Introduction Immune Checkpoint Inhibitors Research Articles

Efficacy of Immune Checkpoint Inhibitors in Lung Sarcomatoid Carcinoma.

Immune checkpoint inhibitors (ICIs) have improved cancer prognosis but have not been evaluated specifically in sarcomatoid carcinoma (SC), a rare lung cancer subtype with poor prognosis. As such, our study sought to retrospectively assess the efficacy of ICI in SC. All consecutive patients with centrally confirmed SC treated using ICI as a second-line treatment or beyond between 2011 and 2017 were enrolled. Programmed death-ligand 1 (PD-L1) tumor expression was assessed using immunohistochemistry (SP263 clone) and the tumor mutational burden (TMB) with the Foundation One panel. TMB was considered high if it was greater than or equal to 10 mutations per megabase. Overall, 37 patients with SC were evaluated, predominantly men (73%) with a median age of 63.2 years (36.8-79.7) and who were current or former smokers (94.6%). Immunotherapy (nivolumab, 86.5% of cases) was given as a second-line treatment in 54% of the patients and as third-line treatment or beyond in 46% of the patients. The objective response rate was 40.5% and disease control rate was 64.8%, regardless of PD-L1 status. Median overall survival was 12.7 months (range: 0.3-45.7). One-third of patients exhibited early progression. The median PD-L1 expression was 70% (0-100). There was a trend toward higher PD-L1 expression in responsive diseases, with an objective response rate of 58.8% in patients with PD-L1+ and 0% in the one patient with PD-L1- (p= 0.44). The median TMB was 18 (4-39) mutations per megabase, with 87.5% of the cases displaying a high TMB. There was a trend toward higher TMB in responders versus stable or progressive diseases (p= 0.2). Patients with SC exhibited high response rates and prolonged overall survival under ICI treatment. These data support the prospective investigation of ICI in patients with SC who are under first-line treatment.

Immunotherapy in metastatic sarcomatoid renal cell carcinoma: A single institution experience

IntroductionImmune checkpoint inhibitors (CPIs) were recently approved in advanced clear cell renal cell carcinoma (RCC) and could be a promising option for metastatic RCC with sarcomatoid differentiation (sRCC) which otherwise carry a poor prognosis. We sought to compare outcomes between patients who received immunotherapy (IO) including CPIs or high dose interleukin-2 (HD IL2) for metastatic sRCC versus those who did not. Patients and MethodsWe performed a single-center retrospective data analysis of 44 consecutive sRCC patients with any percentage of sarcomatoid differentiation from our institutional RCC database of whom 34 received IO and 10 patients did not. ResultsBaseline variables between the two groups were not significantly different except for a greater percentage of patients with ≥40% sarcomatoid differentiation in the non-IO cohort. At a median follow-up of 27.6 months, patients treated with IO had a median overall survival of 57.6 months compared to 6.6 months in patients not treated with IO (p = 0.0002). Overall response rates (ORR) between the IO and non-IO group were 35.3% and 0% respectively (p = 0.06). When IO was given in the 1st line setting, the ORR was 25.0%, as compared to 44.4% in the 2nd line setting and beyond though limitations of small sample sizes apply. Immune-related adverse events (IRAE) occurred in 38.2% of patients in the IO group, with grade 3 events (mostly gastrointestinal) in 20.6% with no grade 4 or 5 events. IRAEs led to interruption or discontinuation of immunotherapy in 26.5%. ConclusionOur results support IO as an effective therapeutic option for patients with metastatic sarcomatoid RCC. Further study of various IO regimens, including those affecting the interleukin-2 signaling pathway, and their efficacy in neoadjuvant and adjuvant settings are warranted in sRCC.

