恶性黑色素瘤治疗新药CTLA-4抗体Ipilimumab的研究进展

Ipilimumab是一种新型的抗CTLA-4(细胞毒性T淋巴细胞相关抗原4)的全人源单克隆抗体。阻断CTLA-4的免疫效应可以打破免疫系统对自身组织的外周免疫耐受及诱导或增强抗肿瘤免疫反应。Ipilimumab是第一个被发现的可延长晚期黑色素瘤患者总生存期的药物,该药已于近期先后被FDA和欧盟委员会批准使用于晚期黑色素瘤的一线治疗。目前,多项关于Ipilimumab联合其他治疗方案的临床研究正在开展中。作为新型的T细胞增强剂和免疫系统激活剂,Ipilimumab在晚期恶性黑色素瘤免疫治疗临床治疗中具有重要的研究意义和应用前景。

Ipilimumab联合化疗治疗晚期肺鳞癌的单中心安全性观察

背景与目的:以检查点(checkpiont)为靶点的免疫治疗在实体瘤治疗领域有巨大的应用价值,引发了免疫靶向药物的研究热潮。一项研究结果为ipilimumab联合化疗治疗非小细胞肺癌(non-small cell lung cancer,NSCLC)患者的后续研究提供了依据。该研究统计ipilimumab或安慰剂与紫杉醇和卡铂联合作为一线治疗方案治疗Ⅳ期或复发性、组织学为肺鳞状细胞癌的不良事件(adverse events,AEs),评价ipilimumab联合化疗治疗晚期肺鳞癌的安全性。方法:共入组13例经上海交通大学附属胸科医院收治的ⅣA期或ⅣB期ECOG评分标准均小于等于1的肺鳞癌患者。采用随机对照双盲试验,试验组方案为ipilimumab联合紫杉醇与卡铂,对照组方案为安慰剂联合紫杉醇与卡铂。统计治疗过程中发生的AEs。结果:最常见的AEs主要是1级和2级AEs。Ipilimumab单抗组出现的免疫相关AEs(immune-related AEs,ir AEs)包括Ⅰ级的腹泻及皮肤瘙痒,Ⅱ级的皮疹及皮肤瘙痒和Ⅲ级的垂体炎。结论:Ipilimumab单抗的不良反应轻微,可耐受,可处理。

Colonic ulcerations may predict steroid-refractory course in patients with ipilimumab-mediated enterocolitis

AIM To investigate management of patients who develop ipilimumab-mediated enterocolitis, including association of endoscopic findings with steroid-refractory symptoms and utility of infliximab as second-line therapy.METHODS We retrospectively reviewed all patients at our centerwith metastatic melanoma who were treated with ipilimumab between March 2011 and May 2014. All patients received a standard regimen of intravenous ipilimumab 3 mg/kg every 3 wk for four doses or until therapy was stopped due to toxicity or disease progression. Basic demographic and clinical data were collected on all patients. For patients who developed grade 2 or worse diarrhea(increase of 4 bowel movements per day), additional data were collected regarding details of gastrointestinal symptoms, endoscopic findings and treatment course. Descriptive statistics were used.RESULTS A total of 114 patients were treated with ipilimumab during the study period and all were included. Sixteen patients(14%) developed ≥ grade 2 diarrhea. All patients were treated with high-dose corticosteroids(1-2 mg/kg prednisone daily or equivalent). Nine of 16 patients(56%) had ongoing diarrhea despite highdose steroids. Steroid-refractory patients received one dose of intravenous infliximab at 5 mg/kg, and all but one had brisk resolution of diarrhea. Fourteen of the patients underwent either colonoscopy or sigmoidoscopy with variable endoscopic findings, ranging from mild erythema to colonic ulcers. Among 8 patients with ulcers demonstrated by sigmoidoscopy or colonoscopy, 7 patients(88%) developed steroidrefractory symptoms requiring infliximab. With a median follow-up of 264 d, no major adverse events associated with prednisone or infliximab were reported.CONCLUSION In patients with ipilimumab-mediated enterocolitis, the presence of colonic ulcers on endoscopy was associated with a steroid-refractory course.

