Receiving Checkpoint Inhibitors Research Articles

Abstract 371: A single-center retrospective review assessing the use of tumor mutation burden as a predictor of therapeutic success in patients receiving immunotherapy

Abstract Background Cancer is a genetic disease in which cells may accumulate somatic mutations. The measurement of the frequency these somatic mutations occur is referred to as tumor mutational burden or TMB. A minority of these mutations may give rise to neoantigens that could in turn be recognized and targeted by the immune system. The more somatic mutations a tumor develops, the more likely these neoantigens are to form. Recent studies, namely KEYNOTE-158, found high TMB status to be associated with improved outcomes in patients receiving pembrolizumab monotherapy. Materials and Methods This was a single-center retrospective study that analyzed 73 patients who received cancer treatment at Avera Cancer Institute between June 2016 and July 2019. Patients were included/excluded from the final analysis based on having received at least one dose of pembrolizumab, ipilimumab, and/or nivolumab. Information was collected on patient characteristics, treatment, and clinical outcomes. The primary outcomes were complete and partial response rates and were assessed objectively based on a composite of radiographic reports, physician documentation, and treatment course. Secondary outcomes were clinical outcomes in patients with PD-1 and/or PD-L1 expression, clinical outcomes in patients receiving mono-immunotherapy vs combination therapy, and clinical outcomes based on the line of treatment in which immunotherapy was utilized. Results A total of 34 patients met the inclusion criteria of having a high TMB value (10 mutations/megabase) and having received one dose of pembrolizumab, ipilimumab, or nivolumab. Primary Outcomes•16 patients experienced a partial response (AR = 0.47) and 6 of these patients experienced a complete response (AR = 0.17) Secondary Outcomes•Absolute risk with prior TMB information (PR 0.43, CR: 0.17)•Absolute risks for monotherapy (PR: 0.375, CR: 0.125) vs combination therapy (PR: 0.556, CR: 0.375)•Average line of treatment for TF, PR, and CR were 2.24, 2, and 1.83 respectively. Discussion Studies like KEYNOTE-158 found a significant correlation between high TMB and improved clinical outcomes in patients receiving checkpoint inhibitors. However, in this cohort of patients high TMB status was not a good predictor of therapeutic success compared to the data presented in KEYNOTE-001, CHECKMATE-057, OAK, or PACIFIC. While there are limitations associated with the sample size, the data support that checkpoint therapy benefits patients when it is used earlier in their treatment course and combined with other treatments. Further exploration is required to determine the most appropriate cut point for calling a patient TMB high as well as how TMB and PD-L1 predict response to specific therapies. Citation Format: Khai Nguyen, Bing Xu, Rachel Elsey, Tobias Meissner, Casey Williams. A single-center retrospective review assessing the use of tumor mutation burden as a predictor of therapeutic success in patients receiving immunotherapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 371.

Th1/17 Cells Are Expanded in Bronchial Alveolar Lavage (BAL) Fluid from Leukemia Patients with Checkpoint Inhibitor-Induced Pneumonitis

A number of clinical trials are evaluating immune checkpoint inhibitors in patients with AML/MDS with encouraging results (Daver N et al, EHA 2017; Garcia-Manero et al, EHA 2017). Approximately 5-10% of patients with leukemia treated with checkpoint inhibitors had immune related adverse event (irAE) of pneumonitis, one of the life-threatening irAEs. Increased awareness, distinction from infectious pneumonia, and early intervention are critical in the management of pneumonitis-irAEs in patients with leukemia. Especially in the setting of acute leukemia the ability to distinguish immune mediated pneumonitis from infectious pneumonia is critical to determine whether or not the addition of high-dose steroids is warranted. The mechanisms of pneumonitis-irAE, the most important step for risk stratification and early detection remain elusive.MethodsWe collected bronchial alveolar lavage (BAL) fluid from seven leukemia patients (6 AML/MDs and 1 Richter transformation) who received checkpoint inhibitor based therapy on clinical trials, and subsequently developed respiratory symptoms and had a bronchoscopy. As a control, we collected BAL fluid from two AML/MDS patients who had never received checkpoint inhibitor therapy. We stained BAL CD4 T cell with lineage specific surface markers using the following antibodies; anti-CD4 BUV396, anti-CXCR3 BV 421, anti-CD45RA BV786, anti-CD3 PerCP, anti-CCR6 FITC, anti-CD25 PE, anti-PD-1 PE-Dazzle, anti-CXCR5 APC, and anti-CD127 APC 700. BAL CD4 T cell subsets, including Th1, 2, 17, follicular helper T, and regulatory T cells, were enumerated and the proportion and profile of the CD4 T cell subsets within the total lymphocytes were compared between pneumonitis group and control group.ResultPatient demographics are described in Figure 1A. Mean age of the patients with pneumonitis-irAE was 56. Most of them were on nivolumab in combination with chemotherapy/hypomethylator therapy. The patients developed pneumonitis 52.7 ± 77.8 days (mean ± DS) after the first exposure to a checkpoint inhibitor. Compared to the control group, lymphocytes were expanded in pneumonitis group (% lymphocytes, disease versus control: 32.3% vs. 19.0%). This observation led us to further characterize the lymphocytes in available BAL samples, especially CD4 T cells given their central role in immune efficacy and toxicity. Interestingly, Th1/17 hybrid cells (CXCR3hi CCR6hi), known to be pathogenic in autoimmune diseases, were expanded in the pneumonitis group compared to the control (8.24 % vs 3.19 %) (Figure 1B and C) These Th1/17 hybrid cells express high level of PD-1, suggesting their hyperactive status. Although premature, there was a trend that regulatory T cells were decreased in pneumonitis group (Data not shown). Surface staining of CD4 T cells in BAL fluid revealed that both disease and control had no follicular helper T cells, the CD4 T cell subset governing humoral immunity. Consistently, B cells were barely detected in BAL in both groups (Data not shown).ConclusionThese results suggest the possibility of increased Th1/17 hybrid cells with decreased Tregs as a biomarker of pneumonitis. The high PD-1 expression on Th1/17 hybrid cells suggests activation (or exhaustion) in the lungs in patients with irAEs. Further investigation of Th1/17 hybrid cells and correlation with peripheral blood may provide an insight into the mechanisms of pneumonitis-irAEs and biomarkers for early detection. In parallel, decreased Treg in the BAL may indicate an increased susceptibility to immune activation and inflammation seen in irAEs. [Display omitted] DisclosuresKantarjian:Novartis: Research Funding; Amgen: Research Funding; Bristol-Meyers Squibb: Research Funding; Delta-Fly Pharma: Research Funding; ARIAD: Research Funding; Pfizer: Research Funding. Sharma:Jounce: Consultancy, Other: stock, Patents & Royalties: Patent licensed to Jounce; Evelo: Consultancy, Other: stock; Astellas: Consultancy; EMD Serono: Consultancy; Consetellation: Other: stock; Amgen: Consultancy; Kite Pharma: Consultancy, Other: stock; Neon: Consultancy, Other: stock; BMS: Consultancy; Astra Zeneca: Consultancy; GSK: Consultancy. Daver:Otsuka America Pharmaceutical, Inc.: Consultancy; Karyopharm: Consultancy, Research Funding; Sunesis Pharmaceuticals, Inc.: Consultancy, Research Funding; Immunogen: Research Funding; Daiichi-Sankyo: Research Funding; Kiromic: Research Funding; Novartis Pharmaceuticals Corporation: Consultancy; Bristol-Myers Squibb Company: Consultancy, Research Funding; Pfizer Inc.: Consultancy, Research Funding; Jazz: Consultancy; Incyte Corporation: Honoraria, Research Funding.

