Brief Communication PD1-related Nephrotoxicity: Optimizing Its Clinical Management Through Histopathologic Features.

Acute kidney injury (AKI) is a known immune-related adverse event of cancer immune checkpoint inhibitor (ICI) therapy. Further population-based data on AKI incidence, risk factors and practice patterns post-ICI therapy are needed. We measured the cumulative incidence of AKI among advanced cancer patients while receiving ICI therapy and non-ICI systemic therapy in Ontario, Canada (2012-18). An increase in serum creatinine was used to define AKI and graded according to event severity. Time to event modeling was used to compare the risk of developing AKI, pre-disposing factors and survival outcomes. We studied 16 425 patients with advanced cancer receiving either ICI or non-ICI systemic therapy. Among 4380 patients receiving ICI therapy, the overall crude 4-year incidence of AKI (any stage) was 29% and severe AKI (stage ≥2) was 7%. Characteristics associated with a higher risk of AKI included male sex, genitourinary (versus other) malignancy, the presence of hypertension, diabetes or chronic kidney disease, and prescription of a non-steroidal anti-inflammatory drug. The risk of experiencing AKI was significantly lower among patients treated with ICI versus non-ICI systemic therapy [adjusted hazards ratio (aHR) 0.80, 95% confidence interval (CI) 0.74-0.86, P-value <.0001]. Among the 587 patients who experienced an AKI and were both alive and discontinued ICI therapy within 30days, 54 (9%) were re-challenged with ICI in the following 6months and 24 (44%) had a recurrent AKI event. Patients who were re-challenged with ICI therapy had improved overall survival as compared with patients that received other non-ICI systemic therapy (aHR 0.38, 95% CI 0.22-0.67, P-value <.001). Our real-world study demonstrates a modest risk for severe AKI among cancer patients receiving ICI therapy, lower than with exposure to other systemic cancer therapies. Among patients who developed AKI and stopped ICI therapy, re-challenge was uncommon but may warrant consideration for select patients.

11151 Background: Patients undergoing chemotherapy are less likely to complete recommended routine vaccination. Vaccination during immune checkpoint inhibitor (ICI) therapy elicits a significant cytokine response, which could enhance antitumor effects. This study investigates whether co-administration of vaccination with ICI improves cancer patient survival. Methods: Using the California Immunization Registry and Scripps Health’s electronic medical record, we validated vaccination status for patients at a large healthcare system in San Diego and conducted an observational cohort study of all ICI recipients from January 1, 2018, to June 1, 2024. Overall Kaplan-Meier survival curves were compared between patients who received vaccination within 100 days of ICI initiation and those who did not using log rank test. Subgroup analyses focused on patients with stage IV non-small cell lung cancer (NSCLC) and stage IV melanoma. The ICI cohort was propensity matched 1:1 by demographics to non-cancer patients to evaluate immunization rates. Results: 1,854 ICI-treated patients and 1,854 matched patients without cancer were identified for analysis. Vaccination within 100 days of ICI initiation was associated with improved overall survival (HR: 0.43, 95% CI: 0.37 – 0.49, p &lt;.0001). Among NSCLC patients ( n =241), overall survival improved when any vaccination was administered within 100 days of ICI initiation (HR 0.37, p &lt;.0001), with benefits observed specifically for COVID-19 (HR: 0.43, p &lt;.0001) and influenza (HR: 0.38, p &lt;.0001) vaccinations. Similarly, melanoma patients ( n =216) demonstrated improved overall survival with COVID-19 (HR: 0.53, p =.0214) and influenza (HR: 0.59, p =.0468) vaccinations. Findings remained robust upon censoring deceased unvaccinated patients within 100 days of ICI initiation to mitigate guarantee-time bias. No significant differences were observed in demographics, BMI, smoking status, medical comorbidities, PD-L1 expression (for NSCLC), or LDH levels (for melanoma) between patients who had received a vaccine within 100 days of ICI initiation and those that did not, that would otherwise explain this difference in mortality. There was no difference between the vaccinated and unvaccinated groups in terms of vaccination-related infection mortality. Active ICI patients were more likely to receive routine vaccinations than non-cancer patients (Influenza 2023 OR: 1.51, p= .0016), though vaccination rates have declined since their 2020 peak (Influenza vaccination rate: 2020, 71%; 2023, 59%). Conclusions: Co-administration of vaccination with ICI therapy improves survival, independent of infection-related outcomes. The associated cytokine response from vaccination during ICI therapy may enhance antitumor effects. Vaccination rates among ICI-treated patients have declined since 2020, highlighting the need for interventions to improve uptake and outcomes.

