PD‐1 Pathway Inhibitors: Immuno‐Oncology Agents for Restoring Antitumor Immune Responses

Immune checkpoint inhibitors are designed to restore a patient's own antitumor immune response that has been suppressed during tumor development. The first monoclonal antibodies against the immune checkpoint programmed death 1 (PD‐1) receptor, nivolumab and pembrolizumab, are now approved for clinical use. Both agents are indicated for the treatment of advanced melanoma, as well as for the treatment of metastatic non–small cell lung cancer (NSCLC). Nivolumab is also approved for the treatment of advanced renal cell carcinoma. In patients with melanoma, these agents result in objective response rates of ~25–40%, with durable responses lasting more than 2 years in some cases. Results from phase III trials have shown improved survival with nivolumab versus standard‐of‐care chemotherapy in both patients with advanced melanoma and those with advanced NSCLC. In patients with advanced melanoma, both PD‐1 inhibitors (nivolumab and pembrolizumab) have shown improved survival versus ipilimumab. PD‐1 inhibitors are associated with adverse events that have immune etiologies, with grade greater than 3 adverse events typically reported in 16% or less of patients. However, most immune‐mediated adverse events (including grade 3–4 adverse events) can be managed by using published management algorithms without permanent discontinuation of the agent. As nivolumab and pembrolizumab enter the clinic, and with more PD‐1 pathway agents in development for a range of tumor types, this review aims to provide pharmacists with a basic understanding of the role of PD‐1 in modulating the immune system and their use in the cancer treatment. The most recent clinical efficacy and safety data are discussed, highlighting the response characteristics distinctive to immune checkpoint inhibitors, along with pharmacokinetic and pharmacodynamic data and cost considerations.     

Evaluation of the pharmacokinetics and metabolism of pembrolizumab in the treatment of melanoma

Introduction: Advanced melanoma is a devastating disease that has propelled research in therapeutics beyond chemotherapy and radiotherapy. Being highly immunogenic, melanoma is a model tumor for immunotherapy and has highlighted the therapeutic potential of the immune checkpoint inhibitors.

Areas covered: This review discusses the pharmacologic properties, clinical efficacy, and safety profile of pembrolizumab, an IgG4-kappa humanized monoclonal antibody against the programmed cell death protein 1 (PD-1) receptor, for the treatment of unresectable or metastatic melanoma.

Expert opinion: Pembrolizumab was the first PD-1 inhibitor to be approved by the U.S. Food and Drug Administration (FDA). Remarkably, this accelerated approval for the treatment of advanced, heavily pretreated melanoma was based on response rates alone from a phase I trial. As anticipated, pembrolizumab confirmed a survival advantage in phase II and III trials and has led the way for the study of other drugs that share its mechanism of action. Defining disease and patient characteristics associated with a response remains amongst the most pressing priorities.     

Time dependent pharmacokinetics of pembrolizumab in patients with solid tumor and its correlation with best overall response

Pembrolizumab is a monoclonal antibody that targets the programmed death-1 receptor to induce immune-mediated clearance (CL) of tumor cells. Originally approved by the US Food and Drug Administration in 2014 for treating patients with unresectable or metastatic melanoma, pembrolizumab is now also used to treat patients with non-small-cell lung cancer, classical Hodgkin lymphoma, head and neck cancer, and urothelial cancer. This paper describes the recently identified feature of pembrolizumab pharmacokinetics, the time-dependent or time-varying CL. Overall results indicate that CL decreases over the treatment period of a typical patient in a pattern well described by a sigmoidal function of time with three parameters: the maximum proportion change in CL from baseline (approximately I_max or exactly e^Imax ? 1), the time to reach I_max/2 (TI₅₀), and a Hill coefficient. Best overall response per response evaluation criteria in solid tumor category was found to be associated with the magnitude of I_max.     

