Anti-PD-1 therapy in patients with advanced melanoma and preexisting autoimmune disorders or major toxicity with ipilimumab

BackgroundAnti-PD-1 antibodies (anti-PD-1) have clinical activity in a number of malignancies. All clinical trials have excluded patients with significant preexisting autoimmune disorders (ADs) and only one has included patients with immune-related adverse events (irAEs) with ipilimumab. We sought to explore the safety and efficacy of anti-PD-1 in such patients.Patients and methodsPatients with advanced melanoma and preexisting ADs and/or major immune-related adverse events (irAEs) with ipilimumab (requiring systemic immunosuppression) that were treated with anti-PD-1 between 1 July 2012 and 30 September 2015 were retrospectively identified.ResultsOne hundred and nineteen patients from 13 academic tertiary referral centers were treated with anti-PD-1. In patients with preexisting AD (N=52), the response rate was 33%. 20 (38%) patients had a flare of AD requiring immunosuppression, including 7/13 with rheumatoid arthritis, 3/3 with polymyalgia rheumatica, 2/2 with Sjogren’s syndrome, 2/2 with immune thrombocytopaenic purpura and 3/8 with psoriasis. No patients with gastrointestinal (N=6) or neurological disorders (N=5) flared. Only 2 (4%) patients discontinued treatment due to flare, but 15 (29%) developed other irAEs and 4 (8%) discontinued treatment. In patients with prior ipilimumab irAEs requiring immunosuppression (N=67) the response rate was 40%. Two (3%) patients had a recurrence of the same ipilimumab irAEs, but 23 (34%) developed new irAEs (14, 21% grade 3–4) and 8 (12%) discontinued treatment. There were no treatment-related deaths.ConclusionsIn melanoma patients with preexisting ADs or major irAEs with ipilimumab, anti-PD-1 induced relatively frequent immune toxicities, but these were often mild, easily managed and did not necessitate discontinuation of therapy, and a significant proportion of patients achieved clinical responses. The results support that anti-PD-1 can be administered safely and can achieve clinical benefit in patients with preexisting ADs or prior major irAEs with ipilimumab.     

Cutaneous,gastrointestinal, hepatic,endocrine, and renal side-effects of anti-PD-1 therapy

BackgroundAnti-programmed cell death receptor-1 (PD-1) antibodies represent an effective treatment option for metastatic melanoma as well as for other cancer entities. They act via blockade of the PD-1 receptor, an inhibitor of the T-cell effector mechanisms that limit immune responses against tumours. As reported for ipilimumab, the anti-PD-1 antibodies pembrolizumab and nivolumab can induce immune-related adverse events (irAEs). These side-effects affect skin, gastrointestinal tract, liver, endocrine system and other organ systems. Since life-threatening and fatal irAEs have been reported, adequate diagnosis and management are essential.Methods and findingsIn total, 496 patients with metastatic melanoma from 15 skin cancer centers were treated with pembrolizumab or nivolumab; 242 side-effects were described in 138 patients. In 116 of the 138 patients, side-effects affected the skin, gastrointestinal tract, liver, endocrine, and renal system. Rare side-effects included diabetes mellitus, lichen planus, and pancreas insufficiency due to pancreatitis.ConclusionAnti-PD1 antibodies can induce a plethora of irAEs. The knowledge of them will allow prompt diagnosis and improve the management resulting in decreased morbidity.     

The development of immunotherapy in older adults: New treatments,new toxicities?

Monoclonal antibodies targeting immune checkpoint molecules CTLA-4, PD-1 or PD-L1 are emerging as promising anticancer therapeutics in multiple cancer subtypes resulting in remarkable and long-lasting clinical responses. These immune checkpoint blockers (ICBs) have already obtained approval for the treatment of patients with metastatic melanoma, advanced/refractory non-small cell lung cancer and renal cell cancer. ICBs enhance immune responses against cancer cells but can also lead to inflammatory side effects called immune-related adverse events (irAEs). Such toxicities are distinct from those associated with traditional chemotherapeutic agents or molecularly targeted therapies. Although severe irAEs remain rare (~ 10% of cases under monotherapy), they can become life-threatening if not anticipated and managed appropriately. As malignancies are frequently diagnosed in older patients, ICB treatment of elderly presents a unique challenge. However, the knowledge about efficacy and toxicity of these molecules in this specific population is limited, as most of the studies have involved a low number of older patients. In this review, we will discuss about the different ICB efficacy data available for older patients. We will then highlight the specific spectrum of immunotherapy toxicities and talk about their management in the context of older adults.     