Immune Checkpoint Inhibitor (ICI) therapy is the most exciting development in cancer treatments in recent years. As of the end of 2021, more than a hundred of clinical trials have been carried out by several major drug makers and research hospitals all over the world just to explore the use of ICI antibodies in almost every type of cancer and under various clinical settings. These clinical trials have resulted waves of good news in every year’s major academic conferences and FDA approvals, and now ICI therapy is in the move to take over traditional therapy to become the major player in clinical management of cancer. On the other hand, most of these clinical trials have failed to show clear benefits in most cancer patients, and only few have been reported in public. In real-world clinical setting, ICI antibodies are being massively and sometimes abusively prescribed for almost every desperate situation with clear clinical benefit in only a few (&lt;10%). Yet, the enthusiasm behind ICI therapy is not dampened by the massive clinical failure but has been growing. The reason for the consistent enthusiasm among clinicians and patients is the miracle-like clinical responses seen in some of the responders that even including late-stage hopeless cases. Every clinician wants to repeat this miracle in the next seemingly identical patient, and every patient and their family members want to believe that they are in line for that miracle. But the reality is disheartening in that clinicians do not see the predictable repeat of miracle-like responses in seemingly identical patients and most patients selecting ICI therapy as the last straw in life did not benefit from it, if not hurt by it. What then are the reasons that ICI therapy is so impressive when working and so unpredictable in responses? This review attempts to draw some mechanistic aspects based on our own experiences in ICI therapy and to come up with a different explanation for the unexplained clinical observations. The goal of this review is to alert the clinical field about the danger and irreversible damages that wrongly used ICI antibodies may cause, and at the same time to introduce some preliminary criteria to select proper patient for the benefits and to avoid the harms of ICI therapy.

2613 Background: Proton pump inhibitors (PPIs) were revealed to regulate gut microbiome alterations and further impact the response to immune checkpoint inhibitors (ICIs). Contradictory impacts on survival were observed in ICI-treated patients when concomitantly use PPI or not. We performed this systematic review and meta-analysis to analyze the association of PPI use with survival outcomes in ICI-treated cancer patients. Methods: EMBASE, MEDLINE/PubMed, Cochrane Library databases and major oncology conferences proceedings were comprehensively searched. Studies comparing overall survival (OS) and progression-free survival (PFS) between PPI use and PPI non-use in ICI-treated cancer patients were included. Data regarding the characteristics, ICI and PPI treatments and survival outcomes for patients were extracted. Hazard ratios (HRs) with 95% confidence intervals (CIs) were pooled using random-effect models. Subgroup meta-analyses and meta-regressions were performed to explore possible factors of heterogeneity among study results. Results: A total of 20 studies were included, comprising 2812 ICI- and PPI-treated patients and 3990 ICI-treated and PPI-free patients. The pooled HR is 1.30 (95% CI, 1.17-1.45; P &lt;.001) for OS and 1.20 (95% CI, 1.08-1.34; P &lt;.001) for PFS, indicating a significant negative association between PPI use and survival of ICI-treated patients. Subgroup meta-analyses by factors including cancer types, ICI types and time window of PPI use, revealed such associations were in patients with non-small cell lung cancer (OS: HR = 1.40, 95% CI = 1.23 to 1.59, P &lt;.001; PFS: HR = 1.27, 95% CI = 1.16 to 1.40, P &lt;.001) or urothelial cancer (OS: HR = 1.50, 95% CI = 1.26 to 1.80, P &lt;.001; PFS: HR = 1.37, 95% CI = 1.17 to 1.60, P &lt;.001), patients treated with anti-PD-1/PD-L1 (OS: HR = 1.41, 95% CI = 1.30 to 1.53, P &lt;.001; PFS: HR = 1.29, 95% CI = 1.20 to 1.38, P &lt;.001), patients receiving PPI as baseline treatment (OS: HR = 1.43, 95% CI = 1.21 to 1.69, P &lt;.001; PFS: HR = 1.29, 95% CI = 1.16 to 1.44, P &lt;.001) or 60 days before ICI treatment initiation (OS: HR = 1.28, 95% CI = 1.11 to 1.48, P &lt;.001; PFS: HR = 1.27, 95% CI = 1.16 to 1.40, P &lt;.001), rather than concomitantly with ICI initiation. Conclusions: PPIs use in patients treated with ICIs is associated with a shorter OS and PFS, especially in several specific subgroups of cancer patients. PPIs should be strictly controlled, and appear to not impact survival if given temporarily after ICIs initiation. These detailed observations could provide basis for clinical guidelines when concomitantly use PPIs and ICIs.

