-tumor effect through blocking the interaction of the immune inhibitory molecule PD-1 with its ligands. Its effect has been most convincingly demonstrated in the setting of advanced melanoma, with growing evidence of clinical responses across a broad spectrum of other solid and hematological malignancies.     

抗PD-1治疗贲门癌诱发的1例糖尿病酮症的用药分析

报道1例使用ICI治疗晚期贲门癌后出现1型糖尿病(T1DM)的病例.患者为72岁男性,因贲门癌接受抗程序性死亡蛋白1(PD-1)治疗,用药治疗9周后出现口渴、多饮、多尿、乏力、纳差,4周后进展为糖尿病酮症,血糖升高至40.3 mmol·L-1,HbA1C9.4％,空腹及75 g糖负荷后血清C肽均<0.1 ng·mL-1...     

PD-1抑制剂治疗恶性黑色素瘤:系统评价再评价

目的:再评价已发表PD-1抑制剂治疗恶性黑色素瘤的系统评价的方法学质量和证据质量.方法:计算机检索TheCochrane Library、PubMed、EMbase、Web of Science、CNKI(知网)、VIP(维普)及WanFang Data(万方)等数据库,纳入迄今所有基于随机对照试验的PD-1抑制剂治疗...     

免疫检查点抑制剂在晚期黑色素瘤应用中的免疫相关不良反应研究进展

免疫检查点抑制剂自出现以来,在临床上应用越来越广泛,但随着适用范围的扩大和使用时间的延长,其导致的免疫相关不良反应也越来越突出。严重的免疫相关不良反应可以影响患者的生存质量,因此,临床工作中必须对这些不良反应予以重视。本文综合了不同的临床试验结果,对免疫检查点抑制剂在治疗晚期黑色素瘤中发生的免疫相关不良反应进行了总结。     

An update on the pharmacodynamics,pharmacokinetics, safety and clinical efficacy of nivolumab in the treatment of solid cancers

Introduction: Nivolumab is a programmed cell death 1 (PD-1) inhibitor that has been approved for treatment of advanced melanoma, non-small cell lung carcinoma, renal cell carcinoma and classical Hodgkin’s lymphoma.

Areas covered: This review summarizes the latest evidence on nivolumab’s pharmacodynamics, pharmacokinetics, safety and clinical efficacy in different solid tumors, based on published studies and abstracts from international conferences.

Expert opinion: Multiple high-level evidence has confirmed the efficacy and safety of nivolumab in solid tumors. Further studies should focus on the identification of potential predictive biomarkers and possibility of combining with other immunotherapeutic or cytotoxic agents. The optimal sequence, treatment duration and possibility of re-challenging patients who had prior nivolumab are yet to be defined.     

Cost-effectiveness of pembrolizumab in combination with chemotherapy versus chemotherapy and pembrolizumab monotherapy in the first-line treatment of squamous non-small-cell lung cancer in the US

Objective: To describe the cost-effectiveness of pembrolizumab plus chemotherapy (carboplatin and paclitaxel or nab-paclitaxel; P?+?C) in metastatic, squamous, non-small-cell lung cancer (NSCLC) patients in the US.

Methods: A model comparing P?+?C versus C alone is developed utilizing partitioned survival analysis. Primary clinical efficacy, treatment utilization, health utility and safety data are derived from the KEYNOTE-407 trial and projected over 20?years. Costs for drugs and non-drug disease management are also incorporated. Additionally, the cost-effectiveness of P?+?C vs. pembrolizumab monotherapy (P) is evaluated via an indirect treatment comparison, for patient subgroups with PD-L1 Tumor Proportion Score (TPS)?≥?50% and 1–49%.

Results: Overall, P?+?C is projected to increase life expectancy by 1.95?years vs. C (3.86 versus 1.91). The resultant ICER is $86,293/QALY. In patients with PD-L1?≥?50%, 1–49% and <1 the corresponding incremental cost-effectiveness ratios (ICERs) are $99,777/QALY, $85,986/QALY and $87,507/QALY, respectively. Versus P, in the PD-L1?≥?50% subgroup, P?+?C appears cost saving; however, this result should be interpreted with caution as there is considerable uncertainty in the relative efficacy of these comparators.

Conclusions: Across all eligible patients, the addition of pembrolizumab to chemotherapy is projected to approximately double life expectancy, yielding an extension to a point not previously seen in metastatic squamous NSCLC. Overall, and within all relevant PD-L1 subgroups, use of P?+?C yields an ICER below $100,000/QALY, and can be a cost-effective first-line treatment for eligible metastatic squamous NSCLC patients for whom chemotherapy is currently administered. In the PD-L1?≥?50% subgroup, additional follow-up within trials of pembrolizumab plus chemotherapy and pembrolizumab monotherapy are needed to better define cost-effectiveness between these comparators.     

Targeting the PD-1 pathway: a new hope for gastrointestinal cancers

Background: VEGF, HER2 and EGFR targeted agents are currently used in gastric, esophageal and colorectal cancers. However, treatment outcomes are still poor in most gastrointestinal (GI) cancers. Immune checkpoints are one of the most promising immunotherapy approaches. In this review article, we aim to discuss the efficacy and safety of anti-PD-1/PD-L1 therapies in GI cancers, including gastric, esophageal and colorectal cancer in published or reported recent studies.