Pembrolizumab- and/or pazopanib-induced remitting seronegative symmetrical synovitis with pitting edema in a patient with renal cell carcinoma

Immune checkpoint inhibitors and angiogenesis inhibitors are novel treatment options for renal cell carcinoma and widely used in clinical practice. They are related with adverse events that occur as a consequence of immune system activation and inhibition of angiogenesis. Herein, we report a rare case of inflammatory arthritis seen in a patient treated with an anti Programmed cell death-1 pembrolizumab and an anti-vascular endothelial growth factor pazopanib. A 60-year-old Caucasian male presented to our clinic with inflammatory arthritis with pitting edema. He had been started on pembrolizumab therapy for metastatic renal cell carcinoma after enrolling in the KEYNOTE-679 study. After six cycles of treatment with pembrolizumab, metastasis had been determined in the lung. Then, the patient's therapy was changed to pazopanib. While the patient was on pazopanib treatment, he noticed a gradual swelling of both hands. Rheumatoid factor, anti-nuclear antibody and anti-cyclic citrullinated peptide were negative. Joint ultrasonography revealed acute tenosynovitis and soft tissue swelling with pitting edema, and a diagnosis of remitting seronegative symmetrical synovitis with pitting edema was made. Management and outcome: He was started on 10 mg prednisolone daily. His symptoms dramatically responded to corticosteroid. He continued to take pazopanib. Then, the patient was discharged with 10 mg prednisolone daily. Pembrolizumab- and/or pazopanib-induced remitting seronegative symmetrical synovitis with pitting edema can be among the rare rheumatic immune-related adverse events that clinicians may encounter as the immune check point inhibitors and anti-VEGF use increases. Corticosteroid therapy can relieve symptoms and cessation of therapy may not be necessary.

Immune Checkpoint Inhibitors Associated with Cardiotoxicity in Cancer Patients: A Large Single-Center Experience

Introduction Immune checkpoint inhibitors (ICIs) promote immune cells to invade tumor cells. With the increasing use of ICIs, clinicians should be aware of the cardiac toxicity profile of ICIs in order to achieve timely intervention and better outcomes. We report our single-center experience of cardiac immune-related adverse effects (CIRAEs) in patients treated with ICIs. Methods We reviewed consecutive patients who received an ICI at the Cleveland Clinic between 2011 and 2018 for the occurrence of CIRAEs. Disease profile, hospital course, and outcome were studied in patients with CIRAEs. Results Out of 2830 patients initiated on ICIs, 9 patients developed CIRAEs (0.3%). The mean age was 70 ± 9 years, and 55% were males. Four patients developed cardiomyopathy, two patients had acute myocarditis, two patients had acute pericarditis, and one patient had a large pericardial effusion. Most presentations were atypical, and most patients had other associated immune-related adverse effects. The patients with acute myocarditis presented predominantly with symptoms of myasthenia gravis and myositis, while self-described as generalized weakness and fatigue. Patients with cardiomyopathy presented with shortness of breath at exertion, but also with chest pressure and symptoms of autoimmune pancreatitis. In addition to the typical pleuritic chest pain, patients with acute pericarditis manifested other respiratory symptoms (shortness of breath, productive cough) that might be due to their lung cancer or associated autoimmune pneumonitis. Both patients with myocarditis died within a week, reflective of the poor prognosis of myocarditis. All patients with cardiomyopathy except one recovered their systolic function after withholding ICIs. Interestingly, the patient who did not recover was not treated with high dose steroids during his hospitalization. Steroids were not needed in one case of acute pericarditis, and pericarditis did not recur in the patient with acute pericarditis after nivolumab reintroduction. Overall, five patients had no progression of their primary malignancy, two had progression, and the remaining two had a fatal outcome during the admission. Conclusions The incidence of CIRAE with ICIs in our single-center experience was comparable to those reported in the literature. Patients treated with ICIs who present with chest pain, shortness of breath or generalized weakness should be evaluated for potential CIRAEs. The role of early steroid treatment for cardiac involvement should warrant further investigations.

Isolated adrenocorticotropic hormone deficiency and thyroiditis associated with nivolumab therapy in a patient with advanced lung adenocarcinoma: a case report and review of the\xa0literature