Durable complete response to pembrolizumab in microsatellite stable colorectal cancer

IntroductionImmunotherapy by checkpoint inhibitors, i.e., anti-programmed death-1(PD-1) or anti-programmed death-ligand 1 (PD-L1) antibodies, has gained more attention managing solid tumors. Pembrolizumab (an anti-PD-1 antibody) in metastatic colorectal cancer (CRC) was approved in 2017 by the US FDA.Reason for the reportPembrolizumab is not effective in microsatellite stable, mismatch-repair-proficient (MSS-pMMR) molecular phenotype, which comprises most CRC patients. In this report, we present the first case of metastatic CRC with a dramatic and durable response to pembrolizumab despite being of MSS-pMMR phenotype.Case summaryA 34-year-old woman, presented seven years ago with T3N2bM0 colon cancer and an appendix carcinoid tumor. The last relapse with bilateral pulmonary metastases was refractory to all treatments. Although it seemed unresponsive to immunotherapy because of MSS molecular phenotype, due to the high expression level of PD-L1 (85%), we started treatment with pembrolizumab 200 mg every three weeks and continued for the overall 19 courses. Surprisingly, a rapid and complete response was observed that last until now, i.e., 17 months after discontinuation of pembrolizumab.OutcomeDespite non-promising results in the current clinical trials, MSS-pMMR colorectal cancer patients'' deprivation from immunotherapy seems not to be reasonable. There are ongoing clinical trials on checkpoint inhibitors either alone or in combination with other drugs. However, immunostaining for PD-L1 should be considered as a possible response predictor.Graphical abstractImmunotherapy either by cell-based approaches or by checkpoint inhibitors may revolutionize cancer treatmentPembrolizumab has been approved by the FDA in 2017 for colorectal cancer.However, MSS-pMMR molecular phenotype which comprises the majority of CRC patients, has not shown a good response to checkpoint inhibitors.We present a MSS-pMMR case with complete and durable response to pembrolizumabWe suggest immunostaining for PD-L1 as a possible response predictor to checkpoint inhibitors     

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...     

Semimechanistically Based Modeling of Pembrolizumab Time-Varying Clearance Using 4 Longitudinal Covariates in Patients With Non–Small Cell Lung Cancer

Time-varying clearance (CL) has been recently recognized in U.S. Food and Drug Administration drug labels for oncology monoclonal antibodies. Pembrolizumab population CL at steady state decreased about 20% from the first dose, and individual CL changes varied from 75% decrease to 25% increase, which were correlating with disease conditions. From mechanism of action perspective, this research explored the longitudinal covariate effect on pembrolizumab CL based on data from a phase II/III clinical trial in patients with non–small cell lung cancer. Time courses of sum of the longest tumor dimensions, lymphocyte count, albumin, and lactate dehydrogenase were first characterized separately, and the post hoc parameters of each individual patient were fixed in the subsequent semimechanistically based modeling analysis. Pembrolizumab time-varying CL was assumed to be associated with the patient's sum of the longest tumor dimensions, lymphocyte count, albumin, and lactate dehydrogenase, and tumor-related pembrolizumab CL was assumed to be a fraction of total pembrolizumab CL in the semimechanistically based modeling.     

程序性死亡分子1抑制剂Pembrolizumab治疗恶性黑色素瘤研究进展

Pembrolizumab是抗程序性死亡分子1(programmed death-1,PD-1)的单克隆抗体,可与PD-1结合,抑制PD-1与其配体结合,从而激发机体的抗肿瘤作用.在多项临床试验中,Pembrolizumab能显著延长黑色素瘤患者的生存期,因而被美国FDA批准用于治疗晚期不可切除或已转移的恶性黑色素瘤.此文对Pembrolizumab治疗恶性黑色素瘤的研究进展做一综述.     