Background Immune checkpoint inhibitor (ICI) therapy can cause marked lipase elevation which is frequently asymptomatic (ALE). Guidelines treat ALE as a benign laboratory abnormality without need to hold ICI therapy. We hypothesized that ALE represents pancreatitis evidenced by positive positron emission tomography (PET) scan, and/or volume loss on pancreas volumetry (PV). We assessed clinical outcomes in ALE patients who continued ICI therapy. Methods We conducted a retrospective study of 1,146 ICI-treated patients at MD Anderson with PET/CT within one month of lipase measurement. Asymptomatic patients (n=1,123) were stratified by lipase: normal (n=837), 1–3× upper limit of normal (ULN) (n=222), 3–5× ULN (n=35), and &amp;gt;5× ULN (n=29). Symptomatic patients (n=23) were analyzed separately for comparison. For volumetric analysis (n=117), we included: 1. all PET+/CT+ asymptomatic patients (n=5) and age-, sex-matched asymptomatic patients with normal lipase (n=32) or 1–3× ULN (n=26); 2. all asymptomatic patients with lipase &amp;gt;3× ULN who had follow-up CTs, including PET+/CT+ (n=35); and 3. all symptomatic patients with follow-up CTs, including PET+/CT+ (n=19). Patients who continued ICI therapy were followed for clinical outcomes, including new-onset diabetes, exocrine pancreatic insufficiency (EPI), recurrent lipase elevation or subnormal lipase, pancreatic injury on PET/CT, and symptoms on follow-up. Pancreatic injury was defined as positive PET/CT and/or &amp;gt;20% volume loss. Results In ALE, at baseline, PET detected pancreatic injury more frequently than CT (21.5% vs 10.8%, p=0.016). On volumetry, patients with normal lipase showed no volume loss (73.48 to 67.47 cm3, p=0.386). In the combined &amp;lt;3× ULN group (normal + 1–3× ULN, n=63), PET and CT positivity were uncommon (PET+ 7.9%, CT+ 3.2%), and median pancreatic volume change was minimal (67.87 to 64.24 cm3, p=0.066). In ALE &amp;gt;3× ULN, median pancreatic volume decreased significantly (77.8 to 53.1 cm3, p=7.8×10−6); 57% showed &amp;gt;20% volume loss. Fisher’s exact test confirmed significant differences in &amp;gt;20% volume loss between &amp;gt;3× ULN and &amp;lt;3× ULN ALE (57% vs 21%), p=0.0007). Among symptomatic patients with follow-up CTs (n=19), 67% developed &amp;gt;20% volume loss with median volume decreasing from 73.9 to 49.1 cm3 (p=0.012). Of the 33 patients with ALE who continued ICI therapy, 22 (67%) demonstrated pancreatic injury, yet none developed pancreatitis symptoms. Clinical sequelae, including new-onset diabetes or EPI, were rare. Conclusions ALE following ICI therapy represents a mild form of pancreatitis. Sensitivity to detect pancreatic injury increases progressively from CT to PET to pancreas volumetry. Pancreatic volume loss is seen almost always in those with lipase elevation, frequently &amp;gt;3x ULN. Despite evidence of pancreatic injury, adverse clinical outcomes of continued ICI therapy are rare, supporting the safety of continued ICI therapy. Frequent lipase monitoring may be unnecessary, and evaluation for diabetes and EPI can be performed annually and as clinically indicated, respectively. Citation Format: Hamza A. Chaudhry, Yinghong Wang, Suresh T. Chari. Asymptomatic Lipase Elevation after Immune Checkpoint Inhibitors Reflects Pancreatic Injury with Volume Loss but Minimal Clinical Sequelae [abstract]. In: Proceedings of the AACR Immuno-Oncology Conference (AACR IO): Discovery and Innovation in Cancer Immunology: Revolutionizing Treatment through Immunotherapy; 2026 Feb 18-21; Los Angeles, CA. Philadelphia (PA): AACR; Cancer Immunol Res 2026;14(2 Suppl):Abstract nr B066.

