[Comprehensive rehabilitation of immune-mediated adverse events in cancer patients receiving checkpoint inhibitor therapy]. / Kompleksnaya reabilitatsiya immunooposredovannykh nezhelatel'nykh yavlenii u patsientov so zlokachestvennymi opukholyami, poluchayushchikh terapiyu ingibitorami kontrol'nykh tochek.

OBJECTIVE: To evaluate adverse events and clinical effectiveness of complex rehabilitation programs in patients with malignant tumors receiving checkpoint inhibitor therapy. MATERIAL AND METHODS: The study included 144 cancer patients who received immunotherapy for the period from 2019 to 2021. Group 1 consisted of 72 patients who received a comprehensive rehabilitation program including physical therapy, diet therapy, psychotherapy, general magnetotherapy. Patients of the second (control) group (n=72) did not receive rehabilitation procedures. Effectiveness of treatment was evaluated according to RECIST 1.1 criteria, safety of treatment - according to CTCAE criteria (version 5.0, 2017). To assess the quality of life (QoL), the Russian version of the EORTC QLQ-C30 questionnaire was used. RESULTS: Mean follow-up period in the first group was 4.5 months, in the control group - 5 months. Disease progression was observed in 35 (48.6%) patients of the main group and 32 (44.4%) patients of the control group. Two (2.8%) patients in the control group demonstrated complete response to therapy. Partial response was established in both groups in 13 patients (18.1%). Stabilization of disease was detected in 24 (33.3%) and 25 (34.7%) patients, respectively. Adverse events were registered in 54 (75.0%) and 60 (83.3%) patients, respectively. Adverse events grade III-IV occurred in 9.7% and 11.1% of patients, respectively. CONCLUSION. I: Mmunotherapy combined with comprehensive rehabilitation program confirms high effectiveness of these drugs. We observed good tolerability of rehabilitation procedures that do not deteriorate the course of the underlying disease. However, there are certain important issues, in particular influence of rehabilitation procedures on tolerability of immunotherapy in patients with cancer.

Immune-related adverse events in the gastrointestinal tract: diagnostic utility of upper gastrointestinal biopsies.

AIMS: Immune checkpoint inhibitors (ICIs) improve survival across a range of malignancies but are also associated with a spectrum of gastrointestinal (GI) immune-related adverse events (GI-irAEs). The aims of this study were to explore the diagnostic value of gastric and duodenal biopsies and to address considerations in the differential diagnosis. METHODS AND RESULTS: We identified 39 patients who were treated with ICIs and had a subsequent upper GI biopsy. We recorded clinical data and endoscopic findings, and reviewed their gastric, duodenal and colonic biopsies. Twenty-one (54%) patients were treated with an anti-programmed cell death protein 1 (PD-1)/anti-programmed cell death ligand 1 antibody alone, and 17 (44%) patients were treated with a combination of anti-cytotoxic T-lymphocyte-associated protein-4 and anti-PD-1 antibodies. Thirty-two (82%) patients presented with diarrhoea. Gastric alterations included periglandular inflammation and granulomas, and duodenal changes included villous blunting, intraepithelial lymphocytosis, granulomas, and neutrophilic activity. We recognised four patterns of colonic injury: (i) acute self-limiting colitis; (ii) lymphocytic colitis; (iii) collagenous colitis; and (iv) apoptosis-only. Twenty-nine (74%) and 10 (26%) patients were diagnosed clinically as positive and negative for GI-irAEs, respectively. Gastric periglandular inflammation (P = 0.004) and an increased number of colonic lamina propria mononuclear cells (P = 0.04) correlated with the clinical diagnosis of a GI-irAE. Histological alterations associated with ICI injury were more often identified in upper GI biopsies (71%) than in colonic biopsies (65%). CONCLUSIONS: The morphological spectrum of ICI-related GI disease is broad, and mimics a range of infectious and inflammatory diseases. Gastric periglandular inflammation represents one of the more characteristic histological features of GI-irAEs. The study underscores the importance of a comprehensive review of upper and lower GI biopsies for the diagnosis of GI-irAEs.

[The use of immune checkpoint inhibitors in routine oncology]. / Der Einsatz von Immuncheckpoint-Inhibitoren im onkologischen Alltag.