15例帕博利珠单抗致免疫相关性心肌炎的病例分析

目的:了解帕博利珠单抗致免疫相关性心肌炎发生的规律和特点,为临床合理用药提供参考。方法:以"帕博利珠单抗/可瑞达"和"心肌炎""心脏毒性","Pembrolizumab/Keytruda"和"Cardiac toxicity""Myocarditis""Cardiotoxity""Cardiotoxicity"等为中英文检索词,检索中国生物医学文献数据库、维普网、中国知网、万方数据、PubMed、Wiley Online Library、Embase等数据库中收录的帕博利珠单抗致免疫相关性心肌炎的个案报道,检索时限从建库起至2020年8月。剔除疑似病例文献和重复文献后,对纳入文献中患者性别、年龄、用药原因、既往病史、联合用药、用药剂量、不良反应(ADR)发生时间、临床表现、干预措施与转归等信息进行分析。结果与结论:共纳入15篇文献,其中英文13篇、中文2篇;涉及15例患者,其中男性12例、女性3例,平均年龄为71.35岁;临床诊断非小细胞肺癌4例,黑色素瘤4例,膀胱癌2例,尿路上皮癌、多发性骨髓瘤、胃癌、胸腺癌、鼻咽癌各1例;有6例患者记录了既往病史,其中5例无心脏疾病史,1例既往患有高血压、高血脂;有9例患者记录了联合用药情况;有12例患者详细记录了帕博利珠单抗的用药剂量和频次。93.3%患者的免疫性心肌炎出现在应用帕博利珠单抗第1~2周期用药后,平均发生时间为末次用药后15.5天;最常见临床症状为呼吸困难、乏力、头晕或晕厥等;9例患者心电图检查显示心脏传导阻滞;所有患者都使用了糖皮质激素处理;5例患者经住院治疗后死亡,其中1例患者在心肌炎控制后重启帕博利珠单抗治疗1周期,心肌炎复发并最终死于该ADR。结论:在患者使用帕博利珠单抗免疫治疗时,建议做好心脏功能相关基线检查和常规监测,一旦怀疑出现免疫相关性心肌炎,应及时完善心电图等心功能相关检查,并尽早使用大剂量糖皮质激素治疗,同时应警惕再次用药后心肌炎复发致死的风险。     

The Targeting of Indoleamine 2,3 Dioxygenase ‐Mediated Immune Escape in Cancer

The era of immunotherapies was unleashed in 2010 with the Food and Drug Administration (FDA) approval of the first therapeutic vaccine sipuleucel‐T as a standard treatment for metastatic prostate cancer. Next, the first immune‐activating anticytotoxic lymphocyte antigen‐4 (CTLA‐4) antibody ipilimumab exhibiting ‘immune checkpoint blockade’ was approved by FDA and European Medical Agency (EMA) for the treatment of patients with metastatic melanoma. New generations of immune checkpoint blockading antibodies targeting programmed cell death 1 (PD‐1) and its ligand (PD‐L1) are now under intense investigation in metastatic melanoma (MM) and non‐small‐cell lung cancer (NSCLC), and impressive clinical results are anticipated. Despite these successes, only a fraction of patients become clinical responders to therapy. Thus, to improve the selection of patients likely to respond, scrutinizing different immune parameters during treatment is essential. In the summary of this PhD thesis, we investigated changes in immune parameters and their possible correlation with clinical efficacy in patients with MM during treatments with the standard chemo‐ and immunotherapies, temozolomide (TMZ) and interferon‐α2b/interleukin‐2 (IFN‐α/IL‐2) immunotherapy. The overall aim was to assess changes in frequency and absolute counts of different immune cell subsets before and after treatment and correlate to clinical benefit. Furthermore, the thesis covers a finalized, clinical phase 1 study in patients with NSCLC testing a peptide vaccination with a HLA‐A2‐restricted epitope derived from indoleamine 2,3 dioxygenase (IDO). The overall aim in this trial was to evaluate safety and tolerability of IDO as an anticancer vaccine target in patients with NSCLC and to assess whether immunity correlated to clinical response.     