Immune checkpoint inhibitor-associated acute kidney injury and mortality: An observational study.

BackgroundImmune checkpoint inhibitors, approved for the treatment of various types of cancer, are known to cause a unique spectrum of side effects, including acute kidney injury (AKI). The aim of this study was to describe the incidence, risk factors, renal outcomes, and mortality of AKI in patients receiving checkpoint inhibitors.MethodsPatients receiving checkpoint inhibitors between January 2013 and May 2020 at the University Medical Center Utrecht, the Netherlands, were identified using the Utrecht Patient Oriented Database. AKI was defined as an increase in serum creatinine of ≥1.5 times the baseline value, based on the Kidney Disease: Improving Global Outcomes criteria. Cox proportional hazard regression analysis was used to assess risk factors for AKI and to evaluate the relationship between AKI and mortality. Persistent renal dysfunction was diagnosed in AKI patients with a final serum creatinine measurement of >1.3 times the baseline value.ResultsAmong 676 patients receiving checkpoint inhibitors, the overall incidence of AKI was 14.2%. Baseline variables independently associated with AKI were a gynecologic malignancy, monotherapy with ipilimumab, and the use of a diuretic, angiotensin-converting enzyme inhibitor or angiotensin-receptor blocker, or proton pump inhibitor at baseline. AKI was checkpoint inhibitor-associated in one third of all patients with AKI. Checkpoint inhibitor-associated AKI was mostly low-grade, occurred a median of 15 weeks after checkpoint inhibitor initiation, and resulted in persistent renal dysfunction in approximately 40% of the patients. Patients with all-cause AKI had a twofold increased mortality risk, but checkpoint inhibitor-associated AKI was not associated with increased mortality.ConclusionsIn this study, patients receiving checkpoint inhibitors frequently developed AKI due to various etiologies. AKI directly related to the effect of checkpoint inhibitor toxicity did not increase mortality. However, AKI not related to the effect of checkpoint inhibitor toxicity was associated with increased mortality.