BACKGROUND: The advent of immune checkpoint inhibitors has dramatically changed the treatment landscape of many different tumor types. In the clinical routine, humanized antibodies against the immune checkpoints cytotoxic T­lymphocyte associated protein 4 (CTLA-4) and programmed cell death 1/programmed cell death ligand 1 (PD1/PD-L1) are generally applied. OBJECTIVE: This article provides an overview of the treatment landscape with immune checkpoint inhibitors, especially for solid tumors in oncology. MATERIAL AND METHODS: Description and discussion of recent trial results as well as current treatment recommendations and treatment approval indications. RESULTS: In the clinical routine seven different immune checkpoint inhibitors are applied in oncology: one anti-CTLA­4 antibody, three anti-PD1 antibodies and three anti-PD-L1 antibodies. On the US market FDA approval for 17 different tumor entities and one agnostic indication (tumors with mismatch repair mechanism deficiency/high microsatellite instability). Long-term remission can be achieved for ca. two thirds of patients with tumor response. CONCLUSION: Clinical benefits for only a part of patients treated with immune checkpoint inhibitors. The understanding of primary and secondary mechanisms of resistance to immune checkpoint inhibitors has just begun to evolve. Combination strategies of immune checkpoint inhibitors with e.g. chemotherapy, new immune checkpoint inhibitors (e.g. anti-LAG3 antibody) or targeted therapies (e.g. CDK4/6, PARP inhibitors) to improve efficacy are under clinical investigation. Reliable and predictive biomarkers are urgently needed.

Tocilizumab for the management of immune mediated adverse events secondary to PD-1 blockade.

BACKGROUND: Immune checkpoint inhibitors are poised to revolutionize the management of a growing number of malignancies. Unfortunately, the management of steroid-refractory immune mediated adverse events is based on a paucity of randomized data and limited to single center experiences. Our initial experience with the IL-6 receptor antagonist tocilizumab showed clinical improvement in a wide variety of irAEs. As a result, we adopted the use of tocilizumab for the management of steroid refractory irAEs. METHODS: The character and clinical course of irAEs were abstracted from the medical record and analyzed. The dose of tocilizumab was 4 mg/kg given IV over one hour. C-reactive protein was drawn at first nivolumab infusion and at q two weeks (and with irAEs) thereafter. Clinical improvement was defined as either: documentation of resolution of symptoms or hospital discharge within seven days. RESULTS: Of the initial 87 patients that were treated with nivolumab, 34 required tocilizumab (39.1%). All patients were on corticosteroids. The majority (88.2%) were lung cancer patients. The index grade 3/4 irAE was pneumonitis in 35.3%, serum sickness/SIRS in 35.3%, cerebritis in 14.7% and one case each of hypophysitis, colitis, pancreatitis, hepatitis and immune mediated coagulopathy. Median time between first nivolumab and initiation of tocilizumab was 76 days (range 1-429). There was a statistically significant increase in C-reactive protein from a median of 23 mg/L (range 0.1-238.5) at baseline to 109.3 mg/L (21.5-350.4) at the time of index irAE, followed by a decrease to 19.2 mg/L (0.25-149) after tocilizumab ( p < 0.00001). Clinical improvement was noted in 27/34 patients (79.4%). Some patients (52.9%) required a single dose, while 38.2% required two, 8.8% required three and 1 patient required four doses. Twenty-seven doses were given in the inpatient setting (49.1%). Median time to discharge was four days (range 1-27). Seventy-four percent of patients were discharged home. For the 53 doses of tocilizumab that were delivered when infliximab was an option, there was a cost savings of $141,048.72 (WAC) during the 18 month study period. CONCLUSIONS: Tocilizumab may be a therapeutic option for the management of steroid refractory irAEs secondary to immune checkpoint blockade. However, randomized trials are needed to better elucidate the relative efficacy and safety of these agents.

A Multicentric, Retrospective, Real-world Study on Immune-related Adverse Events in Patients with Advanced Non-small Cell Lung Cancers Treated with Pembrolizumab Monotherapy.