派姆单抗在非小细胞肺癌治疗中的研究进展

近年来,程序性死亡受体-1（programmed cell death-1,PD-1）抑制剂派姆单抗（Pembrolizumab）在非小细胞肺癌（non-small cell lung cancer,NSCLC）的治疗中显示出良好的疗效。2015年10月,派姆单抗获得美国FDA快速审批,用于治疗程序性死亡配体-1（programmed cell death-L1,PD-L1）阳性且在其他治疗后疾病进展的转移性NSCLC。随着临床试验的开展,派姆单抗在NSCLC治疗中的适用范围逐渐扩大,本文对派姆单抗治疗NSCLC的临床研究现状进行综述。     

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.     

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.     

A Review of Immune Checkpoint Inhibitors for the Management of Locally Advanced or Metastatic Urothelial Carcinoma

Urothelial carcinoma (UC) is the second most common malignancy of the genitourinary system and the sixth most common cancer in the United States. The overall incidence of UC appears to be on the decline, but death rates have remained stable. Stage IV metastatic disease is associated with only a 5% survival rate at 5 years. Gemcitabine and cisplatin combinations or dose‐dense methotrexate, vinblastine, doxorubicin, and cisplatin are the preferred regimens for individuals with advance, metastatic disease and a good performance status and organ function. Second‐line therapies in this setting are limited. During the course of 1 year, five immune checkpoint inhibitors were approved for treatment of cancers in the locally advanced or metastatic setting: atezolizumab, nivolumab, durvalumab, avelumab, and pembrolizumab. Immunotherapies have played a significant role in the treatment of various cancers and have continued to expand. It is of utmost importance that practitioners include checkpoint inhibitors as treatment options for UC. Based on the limited data, pembrolizumab and atezolizumab may be the drugs of choice, as they are supported by the most influential data to date; however, further research is warranted. Ongoing clinical trials will further assess the benefits of inducing cellular immunity in the treatment of UC. These therapies mark a new landscape in the treatment of UC. In this article, the available data on immune checkpoint inhibitors for the treatment of locally advanced or metastatic UC and their place in therapy are reviewed.     

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.     

Successes and setbacks of early investigational drugs for melanoma

Treatment of advanced and metastatic melanoma is a rapidly changing field. Over the past 10 years, there have been six new drugs approved by the FDA for the treatment of metastatic melanoma. These approved drugs include a number of immune checkpoint inhibitors and MAPK-pathway-targeted therapies. The discovery of such agents as ipilimumab, pembrolizumab, nivolumab, vemurafenib, trametininb and dabrafenib have revolutionized the way in which melanoma in managed. While these agents have succeeded in both early and later phase clinical trials, a large number of investigational therapies have not yet been developed or researched past Phase I clinical studies. Furthermore, there are dozens of potential agents in Phase I and Phase II clinical development that appear promising and are currently being explored. The field currently aims to determine the optimal sequence and combination of these therapies to best overcome such setbacks as toxicity and resistance and build upon the successes previously seen.     

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.     

A novel binuclear palladacycle complex inhibits melanoma growth in vitro and in vivo through apoptosis and autophagy

Malignant melanoma is an aggressive skin cancer and it is reported to be the most treatment-resistant human cancer. Here we describe the anti-tumour activity of a novel binuclear palladacycle complex (AJ-5) in vertical growth phase (ME1402) and metastatic (WM1158) melanoma cell lines. We show that compared to normal control cell lines, AJ-5 is more effective in inhibiting the proliferation of ME1402 and WM1158 melanoma cells with IC₅₀ values of 0.19 and 0.20 μM, respectively. Flow cytometry analyses showed that AJ-5 induced apoptosis (sub-G1 peak) which was confirmed by Annexin V-FITC/propidium iodide double-staining, nuclear fragmentation and an increase in the levels of PARP cleavage. Furthermore, AJ-5 was shown to induce both intrinsic and extrinsic apoptotic pathways as measured by PUMA, Bax and active caspases. Interestingly, AJ-5 treatment also simultaneously induced the formation of autophagosomes and led to an increase in the autophagy markers LC3II and Beclin1. Inhibition of autophagy reduced AJ-5 cytotoxicity suggesting that AJ-5 induced autophagy was a cell death and not cell survival mechanism. Moreover we show that AJ-5 induces the ATM-CHK2 DNA damage pathway and that its anti-tumour function is mediated by the p38 and ERK1/2 signalling pathways. Importantly, AJ-5 treatment efficiently reduced tumour growth in melanoma bearing mice and induced high levels of autophagy and apoptosis markers. Together these findings suggest that AJ-5 may be an effective chemotherapeutic drug in the treatment of melanoma, a highly aggressive and intractable cancer.     