Ipilimumab and Nivolumab induced steroid-refractory colitis treated with infliximab: A case report

BACKGROUND A variety of immune-modulating drugs are becoming increasingly used for various cancers. Despite increasing indications and improved efficacy, they are often associated with a wide variety of immune mediated adverse events including colitis that may be refractory to conventional therapy. Although these drugs are being more commonly used by Hematologists and Oncologists, there are still many gastroenterologists who are not familiar with the incidence and natural history of gastrointestinal immune-mediated side effects, as well as the role of infliximab in the management of this condition.CASE SUMMARY We report a case of a 63-year-old male with a history of metastatic renal cell carcinoma who presented to our hospital with severe diarrhea. The patient had received his third combination infusion of the anti-CTLA-4 monoclonal antibody Ipilimumab and the immune checkpoint inhibitor Nivolumab and developed severe watery non-bloody diarrhea the same day. He presented to the hospital where he was found to be severely dehydrated and in acute renal failure. An extensive workup was negative for infectious etiologies and he was initiated on high dose intravenous steroids. However, he continued to worsen. A colonoscopy was performed and revealed no endoscopic evidence of inflammation. Random biopsies for histology were obtained which showed mild colitis, and were negative for Cytomegalovirus and Herpes Simplex Virus. He was diagnosed with severe steroid-refractory colitis induced by Ipilimumab and Nivolumab and was initiated on Infliximab. He responded promptly to it and his diarrhea resolved the next day with progressive resolution of his renal impairment. On follow up his gastrointestinal side symptoms did not recur.CONCLUSION Given the increasing use of immune therapy in a variety of cancers, it is important for gastroenterologists to be familiar with their gastrointestinal side effects and comfortable with their management, including prescribing infliximab.

A Real-World Observational Study of Patients with Advanced Melanoma Receiving First-Line Ipilimumab in a Community Practice Setting

Background: Following approval of ipilimumab, this observational cohort study (CA184-332) was initiated to describe patient and disease characteristics, patterns of care, survival, and adverse events (AEs) in advanced melanoma (AM) patients treated with first-line ipilimumab in realworld US community practice. Methods: Adult patients with treatment-naive AM who received ≥1 dose of ipilimumab 3 mg/kg between April 2011 and September 2012 were retrospectively identified at US Oncology sites. Clinical data were abstracted from patient medical records. Results: Median age of the 157 patient cohorts was 66 years (range 21 - 91). 68.2% were male, and 90.5% had a cutaneous primary site. At ipilimumab initiation, 80.9% of patients had an ECOG performance status of 0 or 1;54.1% were stage M1c;34.4% had brain metastases;24.8% had elevated lactate dehydrogenase, and 13.4% were positive for BRAF mutation. All 4 cycles of ipilimumab were completed by 55.8% of patients. At a median follow-up of 8.5 months (range 2.9 - 15.0), median overall survival was 11.5 months (95% CI: 8.9 - 16.6) and 1-year survival was 46.7% (95% CI: 38.1 - 54.9). During ipilimumab treatment, AEs were experienced by 63.7% of patients. The most frequent AEs were gastrointestinal (41.4%;diarrhea in 19.1%) and skin-related (28.0%;rash in 17.8%);17.8% of patients had an AE that led to ipilimumab discontinuation. Conclusions: These real-world results are consistent with those from clinical trials and provide evidence supporting the effectiveness and safety of first-line ipilimumab 3 mg/kg monotherapy in patients with AM treated in a community practice setting.

Healthcare Resource Utilization and Associated Costs in Patients with Advanced Melanoma Receiving First-Line Ipilimumab

Background: To describe healthcare costs, excluding ipilimumab drug costs, in patients with advanced melanoma receiving ipilimumab in the US community practice setting. Methods: This was a retrospective chart review of unresectable stage III/IV melanoma patients who received first-line ipilimumab monotherapy between 04/2011 and 09/2012. Healthcare resource utilization included inpatient, emergency, specialist and hospice visits, laboratory tests, radiation, surgeries, and nursing home stays. Publicly available US unit costs were applied to each resource type to estimate costs, which were analyzed by time periods: during ipilimumab treatment, post-ipilimumab treatment (post-regimen), and within 90 days prior to death (pre-death). Generalized linear mixed models were used to explore cost predictors during the treatment period, on a per-dose-interval basis, defined as the time between ipilimumab doses. Results: Data were abstracted from 273 patient charts at 34 sites. Excluding ipilimumab drug costs, total monthly costs during the treatment regimen, post-regimen, and pre-death periods were $690, $2151, and $5123, respectively. Total healthcare costs were 27 times higher during dose intervals with a grade 3/4 adverse event compared with intervals without a grade 3/4 adverse event. Eastern Cooperative Oncology Group performance status ≥ 2 (vs 0) was also associated with significantly higher cost per dose interval. Conclusions: In this population, monthly costs exclusive of drug were significantly lower during the treatment period than in subsequent periods. Unfavorable ECOG PS was associated with significant increases in cost per dose interval. Grade 3/4 adverse events were associated with a marked increase in healthcare costs, but occurred in a small proportion of dose intervals.