Rationale: Indications for immune checkpoint inhibitors (ICIs) in cancer treatment are increasing, but some patients develop respiratory failure due to checkpoint inhibitor pneumonitis (CIP) or other ICI-related complications. This study aimed to determine if time from ICI exposure to respiratory failure and survival outcomes differ between CIP and non-CIP etiologies of respiratory failure. We hypothesized that CIP-related respiratory failure occurs sooner after ICI initiation and portends worse outcomes than non-CIP-related respiratory failure. Methods: We conducted a retrospective study of ICI-treated patients who developed respiratory failure at a 5-hospital academic institution (Johns Hopkins) from July 2017 to July 2024. Respiratory failure was defined as ≥12 consecutive hours of non-invasive or invasive mechanical support. Demographics, clinical characteristics, respiratory failure etiology, and treatment data were collected from electronic health records. The primary exposure of CIP-related respiratory failure was identified based on clinical suspicion and CIP management with immunosuppressive therapy. Primary outcomes were risk of respiratory failure 1 year after first ICI treatment and 30-day mortality after respiratory failure event. Results: Among 237 ICI-treated patients with respiratory failure, CIP was the etiology in 24% (n=58), while 75% (n=179) had non-CIP etiologies. Baseline demographics including mean age (64-65 years, p=0.25), sex (60-70% male, p=0.28), and race (∼65% white, p=0.37) were similar between groups. Median time from first ICI treatment to respiratory failure was not significantly different (124 days for CIP [IQR: 53-298], 195 days for non-CIP [IQR: 65-505], p=0.74). The risk of respiratory failure within 1 year after first ICI treatment was not different between the CIP and non-CIP groups (HR= 0.29, 95% CI: 0.06-1.23). As shown in the figure, overall mortality at 30 days following respiratory failure was 52% in the CIP group vs. 54% in the non-CIP group (unadjusted HR= 0.85, 95% CI: 0.56-1.28, p=0.44). Survival was not significantly different after adjustment for age, gender, and cancer type (HR= 0.82, 95% CI: 0.54-1.26, p=0.38). Conclusions: In this large cohort, the timing of respiratory failure after initial ICI therapy and incidence of respiratory failure within the first year after ICI therapy were not different between CIP and non-CIP etiologies of respiratory failure. 30-day survival outcomes following respiratory failure were poor for both etiologies of respiratory failure suggesting that further research is needed to anticipate and counsel patients who develop this devastating complication after ICI treatment.

