Immune mediated neuropathy following checkpoint immunotherapy

Checkpoint immunotherapy has revolutionised cancer therapy and is now standard treatment for many malignancies including metastatic melanoma. Acute inflammatory neuropathies, often labelled as Guillain-Barre syndrome, are an uncommon but potentially severe complication of checkpoint immunotherapy with individual cases described but never characterised as a group. We describe a case of acute sensorimotor and autonomic neuropathy following a single dose of combination ipilimumab and nivolumab for metastatic melanoma. A literature search was performed, identifying 14 other cases of acute neuropathy following checkpoint immunotherapy, with the clinical, electrophysiological and laboratory features summarised. Most cases described an acute sensorimotor neuropathy (92%) with hyporeflexia (92%) that could occur from induction up till many weeks after the final dose of therapy. In contrast to Guillain-Barre syndrome, the cerebrospinal fluid (CSF) analysis often shows a lymphocytic picture (50%) and the electrophysiology showed an axonal pattern (55%). Treatment was variable and often in combination. 11 cases received steroid therapy with only 1 death within this group, whereas of the 4 patients who did not receive steroid therapy there were 3 deaths. In conclusion checkpoint immunotherapy – induced acute neuropathies are distinct from and progress differently to Guillain-Barre syndrome. As with other immunotherapy related adverse events corticosteroid therapy should be initiated in addition to usual therapy.     

Clinical Activity of Ipilimumab in Acral Melanoma: A Retrospective Review

Background.

Ipilimumab improves overall survival (OS) in advanced melanoma. Acral melanoma is an uncommon clinical subtype of this disease associated with poor prognosis. The clinical activity of ipilimumab has not been well-defined in advanced acral melanoma.

Methods.

We retrospectively reviewed the demographics, treatment history, and clinical outcomes for all patients with acral melanoma treated with ipilimumab from two academic centers between February 2006 and June 2013. Using Cox proportional hazards models, we assessed for factors that correlated with OS.

Results.

A total of 35 patients with acral melanoma received ipilimumab. Melanomas arose on volar surfaces (n = 28) and subungual sites (n = 7); stage M1c disease was present in 54%, and 45% had elevated serum lactate dehydrogenase (LDH). Best response by RECIST 1.1 criteria was complete response in 1 patient, partial response in 3, and stable disease (SD) in 4 for an objective response rate (ORR) of 11.4% and a clinical benefit rate (ORR + SD) at 24 weeks of 22.9%. Median progression-free survival was 2.5 months (95% confidence interval [CI]: 2.3–2.7 months); median OS was 16.7 months (95% CI: 10.9–22.5 months). Normal LDH and absolute lymphocyte count ≥1,000 at 7 weeks predicted longer OS. Immune-related adverse events (irAEs) were noted in 16 patients including 7 with grade 3/4 irAEs (20%).

Conclusion.

Ipilimumab is clinically active in acral melanoma with similar ORR and OS compared with unselected melanoma populations. Ipilimumab remains a viable therapeutic option for patients with advanced acral melanoma.

Implications for Practice:

Ipilimumab is a commonly used immune therapy that improves survival in metastatic melanoma. The clinical activity of ipilimumab in certain rare melanoma subtypes, such as uveal or mucosal melanomas, is suboptimal. Acral melanoma is another unusual subtype of this disease that arises on the palms, soles, and nailbeds. In this study of 35 patients with acral melanoma from 2 centers, ipilimumab was found to have activity that appears equivalent to unselected melanoma (response rate of 11.4%, median overall survival of 16.7 months). Ipilimumab remains a viable treatment option for this melanoma subpopulation.     