MO363CHECKPOINT-INHIBITOR-ASSOCIATED ACUTE KIDNEY INJURY AND MORTALITY: AN OBSERVATIONAL STUDY

Abstract Background and Aims Immune checkpoint inhibitors, approved for the treatment of various types of cancer, are known to cause a unique spectrum of autoimmune-related side effects, including acute kidney injury (AKI). The aim of this study was to describe the incidence, risk factors, renal outcomes, and mortality of AKI in patients receiving checkpoint inhibitors. Method Patients receiving checkpoint inhibitors between January 2013 and May 2020 were identified using the Utrecht Patient Oriented Database. AKI was defined as an increase in creatinine of ≥1.5 times the baseline value. Cox proportional hazard regression analysis was used to assess risk factors for AKI and to evaluate the relationship between AKI and mortality. Persistent kidney injury was diagnosed in AKI patients with a final creatinine measurement of >1.3 times the baseline value. Results Out of 676 patients receiving checkpoint inhibitors, AKI occurred in 96 (14.2%) patients. Chart review showed that AKI was checkpoint inhibitor-associated in 32 (4.7%) patients. Baseline variables associated with AKI were a primary gynecological malignancy (HR 3.91, 95% CI 1.55 to 9.85), treatment with checkpoint inhibitor ipilimumab (HR 2.31, 95% CI 1.03 to 5.20), and pre-existent use of a diuretic (HR 2.61, 95% CI 1.21 to 5.60), an angiotensin-converting enzyme inhibitor or angiotensin-receptor blocker (HR 2.49, 95% CI 1.10 to 5.60), and a proton pump inhibitor (HR 1.69, 95% CI 1.04 to 2.75). In 35.4% of the patients who had developed AKI, persistent kidney dysfunction was observed at the end of follow-up. Patients who developed AKI had a 2.13-fold (95% CI 1.58 to 2.87) increased mortality risk compared to patients who did not develop AKI. Mortality risk was not increased by checkpoint inhibitor-associated AKI (HR 1.11, 95% CI 0.64 to 1.92), but only by AKI related to other causes (HR 2.87, 95% CI 2.04 to 4.04). Conclusion Patients receiving checkpoint inhibitors frequently develop AKI, however, checkpoint inhibitor-associated AKI does not seem to increase mortality.

Complete Metabolic Response in FDG-PET-CT Scan before Discontinuation of Immune Checkpoint Inhibitors Correlates with Long Progression-Free Survival.

Simple SummaryImmunotherapy is the standard of care in patients harboring metastasized melanoma. However, once further tumor growth is stopped it remains unclear when immunotherapy can be safely ceased. This clinical question is increasingly raised especially in patients with a strong desire to discontinue therapy or in patients who are forced to pause treatment due to severe immune-related side effects. With our study we aim to provide data which may be helpful for clinicians and patients when treatment discontinuation is considered. Further prospective, multicenter studies are needed to further address this important clinical issue.Checkpoint inhibitors have revolutionized the treatment of patients with metastasized melanoma. However, it remains unclear when to stop treatment. We retrospectively analyzed 45 patients (median age 64 years; 58% male) with metastasized melanoma from 3 cancer centers that received checkpoint inhibitors and discontinued therapy due to either immune-related adverse events or patient decision after an (18F)2-fluoro-2-deoxy-D-glucose positron emission tomography (FDG-PET) combined with a low-dose CT scan (FDG-PET-CT) scan without signs for disease progression. After a median of 21 (range 1–42) months of immunotherapy an FDG-PET-CT scan was performed to evaluate disease activity. In these, 32 patients (71%) showed a complete metabolic response (CMR) and 13 were classified as non-CMR. After a median follow-up of 34 (range 1–70) months, 3/32 (9%) of CMR patients and 6/13 (46%) of non-CMR patients had progressed (p = 0.007). Progression-free survival (PFS), as estimated from the date of last drug administration, was significantly longer among CMR patients than non-CMR (log-rank: p = 0.001; hazard ratio: 0.127; 95% CI: 0.032–0.511). Two-year PFS was 94% among CMR patients and 62% among non-CMR patients. Univariable Cox regression showed that metabolic response was the only parameter which predicted PFS (p = 0.004). Multivariate analysis revealed that metabolic response predicted disease progression (p = 0.008). In conclusion, our findings suggest that patients with CMR in an FDG-PET-CT scan may have a favorable outcome even if checkpoint inhibition is discontinued.

Overall survival in patients who received checkpoint inhibitors after completing tebentafusp in a phase 3 randomized trial of first-line metastatic uveal melanoma.

9526 Background: Tebentafusp (tebe) is a bispecific consisting of an affinity-enhanced T cell receptor fused to an anti-CD3 effector that can redirect T cells to target gp100+ cells. Tebe significantly improved OS compared to investigator’s choice (IC) in first line (1L) mUM [NCT03070392]. In a phase (ph) 2 study of tebe in 2L+ mUM (NCT02570308), several checkpoint inhibitor (CPI) refractory pts who were retreated with CPI after tebe achieved durable clinical benefit [1]. We therefore evaluated clinical outcomes of post-tebe CPI in patients treated on the ph3 trial of tebe versus investigator’s choice (IC) [NCT03070392]. Methods: In the ph3 trial, 378 HLA-A*02:01+ 1L mUM pts were randomized 2:1 to tebe (n=252) or IC (n=126) [pembrolizumab (82%), ipilimumab (12%) or dacarbazine (6%)]. No crossover to tebe was permitted, investigators were free to choose subsequent therapy, and there was no re-randomization at time of subsequent therapy. This analysis was conducted on the first interim analysis (data extracted Nov-2020). When pts received more than one subsequent therapy, the first was used in these analyses. Medians and 1-yr OS from the start of post-study therapy are obtained from standard Kaplan-Meier analyses; hazard ratios (HR) are from Cox regression models adjusted for age and gender. Results: 106/252 (42%) tebe pts received ≥ 1 subsequent therapy: 35% CPI, 9% chemo, 6% liver directed therapy (LDT), 6% other. 55/126 (44%) of IC pts received ≥ 1 subsequent therapy: 21% CPI, 10% chemo, 12% LDT, 10% other. Median time to first subsequent therapy was longer for tebe pts at 5.2 mo vs. IC pts at 3.8 mo. The median duration from start of first subsequent CPI to end date was longer in the prior tebe pts at 4 mo vs prior IC pts at 2.8 mo. From the start of any first subsequent therapy, prior tebe pts had longer OS compared to prior IC pts, HR 0.67 (95% CI 0.42, 1.07). Most of the subsequent therapy was CPI, and the OS benefit was also seen in this subset, HR 0.62 (95% CI 0.34, 1.14). For prior tebe pts, the median and 1-yr OS rates from start of any first subsequent therapy were 13 mo and 53% and from start of first subsequent CPI were 16 mo and 63%. Both were higher than the sequence of IC followed by any therapy (11 mo and 44%), IC followed by CPI (9 mo and 47%) and a recent meta-analysis of 2L+ mUM (7 mo and ̃35% 1-yr OS rate). Conclusions: Pts who progressed on tebe and then received CPI had better OS compared to pts who progressed on IC and then received CPI. Further analysis will explore whether confounding factors are influencing this effect. These exploratory data suggest that tebe, relative to IC, may improve outcomes to subsequent CPI. (1)Yang J. et al. ASCO 2019, J . Cli n Oncol 37:15_suppl, 9592. Clinical trial information: NCT03070392.