Suppression of melanoma growth and metastasis by DNA vaccination using an ultrasound-responsive and mannose-modified gene carrier

DNA vaccination has attracted much attention as a promising therapy for the prevention of metastasis and relapse of malignant tumors, especially highly metastatic tumors such as melanoma. However, it is difficult to achieve a potent cancer vaccine effect by DNA vaccination, since the number of dendritic cells, which are the major targeted cells of DNA vaccination, is very few. Here, we developed a DNA vaccination for metastatic and relapsed melanoma by ultrasound (US)-responsive and antigen presenting cell (APC)-selective gene carriers reported previously, named Man-PEG???? bubble lipoplexes. Following immunization using US exposure and Man-PEG(2000) bubble lipoplexes constructed with pUb-M, which expresses ubiquitylated melanoma-specific antigens (gp100 and TRP-2), the secretion of Th1 cytokines (IFN-γ and TNF-α) and the activities of cytotoxic T lymphocytes (CTLs) were specifically enhanced in the presence of B16BL6 melanoma antigens. Moreover, we succeeded in obtaining potent and sustained DNA vaccine effects against solid and metastatic tumor derived from B16BL6 melanoma specifically. The findings obtained from this study suggest that the gene transfection method using Man-PEG???? bubble lipoplexes and US exposure could be suitable for DNA vaccination aimed at the prevention of metastatic and relapsed cancer.     

PD-1单抗Pembrolizumab治疗28例晚期肺癌的有效性及安全性观察

目的观察程序性死亡受体1(PD-1)单克隆抗体(单抗)Pembrolizumab治疗晚期肺癌的疗效和毒副反应。方法28例晚期肺癌患者,均接受PD-1单抗Pembrolizumab治疗,评价其近期疗效和毒副反应发生情况。结果28例患者中,3例患者于治疗1个月内因原发肿瘤进展、病情加重而死亡。其余25例患者,完全缓解1例、部分缓解4例、疾病稳定14例、疾病进展6例,客观反应率20.0%(5/25),疾病控制率76.0%(19/25)。可评价疗效的25例患者中位无进展生存期(PFS)为5.1个月,95%CI=(2.9,7.4)。28例患者常见的不良反应为疲乏5例(17.9%)、发热4例(14.3%)、免疫相关性肺炎6例(21.4%),其次为甲状腺功能减退3例(10.7%)、皮疹2例(7.1%)、腹泻2例(7.1%)、甲状腺功能亢进1例(3.6%)、心脏毒性1例(3.6%)。结论PD-1单抗Pembrolizumab对晚期肺癌疗效可,毒副作用可耐受。     

Targeted therapies in metastatic melanoma: toward a clinical breakthrough?

Metastatic melanoma is a very aggressive cancer. Dacarbazine has been considered as the standard therapy for decades. Due to a better understanding of melanoma cells signalling and immunological response, new targeted therapies are now proposed. The efficency of these new drugs needs to be confirmed by on larger clinical trials. Ipilimumab (anti-CTLA4 monoclonal antibody) and V600-E-B-raf inhibitor have shown encouraging results, while c-KIT and MEK inhibitors are currently under evaluation. These recently published data shed the light on melanoma management. We review here the latest development of these molecules and the current perspectives in the treatment of metastatic melanoma.