Ipilimumab associated colitis: An Ipi Colitis case series at Med Star Georgetown University Hospital

Although ipilimumab has been shown to improve survival in patients with metastatic melanoma and cause regression of metastatic renal cell carcinoma, the associated immune-related toxicities are of concern.The resultant T cell activation by this monoclonal antibody causes an increased immune response, which has been associated with many immune-regulated adverse effects.One of the most concerning effects is the development of colitis.Upwards to 8% of patients have been reported to develop colitis, with 5% being severe(Grades 3-4).While initial treatment of such adverse effects is generally comprised of supportive and symptomatic treatment, more severe cases warrant the use of high dose steroids.Furthermore, use of anti-TNF agents is usually reserved for those cases that prove to be refractory to steroids.We describe a systematic case review of seven patients who developed gastrointestinal symptoms following initiation of ipilimumab immunotherapy, and present the steps in their evaluation, treatment and outcomes at our institution.

Diarrhoea in a patient with metastatic melanoma:Ipilimumab ileocolitis treated with infliximab

Administration of ipilimumab,a cytotoxic T-lymphocyte associated antigen-4-blocking monoclonal antibody,leads to enhancement of the anti-tumor T-cell respons and as a result shows a significant survival benefit in metastatic melanoma patients.Therefore patients are currently receiving this promising therapy as a secondline strategy.Unfortunately,by activation of the T-cell immune reponse,ipilimumab therapy may lead to an unwanted induction of different autoimmune phenomena.Diarrhoea and colitis occur in up to one third of patients.Here we present a case of ipilimumab induced ileocolitis which was successfully treated with infliximab,an anti-tumor necrosis factor monoclonal antibody,after corticosteroid therapy failure.Although formal trials are lacking,recently publicated series suggest that infusional therapy of infliximab is effective in ipilimumab induced ileocolitis.

ipilimumab与nivolumab联合使用能够清除22%黑色素瘤患者体内的肿瘤

你以前也许未听说过：ipilimumab：与：nivolumab：两个药,不过这2种药物未来将会有效治疗皮肤癌。研究表明,上述两种药物联合使用能够清除22%黑色素瘤患者体内的肿瘤。然而,此前这两类药物一直是分开使用的,如今,科学家们通过联合用药起到了更佳的效果。

Treatment Patterns and Healthcare Costs among U.S. Patients with Advanced Melanoma Initiating Subsequent Systemic Therapy Following Use of Ipilimumab (IPI)

As the treatment landscape for advanced melanoma continues to evolve, it is critical to focus on unmet needs and understand the cost of therapy. While Ipilimumab (IPI), an immunotherapy indicated for unresectable advanced melanoma, has been a mainstay of 1st-line treatment, there was no standard of care following progression until recently. The objective of this study was to examine real-world treatment patterns and healthcare costs following IPI use in advanced melanoma patients prior to the anti-PD-1 class approval. Adult stage III or IV melanoma patients treated with IPI were selected between April 1, 2011, and September 30, 2013, from a large U.S. commercial and Medicare claims database. Patients were evaluated for therapy after IPI, with an index date set as the first systemic therapy after IPI. Per-Patient Per-Month (PPPM) healthcare costs while on active treatment were evaluated from index until treatment discontinuation, inpatient death, end of insurance enrollment, or September 30, 2013. Of 361 eligible patients, 111 (30.7%) initiated subsequent systemic therapy (mean age, 57 years;64.9% male). The most common therapies, single-agent or combination, included vemurafenib (32.4%), paclitaxel (28.8%), temozolomide (20.7%), and carboplatin (17.1%). During a median follow-up of 130 days, mean [standard deviation] PPPM all-cause total healthcare costs were $20,383 [$18,988], of which $4800 (23.6%), $5899 (28.9%), and $9684 (47.5%) were related to melanoma drug costs, medical claims with a diagnosis of melanoma, and other (non-specified) utilization, respectively. When considering total care, the costs of U.S. patients with advanced melanoma post-IPI were substantial across all commonly used agents.