Disparities in the use of checkpoint inhibitors and CAR T-cell therapy: A systematic review.

e18541 Background: With increasing numbers of newly approved cancer immunotherapy regimens, research is needed to understand whether these costly treatments are equally used by all patients who could benefit from them. The aim of this systematic review was to identify variables linked to whether patients diagnosed with cancer were treated with checkpoint inhibitors and chimeric antigen receptor (CAR) T-cell therapy. Methods: Using the PICO (Patient, Intervention, Comparison, Outcome) framework, we conducted a systematic review searching Medline (New PubMed), Embase.com, and the Cochrane Library (Wiley) for papers published in English between January 1, 1997 and July 27, 2020. Inclusion criteria were: 1) primary, peer-reviewed research article; and 2) article reported variables associated with whether patients were treated with checkpoint inhibitors or CAR T-cell therapy. Seven coders independently reviewed titles, abstracts, full texts, and extracted data. The systematic review adhered to PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) guidelines. Results: In total, 5958 titles and abstracts and 134 full texts were screened. Sixteen studies were included in final analyses. All were conducted in the United States using data from national databases (N = 15) or electronic medical records (N = 1). Eleven were cross-sectional, and 5 were cohort studies. Studies looked at melanoma (N = 10), non-small cell lung cancer (N = 3), renal cell carcinoma (N = 2), colorectal cancer (N = 1), prostate cancer (N = 1), and hepatobiliary cancer (N = 1). Studies looked at nivolumab (N = 1), pembrolizumab (N = 1), ipilimumab (N = 1), and sipuleucel-T, (N = 1), and 12 studies did not specify medication names. Treatment facility characteristics (N = 9), geographic location within the United States (N = 1), locale classification (N = 2), distance to treatment facility (N = 2), insurance type (N = 9), age (N = 7), race (N = 5), sex (N = 1), income (N = 4), neighborhood educational attainment (N = 2), comorbidities (N = 6), disease stage (N = 1), metastases (N = 3), clinical trial participation (N = 1), recency of diagnosis (N = 2), other treatments received (N = 3), and lesion characteristics (N = 1) were reported to be associated with whether patients were treated with checkpoint inhibitors or CAR T-cell therapy. Other studies found that insurance type (N = 1), race (N = 3), sex (N = 1), other treatments received (N = 1), and lesion characteristics (N = 1) were not associated with receiving checkpoint inhibitors or CAR T-cell therapy. Conclusions: Findings provide evidence of disparate access to checkpoint inhibitors and CAR T-cell therapy. More studies are necessary to thoroughly understand how the factors highlighted in our findings intersect to create and maintain disparities in cancer treatment. This level of information is necessary to create interventions that promote equitable access to novel cancer immunotherapies.

Implementation and impact of a novel multidisciplinary immune-related adverse events tumor board for patients receiving immune checkpoint inhibitor therapy.

e13541 Background: Given the often atypical and diverse presentations of immune-related adverse events, the utilization of an institutional multidisciplinary irAE tumor board is an effective strategy to deliver comprehensive, collaborative, and efficient care to patients experiencing these effects. We report the clinical impact of a multidisciplinary tumor board dedicated towards management of irAEs in patients receiving checkpoint inhibitor therapy. Methods: We completed a retrospective review of patients discussed during our multidisciplinary irAE tumor board at Cleveland Clinic Taussig Cancer Center. Pertinent data collection regarding malignancies, therapies, and reported irAEs was completed through the electronic medical system. Results: Between September 2017-January 2021, 96 patients were discussed in our institutional irAE tumor board. 48 males and 48 females were discussed with the most common primary malignancies being melanoma (53%, 51/96), lung neoplasms (25%, 24/96), and renal cell carcinoma (15%, 14/96). Of the therapies used by these patients, the most frequently associated checkpoint inhibitors were Nivolumab (41%, 39/96), Pembrolizumab (30%, 26/96), and Ipilumumab (17%, 16/96). irAEs affecting the gastrointestinal system such as colitis, hepatitis, and gastritis were most common among discussed patients (40%, 38/96), however several patients also exhibited irAEs targeting the neurological (12.5%, 12/96), rheumatologic (11%, 11/96), dermatologic (8%, 8/96), respiratory (8%, 8/96), and cardiac systems (4%, 4/96). The utilization of tumor board was documented in 41 patients’ notes (43%), with increased documentation over the past year (71%, 24/34), and 70 patients (73%) received a pertinent consult for management of their irAE post tumor board recommendations. Conclusions: Clinical utilization of irAE TB recommendations was high as evidenced by clinical documentation and consequent referrals. Increasing institutional awareness of tumor board over the past year was reflected in a proportionate rise in official documentation. irAE tumor board has the capacity to promote more effective cross-specialty collaboration during treatment of irAEs by both streamlining patient care discussions and encouraging cross-fertilization of therapeutic concepts between multiple subspecialties, and may ultimately increase quality of care for patients experiencing these toxicities.