AIMS: We present 7 years of clinical experience with single-agent pembrolizumab immune checkpoint inhibitor immunotherapy in non-small cell lung cancers (NSCLC) from four UK cancer centres. MATERIALS AND METHODS: This multi-institutional retrospective cohort study included 226 metastatic NSCLC patients. Outcomes were number and severity of immune-related adverse events (irAEs), median progression-free survival (mPFS) and median overall survival (mOS). RESULTS: Within our cohort, 119/226 (53%) patients developed irAEs. Of these, 54/119 (45%) experienced irAEs affecting two or more organ systems. The most common irAEs were diarrhoea and rash. The development of an irAE was associated with better mOS (20.7 versus 8.0 months; P < 0.001) and mPFS (12.0 versus 3.9 months; P < 0.001). The development of grade 3/4 toxicities was associated with worse outcomes compared with the development of grade 1/2 toxicities (mOS 6.1 months versus 25.2 months, P < 0.01; mPFS 5.6 months versus 19.3 months, P = 0.01, respectively). Females had a higher proportion of reported grade 3/4 toxicities (13/44 [29.5%] versus 10/74 [13.5%], P = 0.03). Using a multiple Cox regression model, the presence of irAEs was associated with a better overall survival (hazard ratio = 0.42, 95% confidence interval 0.29-0.61; P < 0.01) and better PFS (hazard ratio 0.38, 95% confidence interval 0.27-0.53; P < 0.001). CONCLUSION: In this multicentre retrospective cohort study, the development of at least one irAE was associated with significantly longer mPFS and mOS; however, more severe grade 3 and 4 irAEs were associated with worse outcomes. Delayed-onset irAEs, after the 3-month timepoint, were associated with better clinical outcomes.

An overview and single-arm meta-analysis of immune-mediated adverse events following COVID-19 vaccination.

Background: We conducted an overview to assess immune adverse effects associated with the COVID-19 vaccine, guiding safer choices and providing evidence-based information to clinicians. Methods: Forty-three studies on adverse effects of vaccines were reviewed from PubMed, Embase, and Web of Science. Single-arm meta-analyses estimated summary effects, incidence, presentation, etc. An overview using single-arm meta-analysis and reported the findings following the guidelines outlined in the 'Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) specifically focusing on myocarditis and thrombosis. After screening 2,591 articles, 42 studies met the inclusion criteria. Methodological quality was evaluated using AMSTAR 2. Disagreements were resolved via consensus. Data analysis utilized a random-effects model in R software to estimate incidence rates of selected adverse events. Results: After removing 1,198 duplicates and screening out irrelevant articles from a total of 2,591, we included 42 studies. Adverse reactions to vaccinations include myocarditis, thrombosis, skin reactions, GBS, etc. thrombosis and myocarditis are the most dangerous diseases associated with vaccination. Myocarditis occurred in 6% of Vector vaccine recipients, compared to 61% of mRNA vaccine recipients. Thrombosis was more common after Vector vaccination (91%) than after mRNA vaccination (9%). Furthermore, eight studies conducted anti-PF4 antibody tests and yielded a positivity rate of 67%. Meta-analysis showed that among all patients with Vaccine-induced Thrombotic Thrombocytopenia, cerebral venous sinus thrombosis occurred in 66%, and intracranial hemorrhage occurred in 43%. The rates of deep vein thrombosis and pulmonary thromboembolism in vaccinated patients were 13% and 23%, respectively, with a pooled case fatality rate of 30%. Conclusion: The results of this overview indicate the majority of adverse reactions are self-limiting and require minimal intervention, while rare occurrences such as myocarditis and thrombosis pose a potentially fatal threat.

Recurrent pembrolizumab-induced mechanical small bowel obstruction in a patient with metastatic cervical cancer.

•Adverse events of pembrolizumab have been documented, but more severe gastrointestinal effects are not as well described.•We report a case of a patient with cervical cancer treated with pembrolizumab who developed small bowel obstruction (SBO)•Histological analysis and gastrointestinal workup points to pembrolizumab as likely cause of SBO.

Immune checkpoint inhibitors and risk of immune-mediated adverse events: a cohort study comparing extended versus standard interval administration.