IntroductionImmune checkpoint inhibitors are a promising class of anticancer drugs. The clinical benefits afforded by immune checkpoint inhibitors can be accompanied by immune-related adverse events that affect multiple organs, and endocrine immune-related adverse events include thyroiditis and hypophysitis. Hypophysitis is less frequent and has a less severe clinical presentation in patients treated with other immune checkpoint inhibitors, such as nivolumab, pembrolizumab, and atezolizumab, than in those treated with ipilimumab. However, studies have described isolated adrenocorticotropic hormone deficiency cases associated with nivolumab, pembrolizumab, and atezolizumab therapy, most of which occurred during the course of immune checkpoint inhibitor therapy. We report a rare case of patient with isolated adrenocorticotropic hormone deficiency that occurred after nivolumab therapy.Case presentationA 69-year-old Japanese woman with advanced lung adenocarcinoma developed painless thyroiditis with transient elevations of serum thyroid hormones during 3 months of cancer treatment with nivolumab and began thyroid hormone replacement therapy for subsequent primary hypothyroidism. Four months after nivolumab therapy was discontinued, she developed isolated adrenocorticotropic hormone deficiency; corticosteroid replacement therapy relieved her secondary adrenal insufficiency symptoms, such as anorexia and fatigue. Human leukocyte antigen typing revealed the presence of DRB1*04:05-DQB1*04:01-DQA1*03:03 and DRB1*09:01-DQB1*03:03-DQA1*03:02 haplotypes, which increase susceptibility to autoimmune polyendocrine syndrome associated with thyroid and pituitary disorders in the Japanese population.ConclusionsOur patient developed thyroiditis during cancer treatment with nivolumab and subsequently exhibited isolated adrenocorticotropic hormone deficiency 4 months after discontinuing the drug. Administration of nivolumab in combination with a genetic predisposition to polyglandular autoimmunity probably caused both the thyroiditis and hypophysitis, resulting in primary hypothyroidism and isolated adrenocorticotropic hormone deficiency, respectively, in our patient. The present case highlights the need for physicians to be aware that endocrine immune-related adverse events, including hypophysitis, can occur more than several months after discontinuing a drug.

Lymphopenia As an Early Predictor of Immune Related Adverse Events

IntroductionImmune checkpoint inhibitors (ICI) are a novel class of medications which offer a potential curative option for many cancer patients who previously had a more dismal prognosis. Programmed cell death protein 1 (PD-1) is a molecule that modulates cellular immunity to limit autoimmunity, but can also be co-opted by cancers and infections to create immune tolerance. Nivolumab and pembrolizumab are fully human IgG4 PD-1 checkpoint-inhibitors. Ipilimumab on the other hand is an inhibitor of cytotoxic T-lymphocyte-associated protein 4 (CTLA-4). ICI can result in immune activation in non-target tissues, resulting in immune-related adverse events (irAEs) in a subset of patients and these toxicities have varying times to onset and affect different organs. Some studies suggest that patients with irAEs have higher response rates than patients without such events, but these findings have not been universally verified. There are few studies which also showed relationship between lymphopenia and survival in patient on chemotherapy. In this single center retrospective study we analyzed the relationship between CBC parameters and rates of irAEs.MethodsWe conducted a retrospective study at a single health care network aimed at understanding if CBC parameters could be used for early prediction of irAEs. Between July 2015 and September 2017 we found 106 patients who developed irAEs across three cancer types, renal cell carcinoma, melanoma, and lung cancer. Patients who did not receive immunotherapy as a first-line therapy were excluded from this study. All patients had stage IV disease at the start of ICI. A total of 34 patients met inclusion criteria, but, 5 patients were excluded on the basis of only receiving one dose of ICI so there were no other CBC to compare. We then analyzed the CBC and differential of this population prior to the commencement of immunotherapy and immediately prior to reported irAEs and before the start of systemic steroids. The primary objective of the study was to find a hematological parameter which can predict the onset of irAEs.ResultsThe average age of the study population was 59.9 years and was predominantly male (62.1%). The most frequent CBC parameter which changed prior to the onset of irAE was a reduction in the lymphocyte count (14%). We found that nearly 70% (20/29) of patient had reduction in their lymphocyte count immediately prior to the onset of the reported irAE. The vast majority of patients had grade 3 toxicities and there was a trend towards higher toxicities being associated with a greater degree of lymphopenia. In addition, lymphopenia was more frequently found in patients treated with Nivolumab than other ICIs. We found that the average number of ICIs cycles were 9.1 and 9.0 in the groups which developed and did not develop lymphopenia, respectively. In terms of the other CBC parameters, we found no significant differences in hemoglobin/hematocrit, platelet count, neutrophil count, basophil count, or eosinophil count before IO and prior to the development of irAEs.ConclusionLymphopenia may be an early indicator of irAEs and should be investigated further in prospective trials. DisclosuresNo relevant conflicts of interest to declare.