PD-1 pathway inhibitors: The next generation of immunotherapy for advanced melanoma

Checkpoint inhibitors are revolutionizing treatment options and expectations for patients with melanoma. Ipilimumab, a monoclonal antibody against cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4), was the first approved checkpoint inhibitor. Emerging long-term data indicate that approximately 20% of ipilimumab-treated patients achieve long-term survival. The first programmed death 1 (PD-1) inhibitor, pembrolizumab, was recently approved by the United States Food and Drug Administration for the treatment of melanoma; nivolumab was previously approved in Japan. PD-1 inhibitors are also poised to become standard of care treatment for other cancers, including non-small cell lung cancer, renal cell carcinoma and Hodgkin''s lymphoma. Immunotherapy using checkpoint inhibition is a different treatment approach to chemotherapy and targeted agents: instead of directly acting on the tumor to induce tumor cell death, checkpoint inhibitors enhance or de novo stimulate antitumor immune responses to eliminate cancer cells. Initial data suggest that objective anti-tumor response rates may be higher with anti-PD-1 agents compared with ipilimumab and the safety profile may be more tolerable. This review explores the development and next steps for PD-1 pathway inhibitors, including discussion of their novel mechanism of action and clinical data to-date, with a focus on melanoma.     

Rationale for targeting the immune system through checkpoint molecule blockade in the treatment of non-small-cell lung cancer

BackgroundTreatments of non-small-cell lung cancer (NSCLC)—particularly of the squamous subtype—are limited. In this article, we describe the immunomodulatory environment in NSCLC and the potential for therapeutic targeting of the immune system through cytotoxic T-lymphocyte antigen 4 (CTLA-4) and programmed death-1 (PD-1) immune-checkpoint pathway blockade.Materials and methodsWe searched PubMed and presented abstracts for publications describing the clinical benefit of checkpoint blockade in NSCLC.ResultsAntibody-mediated checkpoint molecule blockade is being investigated in NSCLC, and of these approaches, the anti-CTLA-4 antibody ipilimumab has undergone the most extensive clinical study. By targeting the immune system rather than specific antigens, checkpoint blockade agents differ from vaccine therapy. In a phase II study in advanced NSCLC, phased ipilimumab with chemotherapy demonstrated the greatest efficacy in squamous NSCLC. A phase I study of nivolumab, an anti-PD-1 antibody, has suggested that this agent is also active against squamous and non-squamous NSCLC. Ongoing phase III studies are evaluating the therapeutic potential of these agents.ConclusionsAlthough treatment options for NSCLC are limited, a better understanding of the immune profile of this disease has facilitated the development of immunotherapeutics that target checkpoint blockade molecules, and clinical evaluation to date supports combining checkpoint blockade with chemotherapy for squamous NSCLC.     

Immune checkpoint inhibitors in older adults with melanoma or cutaneous malignancies: The Wilmot Cancer Institute experience

ObjectivesThe purpose of this study was to explore the associations between age and frailty with immune-related adverse events (irAEs) among patients with cutaneous malignancies receiving immune checkpoint inhibitor (ICI) therapy.MethodsA retrospective review of all patients receiving ipilimumab, nivolumab, or pembrolizumab for treatment of cutaneous malignancies at the Wilmot Cancer Institute between 1 Jan 2011 and 3 Apr 2017.ResultsA total of 120 patients (age <70 N = 68, age ≥70 N = 52; range, 26–93) were identified. 44.1%[95%CI:32–57%] of patients age <70 and 31.4%[95%CI:19–46%] of patients age ≥70 experienced ≥1 irAE on 1st line ICI therapy (P = 0.158). A total of 3 adults died of irAEs (2 age ≥70; 1 age <70). Patients ≥70 were more frequently treated with anti-PD-1 monotherapy than dual checkpoint blockade or ipilimumab (P < 0.01) in the first line setting. Among patients on first line anti-PD-1 monotherapy for cutaneous melanoma, 21 were age <70 and 20 were age ≥70, with similar observed rates of irAEs (52.4%[95%CI 29.8–74.3] and 63.2%[95%CI 38.4–83.7]). Indirect frailty markers in patients age ≥70 such as having fallen in the prior six months, ECOG PS ≥2 or Charlson comorbidity scores ≥11 experienced similar rates of response and toxicity. Among 9 patients with a PS = 3, 8 died, 6 due to progressive disease. No deaths due to irAEs occurred in this frail subgroup.ConclusionAnti-PD-1 monotherapy for older adults with cutaneous malignancies have similar response and irAE rates when compared to those of younger patients. Deaths from disease progression were more frequent than those from toxicity in both age subgroups.     