Introduction: Awareness of cardiac toxicity with immune checkpoint inhibitor (ICI) therapy is increasing with emerging data on the manifestations and diagnosis of cardiotoxicity. However, risk stratification of these patients remains undefined. Hypothesis: We examined associations of traditional cardiovascular risk factors with ICI cardiotoxicity and patterns of cardiac evaluation prior to and during ICI therapy within a quaternary integrated health network. Methods: We reviewed patients on ICIs for atherosclerotic cardiovascular disease (ASCVD) risk factors, cardiology office visits, patterns of screening for cardiac disease (ECG, echocardiogram, cardiac biomarkers), and correlated with the incident of cardiac adverse events. Results: We studied 344 patients receiving ICIs for lung cancer (50%), melanoma (15%), and other malignancies (34%). Smoking (75%), hypertension (71%), and hyperlipidemia (49%) were the most common ASCVD risk factors. Pre-ICI initiation cardiac evaluation included ECG in 60%, TTE in 37%, and 63% of patients had at least one ECG or TTE while on ICIs. Less than 20% were seen by Cardiology before ICI therapy, despite 81% having ≥2 ASCVD risk factors. Cardiac toxicity with ICIs was observed in 12% of patients and was significantly more common in those with more ASCVD risk factors (4.6% vs 9.7% vs 16.4% with 0-1 vs 2-3 vs ≥4 ASCVD risk factors, respectively; P= 0.03) and in patients with atrial fibrillation (AFib) before ICI initiation (26.5% vs 8.5% without AFib; P=0.0008). ICIs were discontinued in 87 patients, of which 15% were due to cardiac toxicity. Conclusions: The incidence of cardiac toxicity is high, especially in patients with multiple ASCVD risk factors or AFib, and is often the reason for ICI discontinuation, warranting close surveillance prior to and during therapy. Cardiac evaluation and monitoring for cardiotoxicity were infrequent in patients receiving ICI therapy, despite the high prevalence of ASCVD in this population.

Immune checkpoint inhibitor (ICI) therapy has led to significant improvement in outcomes for patients with nononcogene-driven advanced non-small cell lung cancer (NSCLC). The rate of crossover and receipt of postprotocol ICI in frontline trials for advanced NSCLC has not been systematically evaluated. ClinicalTrials.gov was used to identify phase 3 studies evaluating the use of immunotherapy or combination chemoimmunotherapy against chemotherapy alone in the frontline management of advanced NSCLC. Data on outcomes, rate of crossover and/or subsequent post-protocol receipt of immunotherapy, and the start dates of these clinical trials were then extracted. Twenty-three frontline trials in nononcogene-driven advanced NSCLC were identified. Six trials with ICI monotherapy/dual ICI therapy and 17 trials evaluating chemotherapy/ICI in first-line advanced NSCLC were included in the analysis. The crossover rate ranged 0% to 54% in ICI monotherapy/dual ICI trials and 0% to 52% in chemotherapy/ICI trials. Nineteen of 23 trials provided information on subsequent postprotocol therapies. Among the trials not allowing crossover, postprotocol ICI was administered to 17% to 45.8% of patients. Information regarding the eventual receipt of ICI therapy was available for 22 of 23 trials. Of 6631 patients, 2507 (37.8%) randomized to the control arm eventually received ICI therapy. The rate of crossover and postprotocol ICI use was low in frontline trials for first-line NSCLC incorporating ICI. Given the proven improved overall survival of ICI in a broad population, there is a need to ensure availability of this life-prolonging therapy in future trials, either by crossover treatment or postprotocol administration.