Scope: A literature search was made from PubMed and ASCO Annual Meeting abstracts by using the following search keywords: “nivolumab”, “pembrolizumab”, “avelumab”, “GI cancers” “anti-PD1 therapy” and “anti-PD-L1 therapy”. The last search was on 2 November 2016. The most important limitation of our review is that most of the data on anti-PD-1/PD-L1 therapies in GI cancers relies on phase 1 and 2 trials.

Findings: Currently, there are two anti-PD-1 (nivolumab and pembrolizumab) and one anti-PDL1 (atezolizumab) agents approved by FDA. After the treatment efficacy of immune checkpoint blockade was shown in melanoma, renal cell cancer and non-squamous lung cancer, trials which evaluate immune checkpoint blockade in GI cancers are ongoing. Early results of trials have been promising and encouraging for patients with advanced stage gastroesophageal cancer. According to early results of published trials, response to anti-PD1/PD-L1 agents appears to be associated with tumor PD-L1 levels. According to two recently published phase 2 trials, the clinical benefits of immune checkpoint blockade with both nivolumab and pembrolizumab were limited in patients with microsatellite instability (MSI) positive advanced colorectal cancer. However, several phase 2/3 trials are still ongoing.

Conclusion: Both pembrolizumab and nivolumab show promising efficacy with acceptable safety data in published trials in GI cancers, especially in refractory MSI positive metastatic colorectal cancer.     

PD-1免疫检查点抑制剂在口腔鳞状细胞癌治疗中的研究进展

以靶向免疫检查点为基础的免疫治疗在各种恶性肿瘤的治疗中取得了令人瞩目的疗效,其中,程序性细胞死亡蛋白1(PD-1)抗体开启了铂类耐药复发转移口腔鳞状细胞癌(OSCC)免疫治疗的新时代。研究显示PD-1免疫检查点抑制剂可显著延长OSCC患者的总生存期,且Ⅲ-Ⅳ级药物相关不良反应总发生率较低,但在临床实际应用中仍面临一系列挑战。本文将简要介绍PD-1抑制剂在OSCC临床治疗中的发展概况。     

帕博利珠单抗致肺腺癌患者肾小管间质损伤

1例67岁女性肺腺癌淋巴结转移患者同时接受化疗、免疫和靶向治疗(顺铂、培美曲塞、帕博利珠单抗及仑伐替尼)。第3个周期结束后, 患者血压升高(160/100 mmHg, 1 mmHg=0.133 kPa), 血清肌酐升高(由90 μmol/L升至160 μmol/L), 贫血(血红蛋白90 g/L), 代谢性酸中毒(二氧化碳总量18 mmol/L)。肾脏组织病理检查提示肾小管间质损伤。排除其他药物导致的肾损伤, 考虑为帕博利珠单抗所致免疫不良反应可能性大。停用该药并予激素、降压及对症治疗。5个月后, 患者血压110～120/70～80 mmHg, 血清肌酐降至130 μmol/L, 血红蛋白117 g/L, 二氧化碳总量26 mmol/L。     

帕博利珠单抗致免疫相关性肺炎和心肌炎1例

近年来免疫治疗已成为肿瘤治疗的热点,程序性死亡受体/配体1(PD-1/PD-L1)抑制剂由于其独特的疗效,已成为当今广泛关注的肿瘤治疗新方法[1]。PD-1与肿瘤细胞和抗原提呈细胞上的配体PD-L1或PD-L2结合后,引起信号级联反应,抑制免疫细胞的增殖与活化,从而达到免疫耐受的效果。而PD-1/PD-L1抑制剂就是通过阻断PD-1与PD-L1的结合,使T细胞恢复活性,增强细胞免疫,从而杀伤肿瘤细胞。其中作用于PD-1受体的单抗主要有帕博利珠单抗(pembrolizumab)、纳武利尤单抗(nivolumab)等,目前可用于多种实体瘤的治疗。     

激素预处理对非小细胞肺癌患者免疫检查点抑制剂疗效和安全性影响的网状Meta分析

目的：采用网状Meta分析的方法对非小细胞肺癌患者激素预处理下免疫检查点抑制剂疗效和安全性进行评价。方法：检索PubMed、EMbase、Cocharane、万方、维普、中国知网、中国生物医学文献数据库关于免疫检查点抑制剂联合紫杉醇对比联合白蛋白结合型紫杉醇治疗非小细胞肺癌的大型多中心随机对照试验（RCT）,检索时间为建库至2019年6月。以Stata13.0软件、R-3.6.1软件、WinBUGS软件进行网状Meta分析。结果：最终纳入8项RCT,4项干预措施（免疫检查点抑制剂+铂类+白蛋白结合型紫杉醇,免疫检查点抑制剂+铂类+普通紫杉醇,铂类+白蛋白结合型紫杉醇,铂类+普通紫杉醇）,包含4 005例患者。分析结果显示,在总生存期[HR=0.88,95%CI（0.67,1.17）]及无进展生存期[HR=0.87,95%CI（0.57,1.32）]方面,免疫检查点抑制剂联合铂类+白蛋白结合型紫杉醇与免疫检查点抑制剂联合铂类+紫杉醇相比,差异无统计学意义;在安全性方面,3级及以上不良反应率激素预处理组与未处理组差异无统计学意义。结论：激素预处理对免疫检查点抑制剂的疗效以及安全性无影响,需纳入直接比较研究进一步验证。     