Increased Hepatotoxicity Associated with Sequential Immune Checkpoint Inhibitor and Crizotinib Therapy in Patients with Non–Small Cell Lung Cancer

IntroductionImmune checkpoint inhibitors (ICIs) are standard therapies in advanced NSCLC. Although genotype-directed tyrosine kinase inhibitors represent the standard of care for subsets of oncogene-driven NSCLC, patients may receive ICIs during their disease course. The impact of sequential ICI and tyrosine kinase inhibitor therapy on the risk of hepatotoxicity has not been described. MethodsPatients with advanced ALK receptor tyrosine kinase (ALK)-driven, ROS1-driven, or MET proto-oncogene, receptor tyrosine kinase (MET)-driven NSCLC treated with crizotinib, with or without preceding ICI therapy, were identified. The cumulative incidences of crizotinib-associated grade 3 or higher increases in transaminase level (per the Common Terminology Criteria for Adverse Events, version 4.0) were compared. ResultsWe identified 453 patients who had NSCLC with an oncogenic alteration in ALK receptor tyrosine kinase gene (ALK), ROS1, or MET proto-oncogene, receptor tyrosine kinase gene (MET) and were treated with crizotinib (11 with and 442 without prior ICI therapy). Among the 11 patients treated with an ICI followed by crizotinib, five (cumulative incidence 45.5% [95% confidence interval (CI): 14.9–72.2]) experienced development of a grade 3 or 4 increase in alanine transaminase level and four (cumulative incidence 36.4% [95% CI: 10.0–64.2]) experienced development of a grade 3 or 4 increase in aspartate transaminase level. In comparison, among the 442 patients who received crizotinib only, a grade 3 or 4 increase in alanine transaminase level occurred in 34 patients (cumulative incidence 8.1% [95% CI: 5.7–11.0, p < 0.0001]) and a grade 3 or 4 increase in aspartate transaminase level occurred in 14 (cumulative incidence 3.4% [95% CI: 1.9–5.5, p < 0.0001]). There were no grade 5 transaminitis events. All cases of hepatotoxicity after sequential ICI and crizotinib use were reversible and nonfatal, and no case met the Hy’s law criteria. ConclusionsSequential ICI and crizotinib treatment is associated with a significantly increased risk of hepatotoxicity. Careful consideration and monitoring for hepatotoxicity may be warranted in patients treated with crizotinib after ICI therapy.

Clinical presentation of immune checkpoint inhibitor-induced inflammatory arthritis differs by immunotherapy regimen

IntroductionImmune checkpoint inhibitors (ICIs) are a class of cancer immunotherapy, increasingly utilized to treat malignancies. Inflammatory arthritis (IA) is a potential consequence of ICI use, but there is limited information to guide evaluation and management of this immune-related adverse event (irAE). This study aimed to characterize clinical phenotypes, IA treatment and response in the largest cohort of patients with ICI-induced IA reported to date. MethodsPatients with rheumatologist-confirmed IA occurring during or after ICI treatment with no prior history of autoimmune disease were included. Data were analyzed by ICI treatment regimen; treatments included combination CTLA-4/PD-1 inhibition, anti-PD-1 or anti-PD-L1 monotherapy. Relationship to the development of other irAEs, management of IA, and outcomes of IA management were evaluated. ResultsOf 30 patients identified, those treated with combination ICI therapy were more likely to present with knee arthritis, to have higher levels of C-reactive protein, to have already had another irAE, and to have a reactive arthritis-like phenotype. In contrast, patients treated with ICI monotherapy were more likely to have initial small joint involvement and to have IA as their only irAE. Ten patients required additional immunosuppression beyond corticosteroids, with TNF-inhibitors and/or methotrexate. Tumor progression while on non-corticosteroid immunosuppression was not seen in those with initial tumor response to ICIs. ConclusionThese data suggest that distinct IA phenotypes may emerge with exposure to different ICI regimens. The majority of patients referred to rheumatology required systemic immunosuppression to manage their IA symptoms. Tumor progression was not seen in patients requiring TNF-inhibitors.