免疫检查点抑制剂的毒性风险分析

近些年免疫检查点抑制剂在肿瘤治疗领域取得了重大突破,包括恶性黑色素瘤、非小细胞肺癌等,近期并获得微卫星不稳定肿瘤的适应证。但与此同时也伴随一系列毒性的产生,主要为免疫相关不良反应,几乎累及各个系统,与传统化疗药物、靶向药物相关不良事件存在很大区别;同时尽管严重不良事件的发生率不高,但部分为致死性,且治疗干预缺乏足够的证据支持,临床认识不足。本文结合最新文献报道,从免疫检查点抑制剂的毒性风险特征、风险预测标志物、监测管理等方面进行综述。     

免疫检测点抑制剂特殊安全性问题的认识及处理

近几年,美国食品药品管理局（FDA）相继批准了抗细胞毒T淋巴细胞相关抗原4（CTLA-4）和抗程序性死亡受体1（PD-1）两种免疫检测点抑制剂（ICBs）用于黑色素瘤和非小细胞肺癌的治疗。研究发现,ICBs在多种肿瘤亚型的治疗中均有效,包括小细胞肺癌、肾细胞癌、尿道上皮癌、头颈鳞状细胞癌、胃癌、肝细胞癌、卵巢癌、三阴性乳腺癌以及错配修复缺陷型直肠癌等。这些以免疫系统为靶点的药物疗效显著,但同时伴随一定的免疫相关不良事件（irAEs）或者免疫异常毒性的发生,如何管理这些毒副作用尚没有成熟的方法。本综述将对目前国内外关于ICBs免疫异常毒性的管理相关经验进行总结,以期能够给临床医师在肿瘤患者的免疫异常毒性管理工作中提供一些参考。     

Combined low-dose ipilimumab and pembrolizumab after sequential ipilimumab and pembrolizumab failure in advanced melanoma

With the wide use of anti-PD-1 therapy, an increasing number of patients progress under treatment. Combined immunotherapy with anti-CTLA-4 and anti-PD-1 antibodies induces higher response rates as first-line treatment in comparison to single-agent therapy, however, with substantial toxicity since the combination of ipilimumab (3 mg/kg) and nivolumab (1 mg/kg) induced 55% grade 3/4 treatment-related adverse events and treatment discontinuation rates of 39%. In this case series, we investigated the efficacy and toxicity of the combined immunotherapy with low-dose ipilimumab (1 mg/kg) plus pembrolizumab (2 mg/kg) in patients with metastatic melanoma with progressive disease under sequential monotherapy with both agents. All patients had received at least three lines of treatment, 78% of patients were M1c, and 67% had brain metastases. Stable disease was observed in 3 out of 9 patients with a median overall survival of 8 months after double checkpoint inhibition. No treatment-related grade 3/4 adverse events occurred, and none of the patients needed to discontinue the treatment due to toxicity. Further trials are needed to investigate combined immunotherapy as rescue treatment in heavily pretreated melanoma patients to find optimal dosage in regard to outcome and toxicity.     

晚期非小细胞肺癌免疫治疗相关不良反应与疗效的相关性研究进展

非小细胞肺癌(Non-small cell lung cancer, NSCLC)是肺癌最常见的组织学类型,诊断时多为晚期,病死率较高。免疫检查点抑制剂(Immune checkpoint inhibitors, ICIs)的应用显著提高了晚期NSCLC患者的5年生存率,但带来生存获益的同时,也导致免疫相关不良事件(Immune-related adverse events, irAEs)的发生。近年来,irAEs和ICIs临床疗效之间的关联性成为研究的热点。本文就晚期NSCLC中irAEs与免疫治疗疗效的相关性研究进展进行综述。     

Response to Nivolumab and Ipilimumab in Microsatellite Instability-High (MSI-H) Cervical Carcinoma with Acquired Resistance to Pembrolizumab: A Case Report and Literature Review