The COVID-19 pandemic precipitated the implementation of extended interval immune checkpoint inhibitors (ICIs) in an effort to limit hospital visits, but few studies have examined their safety. This study aimed to compare in oncology outpatients, immune-mediated adverse events (IMAEs) in terms of total number, incidence, severity, and time to occurrence, based on exposure to standard or extended interval ICIs. A retrospective cohort study was conducted in patients who received at least one dose of an ICI between 2015 and 2021. Data were collected from patient records and pharmacy software. Adjusted logistic, Poisson, and Cox regression models were estimated. A total of 310 patients with a mean age of 67.1 years were included, 130 of whom had the extended interval. No statistically significant differences were observed between the groups. With the standard and extended intervals, the mean total number of IMAE per participant was 1.02 and 1.18, respectively; the incidence of an IMAE was 62% and 64%. Of the 147 IMAE episodes in the standard interval group, 14 (9.5%) were grade 3 or higher, while there were 15 (12.4%) among the 121 IMAE episodes in the extended interval group. Compared with standard interval, the use of extended interval did not increase the risk of having a first IMAE (adjusted hazard ratio 0.92 (95% CI 0.67-1.26)). This study suggests that the administration of an ICI according to extended interval is as safe as the administration according to standard interval in oncology outpatients.

Adult-Onset Still's Disease After an mRNA COVID-19 Vaccine in an Older Woman.

Adult-onset Still's disease (AOSD) is an uncommon autoinflammatory disorder without a clear etiology that primarily affects young adults. New-onset disease at > 80 years of age is uncommon. We present the case of an 82-year-old woman with AOSD which developed after receiving a messenger ribonucleic acid (mRNA) coronavirus disease 2019 (COVID-19) vaccine. COVID-19 vaccines are known to cause overproduction of cytokines, systemic inflammation, and some immune-mediated adverse events, such as rheumatoid arthritis, systemic lupus erythematosus, dermatomyositis, vasculitis, and polymyalgia rheumatica after the vaccination has been reported. A handful of cases of AOSD after the vaccination have also been reported and the median age was 40s. However, AOSD related to COVID-19 vaccination can develop even in older individuals.

Safety of First-Line Nivolumab Plus Ipilimumab in Patients With Metastatic NSCLC: A Pooled Analysis of CheckMate 227, CheckMate 568, and CheckMate 817.

INTRODUCTION: We characterized the safety of first-line nivolumab plus ipilimumab (NIVO+IPI) in a large patient population with metastatic NSCLC and efficacy outcomes after NIVO+IPI discontinuation owing to treatment-related adverse events (TRAEs). METHODS: We pooled data from three first-line NIVO+IPI studies (NIVO, 3 mg/kg or 240 mg every 2 wk; IPI, 1 mg/kg every 6 wk) in metastatic NSCLC (CheckMate 227 part 1, CheckMate 817 cohort A, CheckMate 568 part 1). Safety end points included TRAEs and immune-mediated adverse events (IMAEs) in the pooled population and patients aged 75 years or older. RESULTS: In the pooled population (N = 1255), any-grade TRAEs occurred in 78% of the patients, grade 3 or 4 TRAEs in 34%, and discontinuation of any regimen component owing to TRAEs in 21%. The most frequent TRAE and IMAE were diarrhea (20%; grade 3 or 4, 2%) and rash (17%; grade 3 or 4, 3%), respectively. The most common grade 3 or 4 IMAEs were hepatitis (5%) and diarrhea/colitis and pneumonitis (4% each). Pneumonitis was the most common cause of treatment-related death (5 of 16). Safety in patients aged 75 years or older (n = 174) was generally similar to the overall population, but discontinuation of any regimen component owing to TRAEs was more common (29%). In patients discontinuing NIVO+IPI owing to TRAEs (n = 225), 3-year overall survival was 50% (95% confidence interval: 42.6-56.0), and 42% (31.2-52.4) of 130 responders remained in response 2 years after discontinuation. CONCLUSIONS: First-line NIVO+IPI was well tolerated in this large population with metastatic NSCLC and in patients aged 75 years or older. Discontinuation owing to TRAEs did not reduce long-term survival.

Successful treatment with carboplatin and paclitaxel in melanoma progression after immune-related adverse events.

The overall survival of melanoma patients has improved using antibodies targeting immune checkpoints (anti-PD-1, anti-CTLA-4 and anti-LAG-3). Systemic chemotherapy was administered in melanoma for many years with limited effectiveness. Here we report a case of a patient who experienced immune-mediated adverse effects from checkpoint blockade therapy and subsequently responded to chemotherapy. The patient presented with melanoma and paraneoplastic digital ischemia. She received a combination of ipilimumab/nivolumab and experienced G3 myocarditis, followed by melanoma progression after a steroid taper. This patient achieved a partial and durable response with platinum and taxane-based chemotherapy. This report suggests the possibility of a subset of patients who experience progression after immune-based side effects where chemotherapy may be effective in the modern age of melanoma treatment.