Sustained Viral Response to Ipilimumab Treatment in a Patient with HCV Chronic Infection and Metastatic Melanoma： A Case Report

The treatment of metastic melanoma has rapidly evolved in the last 5 years, giving clinicians and patients the hope for long lasting responses. In the field of modern immunotherapy, we are reaching the point of an expressive percentage of patients achieving long term survival with anti-CTLA4 and anti-PD1 checkpoint inhibitors. Of note, there is a considerable amount of patients excluded from the checkpoint blockade trials because of comorbidities like chronic viral infections. A precaution to avoid autoimmune induced hepatitis rendered HBV （hepatitis B virus） and HCV （hepatitis C virus） infected patients usually ineligible, but real life data in those patients, who are getting treatment despite of that, is pointing toward the feasibility and safety of immunotherapy in this context. To ilustrate that, we report the case of a metastatic non-BRAF mutated melanoma patient with HCV chronic infection and a surprising benefit derived from ipilimumab and pembrolizumab for his latter condition.

Scalp Melanoma Treated with Ipilimumab in Elderly Patient： A Complete Response to Treatment--Case Report

Melanoma is a malignant neoplasm that affects the melanocytes. Its treatment is based on cancer staging. In immunotherapy, it can be pointed out the ipilimumab, used in the systemic therapy for unresectable and/or metastatic melanoma in the first or the second line treatment with increased survival. However, limiting toxicity and the low complete response discourage its use in the elderly patients. The aim of this study is to report the case of an 83-year-old man, white, with scalp melanoma measuring 3.5 cm in its major axis. After two resections was verified that the deep margin was involved, making the lesions unresectable. The evaluation of distant metastasis, by skull, chest and abdomen CT-scan （computed tomography-scan）, was performed and did not detect the presence of any metastatic loci. The patient underwent the first cycle of chemotherapy with DTIC （dacarbazine） protocol. After the first cycle, the medication was discontinued due to significant myelotoxicity and Grade 3 thrombocytopenia. Underwent second line treatment with ipilimumab by four cycles. After this, the patient follow with complete local response, asymptomatic, with no signs of local recurrence or distant metastasis site, and no limiting toxicity during and after a year of treatment with ipilimumab. Thus, it is possible to suggest that the use of ipilimumab isolatedly as a second line treatment may have a good response even in elderly patients.

转移性黑色素瘤治疗药Ipilimumab

美国FDA于2011年3月25日批准百时美施贵宝（BMS）公司产品ipilimumab（商品名：Yervoy）用于治疗转移性黑色素瘤。本品也于近日获得欧洲人用医疗产品委员会（CHMP）关于其治疗不可手术或转移性黑色素瘤的正性评估结果，有望于2011年8月在欧洲上市。

黑色素瘤治疗新组合--Nivolumab和Ipilimumab

Nivolumab(商品名Opdivo),一种由百时美施贵宝公司研制的单克隆抗体,是程序性死亡受体(PD-1)阻断剂。至2015年10月,FDA已批准其单用或联用ipilimumab(商品名Yervoy)用于黑色素瘤的治疗。Nivolumab作为目前最受关注的新一类抗肿瘤药物,可治疗多种类型的肿瘤,能够实质性提高客观响应率,其通过结合PD-1并阻断肿瘤细胞内部PD-1通路对T细胞的抑制作用,同时联用ipilimumab抑制CTLA-4对T细胞的负调控作用,共同增强活化T细胞,攻击肿瘤,这种治疗手段是免疫治疗的研究热点。笔者就nivolumab及ipilimumab的研发历程、基本性质、作用机制、药动学、药效学、临床试验及不良反应等信息作一概述,希望能对医院临床用药提供帮助和指导。

Ipilimumab在恶性黑色素瘤免疫治疗中的进展

ipilimumab是溶解性T细胞相关抗原(CTLA-4)的单克隆抗体。其作用机制为中和CTLA-4的免疫抑制作用,从而激发机体的抗肿瘤免疫反应。在多中心的Ⅲ期临床试验中,ipilimumab在延长患者生命方面取得了新的进展,因而美国食品药品管理局(FDA)批准ipilimumab用于治疗晚期恶性黑色素瘤患者,是恶性黑色素瘤免疫治疗的重要进步。