Risk of treatment-related mortality in cancer patients treated with ipilimumab: A systematic review and meta-analysis

BackgroundFatal adverse events (FAEs) have been reported in cancer patients receiving ipilimumab—a monoclonal antibody against cytotoxic T-lymphocyte antigen-4, but the risk of treatment-related mortality is unknown. We performed a systematic review and meta-analysis of randomised controlled trials (RCTs) of ipilimumab to determine the overall risk of FAEs associated with ipilimumab.MethodsWe systematically searched MEDLINE, EMBASE, Cochrane CENTRAL, ClinicalTrial.gov and conference proceedings from inception to December 2016, for prospective trials that randomly assigned patients to ipilimumab treatment (with or without concurrent therapy) or controls with available data regarding incidence of FAEs. Two reviewers extracted data independently. Incidence of FAEs was pooled using a random effects model, and the risk of FAEs associated with ipilimumab was estimated using Peto odds ratios (ORs).ResultsA total of 5775 patients with solid tumours included in 12 RCTs (10 from journal reports and 2 from ClinicalTrials.gov) were included in the meta-analysis. The pooled incidence of FAEs for patients treated with ipilimumab was 1.13% (95% confidence interval [CI], 0.56–1.86), compared with 0.22% in the control arms. Ipilimumab was associated with statistically significantly increased risk of FAEs, with a pooled Peto OR of 2.3 (95% CI, 1.4–3.6; P < 0.001). Analyses according to cancer type (melanoma versus other cancers); treatment mode (combination therapy or monotherapy); control type (active control versus placebo/best supportive care only); ipilimumab dose (high versus low dose [10 versus 3 mg/kg every 3 weeks]) found no statistically significantly differential effect by subgroups. Among the specific causes of FAEs, ipilimumab was associated with an increased risk of fatal gastrointestinal toxicity, with an OR of 4.5 (95% CI, 1.5–13.6).ConclusionThe use of ipilimumab, compared with controls, was associated with increased risk of treatment-related mortality.     

Immunotherapy in the treatment of non-small cell lung cancer

Advances in the understanding of the role of the immune system in tumor immunosurveillance have resulted in the recognition that tumors can evade immune destruction via the dysregulation of co-inhibitory or checkpoint signals. This has led to the development of a generation immunotherapeutic agents targeting the immune checkpoint pathway. Recent early phase studies of immune checkpoint modulators, such as CTLA-4, PD-1 and PD-L1 inhibitors in NSCLC have reported promising results with prolonged clinical responses and tolerable toxicity. This article provides an overview of co-stimulatory and inhibitory molecules that regulate the immune response to tumors, recent therapies that have been developed to exploit these interactions and the role of predictive biomarkers in treatment selection.     

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.     

Ipilimumab in melanoma

Introduction: The treatment of melanoma is evolving rapidly over the past few years. Patients with BRAFv600 mutations can be treated with a combination of a BRAF-inhibitor and an MEK-inhibitor. Patients with BRAF wild-type tumors and BRAFv600 mutated tumors can be treated with immunotherapy i.e. check point inhibitors.

Areas covered: We conducted a comprehensive review of the literature on the efficacy and predictive markers, safety, and pharmacoeconomics of ipilimumab in melanoma

Expert commentary: Ipilimumab was the first check point inhibitor reaching the clinic, gaining FDA and EMA approval for metastatic melanoma in 2011. Ipilimumab was also approved by FDA in the adjuvant setting for patients with high risk, stage III melanoma. The anti-PD1 directed antibodies pembrolizumab and nivolumab are superior to single agent ipilimumab, which is no longer considered the standard first line treatment in metastatic melanoma.

The addition ipilimumab to nivolumab is associated with a higher response rate and a better PFS, particularly in patients with PD-L1 negative tumors, albeit at the cost of a steep increase in grade 3–4 adverse event rate. Definitive survival data on this combination are pending and the selection of patients potentially requiring the combination and its pharmacoeconomic implications are to be elucidated.     

Immunotherapeutics in Development for Prostate Cancer

Whereas chemotherapy is the standard of care for metastatic castration‐resistant prostate cancer and is associated with a survival benefit, there remains a need for alternative approaches. Extensive work has been done evaluating multiple immunotherapies for the treatment of prostate cancer. This review discusses clinical results for the most promising developments. These include cytokine‐based therapy with GM‐CSF; vaccines; antibody‐based immunotherapies, including anti–cytotoxic T lymphocyte associated antigen 4 therapy and antibodies against additional targets; and dendritic cell‐based immunotherapy.