Acute neurological adverse events during immune checkpoint inhibition therapy in patients with melanoma brain metastases.

The common adverse effects of immune checkpoint blockade therapy are well recognised. However, neurological adverse effects of checkpoint inhibitor therapy are less widely appreciated, and their clinical management remains challenging. Therefore, we report our experience of managing acute, life-threatening neurological toxicity during immune checkpoint inhibitor therapy. Five male patients with stage IV melanoma underwent anti-programmed cell death protein 1 therapy (monotherapy or combination therapy with anti-cytotoxic T-lymphocyte antigen-4 antibodies) and developed severe neurological symptoms and signs including headache, hemiparesis and dysarthria. The initial diagnosis of brain metastases actually occurred after initiation of checkpoint inhibitor therapy in three of the patients, whereas two patients had pre-existing central nervous metastases and developed cerebral oedema and haemorrhage during immunotherapy. A rapidly fatal outcome occurred in two patients treated with immunotherapy following the development of BRAF-inhibitor and MEK-inhibitor resistance. Four of the patients died owing to neurological complications, and one achieved a complete cerebral response. Immunotherapy and tumour progression can both result in the development of neurological symptoms and signs, making it difficult to determine causality. However, the temporal relationship between the development of neurological symptoms and the first administration of therapy means that patients should be closely monitored for the development of neurological sequelae, which may even herald the presence of occult brain metastases. The decision on whether to continue immunotherapy must balance the risks of symptom - versus disease progression. However, in our case series, it is encouraging to note that the initial acute neurological symptoms were often transient. Nevertheless, pretherapeutic brain imaging to exclude occult brain metastases and stratify the risk of intracerebral oedema and haemorrhage should be considered.

Checkpoint Inhibition May Trigger the Rare Variant of Anti-LAD-1 IgG-Positive, Anti-BP180 NC16A IgG-Negative Bullous Pemphigoid.

Bullous pemphigoid (BP) is an autoimmune blistering skin disease characterized by an autoimmune response to type XVII collagen (BP180). The generation of anti-BP180-NC16A IgG autoantibodies is considered to be central to the pathogenesis of BP, in part due to the close correlation between serum concentration and disease activity. However, ~60% of BP patients also generate IgG autoantibodies against LAD-1, the soluble 120 kDa ectodomain of BP180. Whilst the pathogenic significance of anti-LAD-1 IgG remains unclear, it may be sufficient to precipitate the development of BP, even in the absence of anti-BP180-NC16A IgG, based on several case reports in Japanese patients. There is increasing recognition that immune-checkpoint inhibitors may trigger and/or exacerbate BP as an immune-related adverse event (irAE). Until now, all of these cases have been associated with the induction of anti-BP180-NC16A IgG. Here, we report the case of a female Caucasian patient who developed BP during treatment with the programmed cell death protein 1 (PD-1) inhibitor nivolumab. Intriguingly, the patient exclusively generated anti-LAD-1 IgG, suggesting that anti-LAD-1 IgG was responsible for the development of her autoimmune blistering dermatosis. This is the first such case documented in a non-Japanese patient, thus, lending further support to the pathogenic relevance of anti-LAD-1 IgG in BP.

Sequential Treatment With Targeted and Immune Checkpoint Therapy in Patients With BRAF Positive Metastatic Melanoma: The Importance of Timing?

Background: Immune checkpoint- and targeted therapy have dramatically improved the therapeutic landscape in the management of BRAF mutation positive metastatic melanoma. However, pending the results of clinical trials, not only is it currently unclear whether immune checkpoint- or targeted therapy should be commenced up front, but the optimal time for changing treatment, specifically to prevent resistance whilst maintaining disease control, is unknown. Methods: We retrospectively identified eleven patients with BRAF V600 mutated metastatic melanoma who commenced targeted therapy between 11/2012 and 12/2017 in our center. In 5 cases the decision was made to "electively" switch to immune checkpoint therapy (elective group) following the development of a complete or partial response. In the remaining 6 cases the initial "reactive" switch was necessitated by disease progression or the development of intolerable side-effects (reactive group). Results: Overall, the elective cohort had a more favorable course in terms of overall survival (1,003 vs. 827 days), and 80% of the patients remain alive, in contrast to 17 % of the patients in the reactive group. However, it should be borne in mind that multiple switches due to disease progression were undertaken and this undoubtedly also impacted upon overall survival. Conclusion: Elective switching from targeted to immune checkpoint therapy was associated with a better outcome in terms of survival, at least in everyday clinical practice. It remains unclear whether the choice of initial therapy confers long-term survival and disease-control advantages and this should be addressed in prospective studies.