As the use of immune checkpoint inhibitors (ICIs) in treating a variety of cancer types has increased in recent years, so too have the number of reports on patients acquiring resistance to these therapies. Overcoming acquired resistance to immunotherapy remains an important need in the field of immuno-oncology. Herein, we present a case that suggests sequential administration of combination immunotherapy may be beneficial to advanced cervical cancer patients exhibiting acquired resistance to mono-immunotherapy. The patient’s tumor is microsatellite instability-high (MSI-H), which is an important biomarker in predicting ICI response. Results from recent interim prospective studies using combination immunotherapy (eg, nivolumab and ipilimumab) with anti-PD-1 plus anti-CTLA-4 inhibitor following progression on anti-PD-1 inhibitors (eg, nivolumab) have shown anti-tumor activity in patients with advanced melanoma and metastatic urothelial carcinoma. We also introduce retrospective studies and case reports/case series of dual checkpoint inhibition with anti-PD-1 inhibitor plus anti-CTLA-4 inhibitor after progression on prior anti-PD/PD-L1 monotherapy. To date, there has been no prospective study on the use of combined anti-PD-1 and anti-CTLA-4 therapy at the time of progression on anti-PD-1 therapy in patients with MSI-H tumors or advanced cervical cancer. In this report, we provide evidence that supports future investigations into such treatments.     

Dramatic Response to Concurrent Anti-PD-1 Therapy and Radiation in Resistant Tumors with Sarcomatoid Differentiation

A substantial fraction of patients demonstrate resistance to immune checkpoint inhibitors, which limits their use. Use of radiation concurrently with checkpoint inhibitors has been shown to boost immune responsiveness, resulting in significant tumor regression in patients with metastatic melanoma. However, it is unknown whether radiation could play a role in reversing the inherent resistance to checkpoint inhibition in certain tumor types. Most trials testing this concurrent approach exclude such modestly responsive tumors and pursue checkpoint inhibition using anti-cytotoxic T-lymphocyte-associated protein 4 antibody (anti-CTLA-4, ipilimumab). The efficacy of anti-programmed-death-1 (anti-PD-1) therapy when used concurrently with radiation is less known but remains an attractive option due to less autoimmune toxicity compared with CTLA-4 inhibition. In this first reported experience, we have safely and effectively combined anti-PD-1 therapy (nivolumab) concurrently with radiation to treat two patients with relapsed sarcomatoid renal carcinoma and heavily pretreated pleomorphic sarcoma. Both patients experienced a dramatic response that was durable.     

The Outlook for Immune Checkpoint Targeting Strategies in Colorectal Cancer

Encouraging clinical activity for checkpoint blockade in melanoma, lung cancer, and a growing list of other malignancies has supported enthusiasm for testing this strategy in colorectal cancer. Although frequent observations of T cell infiltration into colorectal cancer and a well-established list of target antigens suggest colorectal cancer should be amenable to this approach, there was limited clinical evidence until recent demonstration of substantial activity for anti-PD-1 antibody therapy in microsatellite instability high colorectal cancers. Addition of other therapeutic modalities such as targeted therapy, other checkpoint molecules, or other immunotherapies to anti-PD-1 antibodies is currently under evaluation with the hope that it will expand the possible spectrum of colorectal cancers treatable with checkpoint blockade.     

Update on immunologic therapy with anti-CTLA-4 antibodies in melanoma: identification of clinical and biological response patterns, immune-related adverse events, and their management

Immune-modifying monoclonal antibodies may induce or enhance the natural immune response against tumor cells. The complex interaction between antigen-presenting cells and T lymphocytes as an immune response is strongly affected by anti-CD152 (cytotoxic T-lymphocyte antigen-4, CTLA-4)-antibodies. However, specific CTLA-4 antibodies can block the CTLA-4 receptor and thus induce an unrestrained T-cell activation. To this stage, treatment of patients with metastatic melanoma with the CTLA-4 antibodies ipilimumab and tremelimumab has only been investigated within clinical trials. The results of a phase III trial in patients with advanced disease treated with ipilimumab alone or in combination with a peptide vaccination (gp100) recently presented at the 2010 annual meeting of the Ameircan Society of Clinical Oncology (ASCO) made groundbreaking news as ipilimumab was demonstrated to be the first drug in melanoma treatment to show a significant prolongation of survival time. Patients undergoing treatment with CTLA-4 antibodies may experience immune-related phenomena and adverse events (irAEs) that differ greatly from the well-known adverse events of cytotoxic drugs and which are due to the CTLA-4 antibodies' specific mode of action. This review gives a condensed overview on the mechanisms of action, an update on clinical data of the two CTLA-4 antibodies, ipilimumab and tremelimumab, and detailed recommendations for adverse event management strategies.     