PD-1抑制剂对比化疗或伊匹单抗治疗晚期黑色素瘤安全性和有效性的Meta分析

目的:分析PD-1抑制剂对比化疗或伊匹单抗治疗晚期黑色素瘤的安全性和有效性。方法:检索PubMed、中国知网(CNKI)、维普和万方数据库,收集PD-1抑制剂治疗晚期黑色素瘤的随机对照试验,检索时限均从建库至2022年5月1日。由2位评价员独立筛选文献、提取资料并评价纳入研究的偏倚风险后,采用RevMan5.4和STATA16软件进行Meta分析。结果:共纳入7项研究。Meta分析结果显示:①安全性:PD-1抑制剂治疗相较于化疗有更少的不良反应事件,尤其是血液系统;PD-1抑制剂联合伊匹单抗相较于伊匹单抗单用有更多的不良反应事件,尤其别是肝功能指标;PD-1抑制剂和伊匹单抗治疗的总不良反应事件发生率差异无统计学意义。②有效性:PD-1抑制剂对比化疗或伊匹单抗治疗的PFS、OS和ORR分别为HR=0.54,95%CI(0.45,0.62),P<0.05、HR=0.69,95%CI(0.58,0.80),P=0.03和OR=3.16,95%CI(2.59,3.86),P<0.05。结论:PD-1抑制剂治疗晚期黑色素瘤具有较好的有效性,但不同的联合方式和不同的对照治疗有不同的安全表现。受纳入研究的数量和质量限制,需要更多研究证据予以佐证。

Long-Term Persistent Absolute Insulin Secretion Deficiency in Diabetes Induced by Immune Checkpoint Inhibitors

Immune checkpoint inhibitors are today an immense hope in the management of cancers. However, since their widespread use, many cases of insulin-requiring diabetes appearing suddenly, as fulminant diabetes have been reported. Here, we describe 4 cases that occurred at different times after the beginning of immune checkpoint inhibitor therapy with Nivolumab alone or associated with Ipilimumab. There are 3 cases of newly diagnosed diabetes and 1 case of known type 2 diabetes formerly quite well balanced with Metformin. The clinical and biological characteristics of these patients are quite similar. They were all insulin-requiring at the discovery of diabetes and remained so throughout their follow-up. This type of diabetes which looks like type 1 diabetes seems rather to be a new entity.

纳武利尤单抗联合伊匹木单抗致垂体炎的药学实践及文献复习

目的探讨恶性肿瘤治疗中免疫检查点抑制剂引起的免疫相关垂体炎的临床特点和药学监护,为类似病例的诊治提供参考。方法临床药师收集1例纳武利尤单抗联合伊匹木单抗致垂体炎患者的诊疗资料,通过评价药物与不良事件之间的关联性,分析患者出现垂体炎的用药因素,并在用药治疗过程中实施药学监护。结果患者经糖皮质激素治疗后,垂体炎症状改善。结论纳武利尤单抗联合伊匹木单抗可能引起垂体炎,在临床中较为罕见,一旦出现类似症状,应积极明确诊断,及时采取治疗措施,保障患者用药安全。

恶性黑素瘤系统治疗的新进展

恶性黑素瘤是一种恶性程度极高、对放化疗不敏感、病死率很高的肿瘤,目前有较多研究对其各种治疗方法进行探索。最近恶性黑素瘤治疗的两项重要进展分别是在分子靶向治疗方面和免疫治疗方面,该文以介绍ipilimumab和vemurafenib两种新药为主,对恶性黑素瘤的系统治疗进展进行了综述。

纳武利尤单抗联合伊匹木单抗一线治疗非小细胞肺癌的疗效

1文献来源研究一:Hellmann MD,Ciuleanu TE,Pluzanski A,et al.Nivolumab plus Ipilimumab in lung cancer with a high tumor mutational burden[J].N Engl J Med,2018,378(22):2093-2104.研究二:Hellmann MD,Paz-Ares L,Bernabe Caro R,et al.Nivolumab plus Ipilimumab in advanced non-small-cell lung cancer[J].N Engl J Med,2019,381(21):2020-2031.2证据水平1b。3背景纳武利尤单抗联合伊匹木单抗治疗非小细胞肺癌(non-small-cell lung cancer,NSCLC)在Ⅰ期临床试验中获得很好疗效,肿瘤突变负荷(tumour mutation burden,TMB)是潜在的生物标志物,但仍需Ⅲ期临床试验来探索在TMB高(≥10个突变/Mb)的人群中双免疫治疗对比含铂双药化疗的无进展生存期(progression-free survival,PFS)。