We describe a patient with a type of skin cancer called melanoma. At first, we tried to treat it with a medication that made the patient's body's defense system fight against it, but it caused problems with her heart so we had to stop it. Instead, we used another type of treatment called chemotherapy, which worked. The patient remains off therapy 4.5 years later. The lesson learned from this case is that chemotherapy is still helpful in certain situations. The initial treatment did not stop the melanoma growth. In addition, the patient had life-threatening toxicity.

Rheumatological Adverse Events of Cancer Therapy with Immune Checkpoint Inhibitors.

Latin America is experiencing a demographic and epidemiological transition, with an increase in non-communicable diseases such as cancer. One of the greatest advances in the therapeutic approach to cancer has been the discovery of immunotherapy, and specifically of checkpoint inhibitors (CPIs). Since inhibition of CTLA-4 and PD-1/PD-L1 enhances the immune response, cancer immunotherapies are associated with a new class of toxicities of autoimmune and/or autoinflammatory origin. These immune-related adverse events (irAEs) result in a broad spectrum of clinical events including rheumatic clinical syndromes, which may resemble classic rheumatic diseases. The most common rheumatic manifestations include inflammatory arthritis, myositis, vasculitis, and sicca syndrome. Recognizing rheumatologic irAEs is challenging due to the wide spectrum of clinical presentations that often do not fulfill traditional classification criteria of rheumatic diseases. A delayed diagnosis and treatment can lead to long-term disability, and disorders may become chronic and require ongoing immunosuppressive therapy. The management of irAEs includes the prompt detection and appropriate grading since their management is dictated by their severity. The growing use of CPIs, and the ensuing increase in irAEs, warrants an increasing collaboration between rheumatologists and oncologists. Understanding the pathophysiology, diagnosis, grading, and therapeutic implications of irAEs in patients with cancer is thus a requirement for Latin American oncologists and rheumatologists alike.

Immune-Related Thyroiditis as a Predictor for Survival in Metastatic Renal Cell Carcinoma.

Immune checkpoint inhibitors (CPI) are indicated for metastatic renal cell carcinoma (mRCC). Immune-related thyroiditis (irT), an immune-related adverse event (irAE), affects up to 30% of patients. We aimed to determine whether irT is associated with overall survival in mRCC. A retrospective cohort study of 123 consecutive patients treated with CPI for mRCC in a single center between 2015 and 2020 was conducted. Disease risk stratification was assessed by two methods: Heng criteria and a novel dichotomic stratification system to "Low risk" versus "High risk" adding number of metastatic sites. Thirty-eight percent of patients developed irT. In the general cohort, irT was not associated with a survival benefit. However, irT was associated with better survival in the poor risk group per Heng criteria (n = 17, HR = 0.25, p = 0.04) and in the novel "High risk" group (HR = 0.28, n = 42, p = 0.01), including after accounting for covariates in multivariate analysis (HR = 0.27, p = 0.003). Having any irAE was associated with improved survival in the whole cohort, with no significant correlation of any specific irAE, in either the whole cohort or the "High risk" group. We conclude that irT is an early and prevalent irAE, associated with prolonged survival in patients with poor/"High" risk mRCC.

Primary results of STRONG: An open-label, multicenter, phase 3b study of fixed-dose durvalumab monotherapy in previously treated patients with urinary tract carcinoma.