Immune Cell Infiltration of the Primary Tumor, Not PD-L1 Status, Is Associated With Improved Response to Checkpoint Inhibition in Metastatic Melanoma.

Immune checkpoint inhibition has resulted in dramatic improvements in overall and relapse-free survival in patients with metastatic melanoma. The most commonly used immune checkpoint inhibitors are monoclonal antibodies targeting programmed cell death protein 1 and cytotoxic T-lymphocyte-associated protein 4. Unfortunately, a significant subset of patients fail to respond to these therapies, which has resulted in intense research efforts to identify the factors which are associated with treatment response. To this end, we investigated immune cell infiltration in primary melanomas and melanoma metastases, in addition to tumor cell PD-L1 expression, to determine whether these factors are associated with an improved outcome after immune checkpoint inhibition. Indeed, the extent of the immune cell infiltration in the primary melanoma, measured by the Immunoscore, was associated with a significantly improved response to immune checkpoint inhibition in terms of increased overall survival. However, the Immunoscore did not predict which patients would respond to treatment. The Immunoscore was significantly reduced in metastases when compared to primary melanomas. In contrast, PD-L1 expression, exhaustively tested using four commercially available anti-PD-L1 clones, did not differ significantly between primary tumors and melanoma metastases and was not associated treatment response. Whilst replication in larger, prospective studies is required, our data demonstrates the relevance of immune cell infiltration in the primary melanoma as a novel marker of improved overall survival in response to immune checkpoint inhibition.

Meningeal melanomatosis following discontinuation of dabrafenib: implications for the maintenance of long-term complete remission.

A subset of 10-20% of patients under continuous BRAF inhibitor monotherapy achieve long-term progression-free and overall survival. Definitive criteria for the safe cessation of BRAF inhibitor monotherapy in treatment-responsive melanoma patients are lacking. We report a patient who remained in complete remission (CR) for 5 years under dabrafenib. The treatment was withdrawn because of concerns about cardiac toxicity. Four months thereafter the patient developed neurological symptoms, including diplopia and bilateral visual loss. Meningeal melanomatosis and parenchymal brain metastases were diagnosed. Extracerebral metastases were excluded. Reinduction of dabrafenib, combined with trametinib, led to the rapid relief of the neurological symptoms, and a partial remission was confirmed radiologically. Unfortunately, the response was not maintained and the patient died 9 months later. This observation demonstrates that discontinuation of BRAF inhibition can result in loss of disease control. On the basis of this observation, we suggest that BRAF-targeted therapy should be withdrawn only when the risks of continued treatment exceed the risk for disease relapse. However, future studies are urgently required to confirm and quantify the risk for rapid disease relapse following withdrawal of BRAF inhibitor monotherapy.

Rapid remission of symptomatic brain metastases in melanoma by programmed-death-receptor-1 inhibition.

Although ∼40% of patients with metastatic melanoma develop brain metastases, the presence of brain metastases often precludes enrolment in clinical trials for advanced melanoma. However, the development of symptomatic brain metastases markedly increases mortality. The antiprogrammed-death-receptor-1 antibody pembrolizumab achieves extracranial metastases disease response rates of up to 50%. Here, we report the rapid and sustained response of symptomatic multifocal brain metastases in a melanoma ipilimumab-pretreated patient under pembrolizumab, combined with high-dose dexamethasone therapy during the induction phase of therapy. Complete remission has been maintained for over 1 year of follow-up and has correlated with the response rate observed in the extracranial metastases. Radiological disease response was identified during the first follow-up visit in the absence of adjuvant radiotherapy. This report highlights the need for further clinical studies to specifically address the therapeutic potential of antiprogrammed-death-receptor-1 monotherapy in the management of untreated brain metastases in melanoma.