Checkpoint Inhibitor-Associated Autoimmune Diabetes Mellitus: A Case Report

Introduction: Checkpoint Inhibitors have revolutionized the management in oncology by stimulating the immunological response to cancer. On the contrary, there is an increase in immune-related adverse effects affecting various systems including the endocrine. We report a unique case of new-onset diabetes with diabetic ketoacidosis (DKA) within 18 days of receiving checkpoint inhibitors for Merkel Cell Carcinoma.Clinical Case: An 86-year-old man diagnosed with locally advanced Merkel cell carcinoma underwent surgery and radiotherapy to his right face and neck. Four months later, the positron emission tomography (PET) scan was consistent with liver metastasis. Pembrolizumab, a programmed death receptor-1 (PD-1) inhibitor was initiated as next line treatment. Prior to starting pembrolizumab, his blood glucose was 92 mg/dL (60–120) with no previous history of diabetes mellitus. He presented 18 days later to the emergency room with altered mental status, polyuria, and polydipsia with a blood glucose of 980 mg/dL, anion gap of 26 mmol/L (5–15), and was managed for DKA with new-onset Diabetes Mellitus. HbA1C was 7.0% (4–5.6). He was discharged on subcutaneous insulin glargine once daily, pre-meals insulin aspart, and was referred to the endocrinology clinic. Further investigations obtained during the clinic visit demonstrated low C-peptide of <0.7 ng/mL (0.8–6), glucose 76 mg/dL, positive glutamic acid decarboxylase (GAD-65) antibodies of >25,000 nmol/mL (<0.02), negative islet antigen-2 antibody, islet cell antibody and zinc transporter 8 antibodies. Other endocrine tests showed normal thyroid function, cortisol, and adrenocorticotrophic hormone (ACTH) levels. The patient was educated on checkpoint inhibitor-associated autoimmune diabetes and the need for a lifelong insulin regimen.Clinical Lesson: Our case highlights the immune-related adverse effect involving the endocrine system from checkpoint inhibitor therapy. In comparison to the other common endocrinopathies associated with checkpoint inhibitors, autoimmune diabetes is rare (~ 1–2% incidence) and only less than half demonstrate antibodies with a median time of 8 weeks since exposure. GAD-65 antibodies are the commonest antibody noted and our patient had a robust GAD-65 antibody of >25,000 depleting C-peptide within 18 days of receiving the Pembrolizumab resulting in DKA with a new onset of diabetes.We conclude that diabetes mellitus is a rare but serious adverse effect of immune checkpoint inhibitor therapy. Society for Immunotherapy of Cancer Toxicity Management Working Group consensus recommendations from 2017 recommends routine screening to include baseline HbA1c, basic metabolic panel, thyroid function test, AM cortisol, and ACTH prior to treatment. It also recommends repeating the thyroid function test and basic metabolic panel to allow the monitoring of glycemic trends before each cycle.

Efficacy and Safety of Checkpoint Inhibitor Treatment in Patients with Advanced Renal or Urothelial Cell Carcinoma and Concomitant Chronic Kidney Disease: A Retrospective Cohort Study.

Simple SummaryImmune checkpoint inhibition plays a pivotal role in the treatment of metastatic renal cell carcinoma and metastatic urothelial carcinoma. The association of chronic kidney disease with these tumors is well established. However, to what extent kidney failure modifies the efficacy or the toxicity profiles of checkpoint inhibitors has been poorly investigated. In this paper, we reviewed the files of 85 patients with renal cell carcinoma and 41 with urothelial cancer who had received checkpoint inhibitor treatment, and found that 37.6% and 41.5% had evidence of chronic kidney disease, respectively. We found that neither general treatment-related nor immune-related adverse events differed between patients with normal or impaired renal function. Using a multivariate analysis, we found that chronic kidney disease had no effect on progression-free survival. However, irrespective of the tumor entity, chronic kidney disease was found to positively influence overall survival. We conclude that treatment with checkpoint inhibitors in patients with chronic kidney disease is safe and efficient.Background: Checkpoint inhibitors are a standard of care in the treatment of advanced renal cell carcinoma (RCC) and urothelial carcinoma (UC). Patients with these tumors often suffer from concomitant chronic kidney disease (CKD). Limited data are available on the efficacy and toxicity of checkpoint inhibitors in patients with CKD. Methods: We retrospectively analyzed 126 patients who received checkpoint inhibitors for RCC (n = 85) or UC (n = 41) and analyzed the frequency of treatment- and immune-related adverse events (AEs). We performed a multivariate analysis to determine progression-free survival (PFS) and overall survival (OS). Results: A total of 38.9% of patients had CKD. Frequencies of general AEs (49.0% in CKD vs. 48.1%, p > 0.99999) and immune-related AEs (28.6 vs. 24.7%, p ≥ 0.9999) did not significantly differ between the groups. There was no difference in PFS for patients with RCC or UC and CKD or without CKD (RCC: 6.81 vs. 7.54 months, HR 1.000 (95%CI 0.548–01.822), p = 0.999; UC:2.33 vs. 3.67 months, HR 01.492 (95%CI 0.686–3.247), p = 0.431). CKD appeared to be a potential effect modifier for OS in both RCC and UC (RCC: NR vs. 23.9 months, HR 0.502 (95%CI 0.219–1.152), p = 0.104; UC:18.84 vs. 15.42 months, HR 0.656 (95%CI 0.296–1.454), p = 0.299). Conclusions: Checkpoint inhibitor treatment in our cohort of patients with CKD was as safe and efficient as in the cohort of patients without CKD.