Background The use of immune checkpoint inhibitors (ICI) has been associated with a 3-fold higher risk for cardiovascular events as compared to cancer patients who did not receive ICI. Therapies targeting vascular endothelial growth factor (VEGF) have also been associated with a wide range of cardiovascular events. The combination use of ICIs and VEGF inhibitors is currently approved as a treatment for patients with renal-cell carcinoma, hepatocellular carcinoma, non-small cell lung cancer, and endometrial cancer. Data are lacking whether the combination of ICIs and VEGF-targeted therapy is associated with an additional increase in cardiovascular events. Purpose To evaluate whether the combination use of ICI and VEGF targeted therapies are associated with a higher risk of cardiovascular events as compared to ICI therapy alone, we performed a retrospective matched case-control study. Methods Cases received both ICI and VEGF-targeted therapy (n=157), and control patients (n=157) only received ICI therapy. The primary outcome was a composite of cardiovascular events (myocardial infarction, coronary revascularization, ischemic stroke, deep venous thrombosis, and pulmonary embolism). Patients were censored at time of first event or at last date of follow up. Cox proportional hazard regression analysis was performed to calculate hazard ratio (HR) with 95% confidence interval (CI), counting only the first cardiovascular event. Results Baseline characteristics for the cases and controls are shown in Table 1. Overall cases (combination ICI and VEGF inhibitor) and controls (ICI alone) were not different with respect to age, type of cancer, and a prior history of any cardiovascular event. Cases received more ICI cycles as compared to controls (median of 7 [4–17] cycles vs. 4 [2–10] cycles, P&amp;lt;0.001). Cases also had a longer follow-up time (334 [127–663] days vs. 201 [60–564] days, P=0.008) as compared to the control group. As compared to ICI alone, a similar risk for a composite cardiovascular event was observed in those who received both ICI and VEGF-targeted therapy (HR, 0.70 [95% CI, 0.39–1.25]; P=0.23, Table 1). In total, 21/157 patients had a composite cardiovascular event among the cases, who received the combination of ICI and VEGF inhibitor (9 DVT, one MI, 9 PE, two ischemic strokes) as compared to 25/157 among the controls, who received ICI alone (14 DVT, 3 MI, 7 PE, one ischemic stroke). The median time to event was not different between the two groups (126 [98–260] days vs. 145 [28–205] days, P=0.47). Conclusion We found that among 157 patients who received a combination of ICI and VEGF-targeted therapy and 157 matched control patients who only received ICI therapy, the risk for cardiovascular events was not different between the two groups. Funding Acknowledgement Type of funding sources: Public grant(s) – EU funding.

As indications for immune checkpoint inhibitor (ICI) therapy have increased in recent years, so has the proportion of patients eligible for this type of therapy. However, a lack of data exists about the risks and benefits of ICI therapy in hospitalized patients, who tend to be frailer and sicker than patients enrolled in clinical trials. We conducted a retrospective cohort study among hospitalized patients with metastatic solid tumors who received ICI therapy at a large academic cancer center over the course of 4 years. We analyzed the characteristics and outcomes of these patients and identified demographic and clinical factors that could be used to predict mortality. During the 4-year study period, 106 patients were treated with ICI therapy while admitted to the hospital; 70 (66%) had Eastern Cooperative Oncology Group Performance Status ≥2, which would have prevented them from enrolling in most clinical trials of ICIs. Fifty-two patients (49%) died either during admission or within 30 days of discharge; median overall survival was 1.0 month from discharge, and 16 patients (15%) were alive 6 months after discharge. Independent predictors of death following receipt of inpatient ICI included a diagnosis of non-small cell lung cancer relative to melanoma and prior treatment with two or more lines of therapy. The poor overall outcomes observed in this study may give clinicians pause when considering ICI therapy for hospitalized patients, particularly those with characteristics that are associated with a greater risk of mortality. Immunotherapy strategies for patients with cancer are rapidly evolving and their use is expanding, but not all patients will develop a response, and secondary toxicity can be significant and challenging. This is especially evident in hospitalized patients, where the economic cost derived from inpatient immune checkpoint inhibitor (ICI) administration is important and the clinical benefit is sometimes unclear. The poor overall outcomes evidenced in the ICI inpatient population in this study highlight the need to better identify the patients that will respond to these therapies, which will also help to decrease the financial burden imposed by these highly priced therapies.