帕博利珠单抗单药与化疗二线治疗晚期或转移性食管癌的成本-效果分析

目的:从我国卫生服务体系角度出发,评价帕博利珠单抗单药与化疗二线治疗晚期或转移性食管癌的经济性,为临床用药及相关卫生决策提供参考.方法:建立无进展生存、疾病进展和死亡3种健康状态的分区生存模型,以3周为模型周期,模拟患者终身,利用KEYNOTE-181临床试验数据和已发表的文献数据计算增量成本-效果比(ICER),并对...     

The safety of nivolumab for the treatment of metastatic melanoma

Introduction: Nivolumab, a human IgG4 monoclonal antibody directed against PD-1, is a checkpoint inhibitor that is licenced in the treatment of metastatic melanoma either as a monotherapy or in combination with ipilimumab, a CTLA-4 inhibitor. The introduction of immune checkpoint inhibitors to the therapeutic landscape has dramatically altered outcomes in a proportion of patients with metastatic melanoma. Immune checkpoint inhibitors result in a toxicity profile that is distinct from that of chemotherapy or targeted therapy based on their immunomodulatory mechanism and similarly can result in patterns of response that are unique.

Areas covered: Herein we will profile nivolumab’s efficacy and safety both as a combination therapy and a monotherapy and discuss the results of relevant clinical trials in this respect.

Expert opinion: The future of immunotherapy in melanoma will evolve around the development of biomarkers, the refinement of criteria to define patterns of response and toxicity and the combination of current immunotherapies with existing and novel agents to maximise responses.     

Pembrolizumab for melanoma- safety profile and future trends

Background: Pregnant women who continue to smoke expose their developing fetus to a wide range of risks. Assisting these patients to stop smoking can be an important intervention for the health of the baby and the mother. The management of pregnant smokers can be challenging, due to the potential risks of pharmacotherapy. There are a number of options available to the clinician to aid smoking cessation in non pregnant women. These include nicotine replacement therapy (NRT), bupropion, varenicline, and a range of non-drug therapies. Objective: To provide guidance to prescribers on the best way to manage smoking cessation in the pregnant patient, reviewing the risks and efficacy of the different approaches. Methods: An extensive literature search was carried out to find original studies which examined issues surrounding the safety and efficacy of methods of smoking cessation in pregnancy. Results/conclusion: NRT is the agent of choice for smoking cessation in pregnancy as the safety of other therapies in pregnancy have not yet been proved.     

信迪利单抗治疗胸腺瘤引发免疫性心肌炎1例

目的 探讨信迪利单抗用于胸腺瘤致免疫性心肌炎的发生机制和药学监护方法.方法 报道2019年9月20日武汉大学人民医院1例信迪利单抗用于胸腺瘤致免疫性心肌炎的病例,并进行相关文献分析.结果 病人使用信迪利单抗两周后出现喘气、心慌,心脏生化及心电图存在异常,诊断为免疫性心肌炎,行激素冲击等治疗后恢复正常[肌酸激酶同工酶(C...     

Cost-effectiveness of pembrolizumab with axitinib as first-line treatment for advanced renal cell carcinoma

Abstract

Objective

Pembrolizumab/axitinib significantly prolonged overall survival (OS) and progression-free survival (PFS), and increased objective response rate versus sunitinib in the phase III trial KEYNOTE-426 among previously untreated patients with advanced renal cell carcinoma (RCC). This study assessed the cost-effectiveness of pembrolizumab/axitinib versus other first-line treatments of advanced RCC from a US public healthcare payer perspective.     

Advances in the non-surgical treatment of melanoma

Immune responses appear to play a role in the natural history of melanoma and immunotherapy has therefore been the subject of a number of studies. The results of several large randomised studies using allogeneic melanoma vaccines have shown minimal benefit and Phase I/II studies with gene transfected melanoma cells do not appear particularly encouraging. The majority of current interest now centres on development of vaccines using defined melanoma antigens recognised by T-cells and given as dendritic vaccines or injected directly as melanoma peptides or DNA. It can be expected that the most effective antigens and method of administration will become apparent over the next few years. It is clear, however, that melanoma shows low response rates to immunotherapy, as for chemotherapy. Both forms of therapy appear to kill melanoma by induction of apoptosis, so it is possible that resistance to apoptosis may underlie the low responses to these forms of therapy. Much is already known about agents that may sensitise melanoma to apoptosis and combining these with chemotherapy and/or immunotherapy provides a promising new approach in treatment of melanoma.