BACKGROUND: Prior durvalumab (anti-PD-L1 agent) studies in platinum-refractory metastatic urothelial carcinoma evaluated a dose of 10 mg/kg administered every two weeks. The nonrandomised phase 3b STRONG study (NCT03084471) evaluated the safety and efficacy of fixed-dose durvalumab at a more convenient dosing schedule in a previously treated patient population, more similar to a real-world clinical setting. PATIENTS AND METHODS: 867 patients with urothelial or nonurothelial urinary tract carcinoma (UTC) who progressed on or after platinum or nonplatinum chemotherapy were treated with durvalumab 1500 mg every four weeks; 87% had an Eastern Cooperative Oncology Group performance status (ECOG PS) of 0-1, and 13% had an ECOG PS of 2. The primary end-point was the incidence of adverse events of special interest (AESIs), including immune-mediated AEs (imAEs). Secondary and exploratory end-points included overall survival (OS), objective response rate (ORR) and disease control rate (at six and 12 months) (DCR). RESULTS: AESIs of any grade were reported in 51% of patients (8% grade ≥ 3). The incidence of imAEs was 11% (2% grade ≥ 3). The median OS was 7.0 months (95% confidence interval [CI]: 6.4-8.2) and ORR was 18% (95% CI: 14.8-20.6), with complete responses in 5% of patients and a DCR at six months of 19% (95% CI: 16.1-22.1). CONCLUSION: Fixed-dose durvalumab monotherapy every four weeks has an acceptable safety profile and yields durable clinical activity in previously chemotherapy-treated patients with UTC. Safety and efficacy are consistent with previous durvalumab studies and other anti-PD-1/PD-L1 agents in this setting. CLINICALTRIALS. GOV IDENTIFIER: NCT03084471https://clinicaltrials.gov/ct2/show/NCT03084471.

CXCR5+CD8 T cells: Potential immunotherapy targets or drivers of immune-mediated adverse events?

CXCR5+CD8 T cells have attracted significant interest within multiple areas of immunology, cancer, and infection. This is in part due to their apparent dual functionality. These cells perform as cytotoxic cells in a variety of infection states including LCMV, HBV, HIV and SIV. However, CXCR5+CD8 T cells also associate with B cells in peripheral organs and function to stimulate B cell proliferation, antibody/B cell receptor class-switch, and antibody production. CXCR5+CD8 T cells are similar to CXCR5+CD4 T follicular helpers in their genetic make-up, B cell interactions, and functionality despite possessing elevated programmed cell death 1 and cytotoxic proteins. Within cancer CXCR5+CD8 T cells have risen as potential prognostic markers for overall survival and are functionally cytotoxic within tumor microenvironments. In inflammatory disease and autoimmunity, CXCR5+CD8 T cells are implicated in disease progression. During viral infection and cancer, CXCR5 expression on CD8 T cells generally is indicative of progenitor memory stem-like exhausted cells, which are more responsive to immune checkpoint blockade therapy. The use of immune checkpoint inhibitors to overcome immune exhaustion in cancer, and subsequent consequence of immune adverse events, highlights the dual nature of the cellular immune response. This review will detail the functionality of CXCR5+CD8 T cells in cancer and autoimmunity with potential repercussions during immune checkpoint blockade therapy discussed.

[Side effects of immune checkpoint inhibitor treatment of urological tumors]. / Nebenwirkungen der Immun-Checkpoint-Inhibitor-Therapie urologischer Tumoren.

Immune checkpoint inhibitors (ICI) are currently routinely used for the treatment of advanced or metastatic urothelial and renal cell carcinomas. Furthermore, several clinical trials are currently investigating their role in adjuvant and neoadjuvant settings as well as in high-risk non-muscle-invasive bladder cancer. As a result, urologists are increasingly confronted with patients who are currently receiving, have recently received or will receive ICI treatment. Care is often interdisciplinary, with urologists playing a central role. Therefore, a profound understanding of immune-mediated adverse events and their differential diagnoses with respect to side effects of other medications in combination treatment are therefore extremely important. This article focusses on the prevention, early diagnosis and clinical management of the most relevant immune-related side effects derived from the new VEGFR-TKI/ICI combinations.

Safety and Efficacy of Nivolumab in Patients With Advanced Clear Cell Renal Cell Carcinoma: Results From the Phase IIIb/IV CheckMate 374 Study.