309 Background: Hypothyroidism is a common immune-related adverse effect (irAE) with ICI therapy, occurring in 4-9% of patients treated with PD-1 ICI, and 10-15% of patients treated with dual PD-1/CTLA-4 ICI therapy. Prolonged thyroid dysfunction increases risk for cardiovascular and cerebrovascular events. Consensus guidelines recommend weight-based dosing for thyroid repletion in younger patients and/or without cardiovascular comorbidities. We observed that patients on thyroid repletion are often underdosed compared to guideline recommendations. To formally evaluate this, we performed a retrospective study to determine the percentage of ICI-treated cancer patients who are receiving guideline-recommended thyroid repletion at an urban comprehensive cancer center. Methods: We identified patients who received PD-1 ICI, either singly or in combination with chemotherapy, TKI, or other ICI to identify patients who met the consensus guideline criteria for weight-based dosing of thyroid repletion. Analysis was restricted to ICI-treated patients who had a thyroid stimulating hormone (TSH) level above 10 mU/L following initiation of therapy. For each patient, we collected the patient’s age, weight, and initial prescribed dose of levothyroxine. We also obtained the date of abnormality and normalization for TSH and free thyroxine (T4). Results: 402 patients received ICI, either singly or in combination. 55 patients had TSH &gt; 10 mU/L. 15 patients who did not have documentation of hypothyroidism or developed it prior to immunotherapy were excluded. The proportion of patients who were eligible for, and who received weight-based repletion is summarized in the table. The proportion of patients who received guideline-recommended thyroid repletion was: 6/17 (35%) SITC-guideline recommended dose, 18/27 (67%) NCCN-guideline recommended dose and 6/22 (28%) ASCO-guideline recommended dose. The median time to free T4 normalization was 9 weeks (IQR 6-15 weeks) and TSH normalization was 13 weeks (IQR 9-30 weeks). Conclusions: At an urban comprehensive cancer center, the incidence of hypothyroidism in ICI-treated cancer patients is 10%. The compliance with guideline recommended weight-based dosing is low, with 33-72% of patients not receiving appropriate therapy, translating into prolonged time to thyroid function normalization. We aim to develop a quality improvement intervention to improve thyroid dosing in this patient population. Proportion of patients receiving guideline-recommended thyroid repletion. Criteria Per SITC Guidelines Per NCCN Guidelines (if lower end of dosing range) Per ASCO Guidelines Patients eligible for weight-based dosing 17 27 22 # of patients who received appropriate initial dosing 6 (35%) 18 (67%) 6 (28%) Average initial dose prescribed 81 mcg 78 mcg 76 mcg Average initial dose per guidelines (based on ideal body weight) 107 mcg 71 mcg 109 mcg

Simple SummaryThis study aimed to assess the prognostic relevance of soluble serum PD-L1 in upper tract urothelial carcinoma (UTUC) patients who underwent surgical or systemic (chemo- or immune checkpoint inhibitor) therapy. We found that high preoperative sPD-L1 levels were correlated with higher pathological tumor stage, grade and the presence of metastasis. In addition, higher pretreatment serum PD-L1 concentrations were associated with shorter survival in both surgically and chemotherapy-treated UTUC patients. We detected a characteristic increase in serum PD-L1 levels in UTUC patients after 3 months of anti-PD-L1 therapy. Based on these results sPD-L1 is a promising prognostic biomarker in UTUC.Programmed death ligand-1 (PD-L1) is an immune checkpoint molecule and a widely used therapeutic target in urothelial cancer. Its circulating, soluble levels (sPD-L1) were recently suggested to be associated with the presence and prognosis of various malignancies but have not yet been investigated in upper tract urothelial carcinoma (UTUC). In this study, we assessed sPD-L1 levels in 97 prospectively collected serum samples from 61 UTUC patients who underwent radical nephroureterectomy (RNU), chemotherapy (CTX), or immune checkpoint inhibitor (ICI) therapy. In addition to pretreatment samples, postoperative and on-treatment sPD-L1 levels were determined in some patients by using ELISA. In the RNU group, elevated preoperative sPD-L1 was associated with a higher tumor grade (p = 0.019), stage (p < 0.001) and the presence of metastasis (p = 0.002). High sPD-L1 levels were significantly associated with worse survival in both the RNU and CTX cohorts. sPD-L1 levels were significantly elevated in postoperative samples (p = 0.011), while they remained unchanged during CTX. Interestingly, ICI treatment caused a strong, 25-fold increase in sPD-L1 (p < 0.001). Our results suggest that elevated preoperative sPD-L1 level is a predictor of higher pathological tumor stage and worse survival in UTUC, which therefore may help to optimize therapeutic decision-making. The observed characteristic sPD-L1 flare during immune checkpoint inhibitor therapy may have clinical significance.