Dermatologic infections in cancer patients treated with checkpoint inhibitors

The incidence of dermatologic infections in patients receiving checkpoint inhibitors (CPIs) has not been systematically described. Identify the incidence of dermatologic infections in patients who received CPIs. Retrospective review of dermatologic infections in patients who received CPIs between 2005 and 2020 and were evaluated by dermatologists at Memorial Sloan Kettering Cancer Center. Of 2061 patients in the study, 1292 were actively receiving CPIs (≤ 90days since the last dose) and 769 had previously been on CPIs (> 90days since the last dose). The dermatologic infection rate was significantly higher in patients with active CPI treatment (17.5%) than in patients not actively being treated (8.2%; P<.0001). In patients on CPIs, 82 (36.2%), 78 (34.5%), and 48 (21.2%) had bacterial, fungal, and viral infections, respectively, and 18 (8.0%) had polymicrobial infections. Anti-cytotoxic T-lymphocyte-associated antigen-4 monotherapy was associated with the highest risk of infection (hazard ratio, 2.93; 95% confidence interval, 1.87 to 4.60; P<.001). Retrospective design and sample limited to patients referred to dermatology. Patients actively receiving CPIs are more susceptible to dermatologic infections, with anti-cytotoxic T-lymphocyte-associated antigen-4 monotherapy carrying the highest risk, suggesting that the index of suspicion for infections should be increased in these patients to minimize morbidity and optimize care.

Impact of Antibiotic Therapy and Metabolic Parameters in Non-Small Cell Lung Cancer Patients Receiving Checkpoint Inhibitors

Introduction: In the current study, we aimed to assess the impact of antibiotics (ATB) and metabolic parameters on clinical outcome of non-small cell lung carcinoma (NSCLC) patients treated with immune checkpoint inhibitors (ICI). Methods: Data from fifty NSCLC patients referred for ICI between December 2015 and May 2019 were analyzed. All patients underwent 18F-fluorodeoxyglucose positron emission tomography computed tomography (18F-FDG PET/CT) and contrast-enhanced CT at baseline and for response assessment after 6–8 weeks. Patients who received ATB within 1 month before or after the first dose of ICI were compared with those who did not. Response assessment according to iRECIST and EORTC was evaluated, as well as progression-free survival (PFS) and overall survival (OS). For semi-quantitative parameters, we computed metabolic tumor volume (MTV), total lesion glycolysis (TLG) and their variations (∆). Results: Twenty NSCLC cases of 50 (40%) had received ATB. Patients receiving ATB had a higher number of metastases (p = 0.046), and were associated with an elevated tumor burden, expressed by TLG (687 vs. 235.3, p = 0.007) and MTV (125.6 vs. 40.6, p = 0.002), compared to no-ATB patients. According to iRECIST, progressive disease rate was significantly higher for ATB group (64.7% vs. 27.6%, p = 0.029). Likewise, PFS was shorter for ATB compared to no-ATB (median 4.1 vs. 12.4 months, p = 0.004), while no difference for OS was detected. On multivariate analysis, the effect of ATB remained significant for poor PFS along with performance status (ECOG ≥ 1), and ∆SUVmax. Conclusions: ATB therapy seems to be associated with a worse treatment response, PFS, and higher metabolic tumor burden in NSCLC patients treated with ICI.

18F]-C-SNAT4: an improved caspase-3-sensitive nanoaggregation PET tracer for imaging of tumor responses to chemo- and immunotherapies.

We rationally designed and synthesized a new PET tracer [18F]-C-SNAT4 to detect cell death both in vitro and in vivo. In vitro radiotracer uptake studies were performed on drug-sensitive and -resistant NSCLC cell lines (NCI-H460 and NCI-H1299, respectively) treated with cisplatin at different doses. In vivo therapy response monitoring by [18F]-C-SNAT4 PET imaging was evaluated with two treatment modalities-chemotherapy and immunotherapy in two tumor xenografts in mice. Radiotracer uptake in the tumors was validated ex vivo using γ-counting and cleaved caspase-3 immunofluorescence. This [18F]-C-SNAT4 PET tracer was facilely synthesized and displayed improved serum stability profiles. [18F]-C-SNAT4 cellular update was elevated in NCI-H460 cells in a time- and dose-dependent manner, which correlated well with cell death. A significant increase in [18F]-C-SNAT4 uptake was measured in NCI-H460 tumor xenografts in mice. In contrast, a rapid clearance of [18F]-C-SNAT4 was observed in drug-resistant NCI-H1299 in vitro and in tumor xenografts. Moreover, in BALB/C mice bearing murine colon cancer CT26 tumor xenografts receiving checkpoint inhibitors, [18F]-C-SNAT4 showed its ability for monitoring immunotherapy-induced apoptosis and reporting treatment-responding mice from non-responding. The uptake of [18F]-C-SNAT4 in tumors received chemotherapy and immunotherapy is positively correlated with the tumor apoptotic level and the treatment efficacy. [18F]-C-SNAT4 PET imaging can monitor tumor response to two different treatment modalities and predict the therapeutic efficacy in preclinical mouse models.