BACKGROUND: The open-label, phase IIIb/IV CheckMate 374 study (NCT02596035) was conducted to validate the safety and efficacy of flat-dose nivolumab monotherapy 240 mg every 2 weeks (Q2W) in previously treated advanced/metastatic renal cell carcinoma (RCC). Three cohorts included patients with predominantly clear cell histology, non-clear cell histologies, or brain metastases. We report safety and efficacy from the CheckMate 374 advanced clear cell RCC (ccRCC) cohort. PATIENTS AND METHODS: Eligible patients received prior treatment regimens (1-2 antiangiogenic; 0-3 systemic) with progression on/after last treatment and ≤ 6 months of enrollment. Patients received nivolumab 240 mg Q2W for ≤ 24 months or until confirmed progression/unacceptable toxicity. The primary endpoint was incidence of high-grade (grade 3-5) immune-mediated adverse events (IMAEs). Exploratory endpoints included objective response rate, progression-free survival, and overall survival. RESULTS: Ninety-seven patients had advanced predominantly ccRCC; 75.3% received only 1 prior systemic regimen in the advanced/metastatic setting. After a median follow-up of 17 months (range, 0.4-26.9 months), no grade 5 IMAEs occurred, and 9.3% of patients reported grade 3/4 IMAEs (hepatitis, 4.1%; diabetes mellitus, 2.1%; nephritis and renal dysfunction, 1.0%; rash, 1.0%; adrenal insufficiency, 1.0%). The objective response rate was 22.7% (95% confidence interval [CI], 14.8%-32.3%). Three patients had a complete response; 19 had partial responses. The median progression-free survival was 3.6 months (95% CI, 2.0-5.5 months). The median overall survival was 21.8 months (95% CI, 17.4 months to not estimable). CONCLUSIONS: This study validates the safety and efficacy of nivolumab 240 mg Q2W flat-dose monotherapy for previously treated advanced ccRCC and adds to previous safety and efficacy data using the 3 mg/kg Q2W dose.

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.

Acute and Long-term Adverse Events Associated With Checkpoint Blockade.

OBJECTIVE: To provide an overview of the spectrum of immune-related adverse events associated with immune checkpoint therapy, including presentation, evaluation, management, and nursing considerations. DATA SOURCES: Peer-reviewed articles, published literature, national guidelines, Internet. CONCLUSION: Immune checkpoint inhibitor therapies are have become a therapeutic treatment options for many cancers. These therapies promote activity of a patient's adaptive immune system to eradicate cancer. The agents are associated with a unique side-effect profile called Immune-related adverse events. Most of these are low severity. However, if they become more severe, they can be life-threatening or result in permanent organ dysfunction. The key to optimizing therapies is collaborative monitoring, evaluation, documentation, management, communication. IMPLICATIONS FOR NURSING PRACTICE: Oncology nurses are the front line of patient care. Nurses must have a thorough understanding of the mechanism of action, potential immune-related adverse events, clinical implications, and management strategies. They are responsible for educating patients about immune checkpoint therapies and the potential side effects that may develop, triage management strategies, and coordination of care.

Autoimmune rhabdomyolysis and a multiorgan display of PD-1 inhibitor induced immune related adverse events during treatment of metastatic melanoma.

BACKGROUND: Programmed death-1 (PD-1) inhibitors are among the immunotherapies that have revolutionized our approach to treating several cancers. These novel agents act by blocking PD-1 receptor/PD-1 ligand interactions that would otherwise allow tumor cells to evade host immune destruction by inhibiting response of cytotoxic T-lymphocytes. They are overall well tolerated, though they have been associated with a constellation of immune mediated adverse events (irAEs). CASE PRESENTATION: We present a case of rare nivolumab mediated adverse events in a patient with nodular recurrence of melanoma. The patient presented with rhabdomyolysis and shortly thereafter developed a constellation of immune-mediated organ derangements. This case further demonstrates the utility and effectiveness of steroid therapy in the setting of irAEs despite our patient's eventual poor clinical outcome. While PD-1 inhibitors have revolutionized the treatment of several cancers, they require vigilance by the clinician for early detection and treatment of uncommon but potentially fatal irAEs. CONCLUSIONS: PD-1 inhibitors are now widely used in a multitude of cancer types including melanoma, advanced non-small cell lung cancer, metastatic renal cell carcinoma, and Hodgkin lymphoma amongst others. While these agents are often well tolerated, they are associated with a unique profile of immune-related toxicities that can cause significant morbidity and mortality. Education of both patients and healthcare providers is essential for diagnosis and treatment of these adverse events early in their course. This case highlights the uncommon but potentially serious PD-1-associated toxicity of myopathy and rhabdomyolysis along with other organ involvement and is directly applicable to use of these agents in patients with advanced cancers.