This pooled analysis of patient-level data from trials evaluated the clinical outcomes of patients with metastatic renal cell carcinoma with or without cytoreductive nephrectomy before a combination of immune checkpoint inhibitor and antiangiogenic therapy. Data from 5 trials of immune checkpoint inhibitors plus antiangiogenic therapy were pooled. Only patients with stage 4 disease at initial diagnosis were included to ensure that nephrectomy was performed for cytoreductive purposes and not to previously treat an earlier stage of disease. The effect of cytoreductive nephrectomy before immune checkpoint inhibitor therapy on outcomes was evaluated using the Kaplan-Meier method and a Cox proportional hazards regression model, adjusted for age, sex, risk group, performance status, and the presence of sarcomatoid differentiation. A total of 981 patients were included. The estimated median progression-free survival with and without nephrectomy was 15 and 11 months, respectively; the adjusted hazard ratio was 0.71 (95% confidence interval = 0.59 to 0.85). The estimated median overall survival with and without nephrectomy was 46 and 28 months, respectively; the adjusted hazard ratio was 0.63 (95% confidence interval = 0.51 to 0.77). Objective response was 60% of patients with vs 46% of patients without cytoreductive nephrectomy. Patients with metastatic renal cell carcinoma who undergo cytoreductive nephrectomy before immune checkpoint inhibitor plus antiangiogenic therapy had improved outcomes compared with patients without cytoreductive nephrectomy. Selection factors for cytoreductive nephrectomy may be prognostic and could not be fully controlled for in this retrospective analysis. Prospective determination of and stratification by prior cytoreductive nephrectomy may be considered when designing clinical trials to assess the impact of this factor on prognosis.

The Symptom Experience of Patients with Advanced Melanoma Undergoing Immune Checkpoint Inhibitor (ICI) Therapy

Norway has one of the highest rates of cutaneous melanoma (CM) incidence and mortality globally. Immune checkpoint inhibitor (ICI) therapy for CM was introduced between 2014 and 2017 to improve treatment and patient prognosis, but knowledge about its clinical usage is limited. This study investigates patient's characteristics and treatment patterns in real-world practice compared to clinical trial results. All adult (≥18) CM patients treated with ICI therapy in Norway from 2014 to 2021 were included, utilizing high-coverage data from multiple national registries to describe patients' health, socioeconomic factors, and treatment management, stratified by first ICI therapy. We compared patient and tumour characteristics with findings from five randomized controlled trials (RCTs). Among 2,083 patients receiving ICI therapy, 975 (47%) received nivolumab as their first treatment in the metastatic setting. Patients on combination therapy were younger and had higher education and income levels compared to those on monotherapy. Overall, real-world patients were older and had a higher incidence of brain metastases than those in RCTs. Approximately, 1 in 5 patients would have been excluded from RCTs due to pre-existing autoimmune diseases. Targeted therapy was the most common secondary systemic treatment after first-line PD-1 inhibitors. This study details ICI therapy in Norway, highlighting differences between real-world ICI users and clinical trial participants, raising questions about the effectiveness of this treatment for patients not eligible for trials.