Acute kidney injury as a risk factor for mortality in oncological patients receiving checkpoint inhibitors.

Checkpoint inhibitors (CPIs) have drastically improved metastatic cancer outcomes. However, immunotherapy is associated with multiple toxicities, including acute kidney injury (AKI). Data about CPI-related AKI are limited. Our aim was to determine risk factors for CPI-related AKI as well as its clinical characteristics and its impact on mortality in patients undergoing immunotherapy. All patients under CPI at our centre between March 2018 and May 2019 and with a follow-up through April 2020 were included. Demographic, clinical and laboratory data were collected. AKI was defined according to the Kidney Disease: Improving Global Outcomes guidelines. We performed a logistic regression model to identify independent risk factors for AKI and actuarial survival analysis to establish risk factors for mortality in this population. A total of 759 patients were included, with a median age of 64 years. A total of 59% were men and baseline median creatinine was 0.80 mg/dL. The most frequent malignancy was lung cancer and 56% were receiving anti-programmed death protein 1 (PD-1). About 15.5% developed AKI during the follow-up. Age and baseline kidney function were identified as independent risk factors for CPI-related AKI. At the end of follow-up, 52.3% of patients had died. The type of cancer (not melanoma, lung or urogenital malignance), type of CPI (not cytotoxic T-lymphocyte-associated protein 4, PD-1, programmed death-ligand 1 or their combination) and the presence of an episode of AKI were identified as risk factors for mortality. A total of 15.5% of patients under immunotherapy presented with AKI. A single AKI episode was identified as an independent risk factor for mortality in these patients and age and baseline renal function were risk factors for the development of AKI.

Detect it so you can treat it: A case series and proposed checklist to detect neurotoxicity in checkpoint therapy.

BackgroundCheckpoint inhibitors show impressive and durable responses in various cancer types and provide new avenues for cancer immunotherapy. However, these drugs have a variety of adverse events. Common autoimmune-related adverse effects include fatigue, hepatitis, skin rash, endocrine deficiencies, and colitis. Neurotoxicity has been reported, but its incidence and course remain unclear.MethodsTo illustrate the broad spectrum of neurotoxicity, we exemplarily report the neurological adverse events of five patients with melanoma and one patient with differentiated thyroid cancer who received checkpoint inhibitors at Essen University Hospital (Essen, Germany).ResultsAfter treatment with ipilimumab, nivolumab or pembrolizumab, neurotoxic effects included hypophysitis-associated neck pain and headache, Guillain-Barré syndrome, transverse myelitis, acute brachial plexus neuritis, and ocular myasthenia gravis.ConclusionsCheckpoint inhibitor therapy remains a success story; however, neurological immune-related adverse events may cause severe life-threatening conditions. We propose a guide for the early detection of neurological adverse events during routine clinical treatment to prevent more severe courses of checkpoint inhibitor-induced neurotoxicity.

Molecular profiling of Asian patients with advanced melanoma receiving check-point inhibitor treatment

ObjectiveMelanoma is major medical challenge and being able to monitor treatment response is critical. This study aimed to use molecular profiling of Asian patients with advanced melanoma who were receiving treatment with check-point inhibitors (CPIs) to identify novel biomarkers of tumor response.MethodsNext-generation sequencing (NGS) was performed using tumor specimens collected from 178 Asian patients with metastatic melanoma receiving CPIs. The NGS data and clinical-pathological factors were analyzed for potential genetic biomarkers of tumor response to CPI treatment.ResultsThe most common melanoma subtype was acral melanoma (40%), followed by cutaneous melanoma (32%), mucosal melanoma (26%), and others (2%). For calculation of treatment efficacy, 164 of the patients could be evaluated. The overall response rate was 45.7%, of which 41 cases exhibited complete responses (25.0%) and 34 showed partial responses (20.7%). There were no significant differences in tumor responses based on melanoma subtype (P = 0.295). Genetically, NRAS mutations, TP53 mutations, and NF2 deletions were significantly associated with resistance to CPIs (P < 0.05). In contrast, MYC and RPS6KB1 amplifications were associated with responsiveness to CPIs (P < 0.05). Median progression-free survival (PFS) for patients treated with CPIs was 5.9 months (95% CI, 3.8-8.05 months). Univariate analysis identified TP53 and BRAF mutations, NF2 deletions, and BIRC2 amplifications as poor prognostic factors for PFS (P < 0.05).ConclusionsThis study determined the integrated genomic profiles of Asian patients with metastatic melanoma receiving CPIs and identified candidate biomarkers that reflected treatment outcomes.