Immunotherapy and the concept of a clinical cure

Immunotherapy has entered a new phase in its history, i.e. the phase of being broadly accepted as a key component of therapeutic strategies to control and cure cancer. Immune-modulation by checkpoint inhibitors have demonstrated to be capable of inducing long lasting tumour responses. Breaking tolerance by ipilimumab has been a crucial event in the past recent years, but PD-1/PD-L1 antibodies have forever changed the landscape in oncology in 2013. The most mature results have been obtained in advanced melanoma patients. High response rates of high quality with prolonged duration have been demonstrated in melanoma, renal cancer and in lung cancer. The broad potential is now being explored across a wide range of tumours. Importantly, synergy with ipilimumab has been demonstrated in melanoma, indicating a bright further future. Long term tumour control now seems achievable and thus the concept of a “clinical cure” is emerging. These antibodies bring immunotherapy to the forefront and indicate that immune-modulation will be a key component of therapeutic strategies from now on. All these observations indicate that “clinical cures” can only be achieved when the immune system is involved, and so the true renaissance of immunotherapy has arrived.     

Drug of the year: Programmed Death-1 receptor/Programmed Death-1 Ligand-1 receptor monoclonal antibodies

Programmed death-1 receptor (PD-1)/its ligand (PD-L1) antibodies have changed the landscape in oncology in 2013. The most mature results have been obtained in advanced melanoma patients. They indicate important response rates and high quality responses or prolonged duration. Also in renal cancer and in lung cancer remarkable activity has been demonstrated. Thus it is clear that these antibodies have a very broad potential and trials in many tumour types are being initiated. Breaking tolerance at the tumour site is a potent phenomenon and the potential for synergy with other checkpoint inhibitors such as ipilimumab have also been demonstrated in 2013. Long term tumour control now seems achievable and thus the concept of a clinical cure is emerging by modulation of the immune system. These antibodies bring immunotherapy to the forefront and indicate that immune-modulation will be a key component of therapeutic strategies from now on. Because of all these reasons PD-1/PD-L1 antibodies are considered ‘drug of the year’.     

Cutaneous adverse effects of the immune checkpoint inhibitors

The immune checkpoint targeted agents, anti–cytotoxic T-lymphocyte–associated antigen 4 (CTLA-4) and anti–programed cell death 1 (PD-1) or anti–programmed death ligand 1 (PD-L1) inhibitors are frequently associated with cutaneous side effects that are often dose limiting and can lead to discontinuation of therapy. Ipilimumab, a CTLA-4 inhibitor, is most commonly associated with a morbilliform eruption on the trunk and extremities and pruritus. More severe cutaneous toxicities reported include toxic epidermal necrolysis and severe drug rash with eosinophila and systemic symptoms. Recent case reports of Sweet syndrome and cutaneous sarcoidosis have also recently been described after treatment with ipilimumab. The cutaneous events usually occur early in the course of treatment and are dose dependent. PD-1 inhibitors, nivolumab and pembrolizumab, induce similar but less severe toxicities compared with the CTLA-4 inhibitors. The most common cutaneous adverse events include lichenoid reactions, eczema, vitiligo, and pruritus. Lichenoid oral mucosal lesions located on the tongue, buccal mucosa, lips, or gingivae or located on all of these have also recently been described. The time of onset of the cutaneous events with the PD-1 inhibitors occurs later than that seen with the CTLA-4 inhibitors. Anti–PD-L1 antibodies, such as atezolizumab, have a similar side effect profile compared with the PD-1 inhibitors. Combination of immune checkpoint inhibitors, ipilimumab and nivolumab, has recently been approved for the treatment of advanced melanoma. The combination therapy is associated with a more severe side effect profile compared with the agents used as monotherapy. We discuss the most frequently encountered cutaneous side effects of the immune checkpoint inhibitors and review the recommended management strategies.