Improved survival without increased toxicity with influenza vaccination in cancer patients treated with checkpoint inhibitors

ABSTRACT In international guidelines, influenza vaccination is recommended to cancer patients receiving antitumor treatment. Whether this recommendation should include patients treated with the recently introduced and now widely used checkpoint inhibitors (CPIs) is unclear. The immune hyperactivation after vaccination in a patient on CPI treatment may strengthen the antitumor immunity and improve patients´ prognosis. On the other hand, the hyperactivation might increase the risk for immune-related adverse events (IRAEs). Furthermore, there is a risk for decreased antitumor effect by the phenomenon of antigenic competition. Only results from few studies addressing survival have been reported and the results from studies on IRAEs are contradictory. We performed a multi-center retrospective cohort study at three Swedish centers in patients with metastatic cancer. All patients previously not treated with CPIs and who received monotherapy with a PD-1 or PD-L1 blocker between January 1st, 2016 until May 31st, 2019 were included. The most common type of malignancy was melanoma (47.8%) followed by non-small cell lung cancer (31.0%). Statistically significant longer PFS and OS were observed in multivariate analyses at 6-month landmark time in the vaccinated compared to the non-vaccinated group after adjustment for age, gender, comorbidity, performance status, CNS metastasis and line of treatment (p = .041 and 0.028, respectively). Furthermore, the incidence of any IRAE grade was comparable between vaccinated and non-vaccinated group (p = .85). In conclusion, the current study indicates that survival improves with influenza vaccination while not increasing the risk for side effects in cancer patients treated with checkpoint inhibitors. Hence, our results strongly support influenza vaccination in cancer patients receiving checkpoint inhibitors.

1098. Norovirus Infection in Cancer Patients Undergoing Chimeric Antigen Receptor T-cell Immunotherapy (CAR-T)

BackgroundCAR-T is used to treat certain refractory hematological malignancies. B-cell aplasia and immunosuppression used to treat CAR-T side effects increase infection risk. Little data are available describing Norovirus (NoV) infections in CAR-T recipients.MethodsWe reviewed the medical records of 134 patients with NoV diarrhea (identified by nucleic acid amplification test) between 2016-2019. Of these patients, nine received CAR-T prior to developing NoV. Here we describe their demographics, clinical characteristics, treatments, and complications.ResultsThe median age was 49 years (Table 1). Patients’ underlying malignancies included Non-Hodgkin’s Lymphoma (4), Acute Lymphoblastic Leukemia (3), Chronic Lymphocytic Leukemia (1) and metastatic Sarcoma (1). Prior to development of NoV, six patients had undergone hematopoietic stem cell transplant, and 1 had received checkpoint inhibitor therapy. Five patients experienced cytokine release syndrome after CAR-T, and 1 experienced CAR-T-related encephalopathy syndrome (Table 2). Two patients received interleukin-6 antagonist therapy, and one received high dose steroids. Time to diarrhea onset post-CAR-T cell infusion was variable(median 256days, IQR 26-523 days).Six had an absolute lymphocyte count< 1000/mm3 at diarrhea onset. Three had diarrhea for >14 days; median diarrhea duration in the other 6 patients was 4 days. Other GI complaints included abdominal pain (3), nausea (4), and vomiting (3). For NoV treatment, three received oral immunoglobulin, and 8 received Nitazoxanide. Complications included development of concomitant GI-GVHD(5), ileus (2), need for TPN (3), renal failure requiring dialysis (2), ICU stay (3), and death (2). Two patients were co-infected with other enteropathogens such as rotavirus, enteropathogenic and enteroaggregative E.Coli and Clostridioides difficile. Three patients with diarrhea lasting >14 days had serial samples collected over time; NoV shedding lasted 81-546 days. NoV was genotyped in 6 patients(Table 3) and included GII.2(2), GII.4(2), GII.6(1) and GII.12(1).Table 1: Patient characteristics (N=9) Table 2: CAR-T related factors Table 3: NoV Genotypes ConclusionNoV belonging to various genotypes is an important cause of acute and chronic diarrhea in patients receiving CAR-T cell therapy.Disclosures Adilene Olvera, MPH MLS (ASCP), MERK (Grant/Research Support, Scientific Research Study Investigator) Robert L. Atmar, MD, Takeda Vaccines, Inc. (Grant/Research Support) Mary K. Estes, PhD, Takeda Vaccines (Consultant, Grant/Research Support)

Modulators of hERAP2 discovered by high-throughput screening.

Endoplasmic reticulum aminopeptidase 2, ERAP2, is an emerging pharmacological target in cancer immunotherapy and control of autoinflammatory diseases, as it is involved in antigen processing. It has been linked to the risk of development of spondyloarthritis, and it associates with the immune infiltration of tumours and strongly predicts the overall survival for patients receiving check-point inhibitor therapy. While some selective inhibitors of its homolog ERAP1 are available, no selective modulator of ERAP2 has been disclosed so far. In order to identify such compounds, we screened an in-house focused library of 1920 compounds designed to target metalloenzymes. Structure-Activity Relationships and docking around two hits led to the discovery of selective inhibitors of ERAP2. Amid those, some bind to yet untapped amino-acids in the S1 pocket. Importantly, we disclose also the first activator of small substrates hydrolysis by ERAP2. Inhibitors and activators identified in this study could serve as useful starting points for optimization.

Evaluating Predictors of Immune-Related Adverse Events and Response to Checkpoint Inhibitors in Myeloid Malignancies

Evaluating Predictors of Immune-Related Adverse Events and Response to Checkpoint Inhibitors in Myeloid Malignancies