Cycle Of Immune Checkpoint Inhibitors Research Articles

Effect of glucocorticoids for the management of immune-related adverse events on outcome in melanoma patients treated with immunotherapy – a retrospective and biomarker study

Immune-related adverse events (IRAEs) during therapy with immune checkpoint-inhibitors (ICIs) are common, and its management sometimes requires glucocorticoids (GC). Predictors for development of IRAEs and data about the impact of GC on clinical outcome are missing. We evaluated the impact of GC to treat IRAEs on clinical outcome, and plasmatic inflammatory proteins as predictors for IRAEs.Patients with melanoma (n=98) treated with ICIs at Karolinska University Hospital were included. Clinical information and data regarding prescription of systemic GC were collected. Baseline plasma samples (n=57) were analyzed for expression of 92 inflammatory proteins.Forty-four patients developed at least one IRAE requiring systemic GC and the most common was hypocortisolemia (n=11). A median overall survival (mOS) of 72.8 months for patients developing IRAEs requiring GC, 17.7 months for those who did not, and 1.4 months for individuals receiving GC at baseline was observed in Kaplan-Meier curves (p = 0.001). In immortal time bias adjusted analysis patients receiving steroids to treat IRAE survived slightly longer, even though this time trend was not statistically significant. The mOS was 29 months for those treated with GC within 60 days after ICIs start and was not reached for patients receiving GC later. The number of ICIs cycles was higher in subjects receiving GC after 60 days (p=0.0053). Hypocortisolemia occurred mainly in males (10/11) and correlated with favorable outcome. Male patients with hypocortisolemia had lower expression of IL8, TGF-alfa and FGF5 and higher expression of DNER.GC may be used to treat IRAEs without major concern. However, GC early during ICIs may impact clinical outcome negatively. The prognostic value of hypocortisolemia and inflammation proteins as biomarkers should be further investigated.

Continuous immunotherapy beyond progression in clinical practice for small cell lung cancer.

In non-small-cell lung cancer, continuous immune-checkpoint inhibitors (ICIs) beyond progression are often used in clinical practice. On the other hand, there is almost no data on whether the concept of continuous ICIs beyond progression can be adopted in small-cell lung cancer (SCLC). We describe the effectiveness of continuous ICIs beyond progression in SCLC. Medical courses of SCLC patients treated with chemo-immunotherapy were retrospectively reviewed at our hospital. The study included 36 patients with a median age of 73 years (range 46-83 years) who introduced chemo-immunotherapy between September 2019 and December 2022. Atezolizumab and durvalumab in combination with platinum plus etoposide were administered in 24 and 12 patients, respectively. The overall response rate was 67% and the disease control rate was 86%. The median progression-free survival and time to treatment failure (TTF) were 5.1 and 10.3 months, respectively. The median cycle of ICIs was 5 (range 1-42). The median overall survival was 13.6 months. ICIs were administered beyond progression in 14 (39%) patients: five were treated again with chemo-immunotherapy and local ablative radiotherapy, four with local ablative radiotherapy and continuous ICIs, three with chemo-immunotherapy, and two with continuous ICIs alone. TTF exceeded 12 months in 12 (86%) of the 14 cases, six of which were still on ICIs. Adverse events ≥grade 3 were observed in 21 (58%) patients. A notable TTF suggested a benefit of continuous ICIs beyond progression. The concept could be suitably adopted and provide a favorable prognosis in selected cases of SCLC that were previously regarded as an aggressive malignancy.

Immune checkpoint inhibitors combined with or without radio(chemo)therapy for locally advanced or recurrent/metastatic esophageal squamous cell carcinoma

ObjectiveThis study was designed to investigate the efficacy and prognostic factors for immune checkpoint inhibitors (ICIs) combined with or without radio(chemo)therapy and to evaluate their toxicity in patients with locally advanced or recurrent/metastatic esophageal squamous cell carcinoma (LA/RM ESCC).MethodsIn this study, 198 patients with locally advanced or recurrent/metastatic (LA/RM) ESCC who received ICIs combined with or without radiotherapy/chemotherapy in the Department of Radiotherapy of the Fourth Hospital of Hebei Medical University were retrospectively analyzed. Univariate and multivariate analyses were performed to determine the prognostic factors for overall survival (OS) and progression free survival (PFS). The factors affecting treatment response and the occurrences of treatment-related adverse events (trAEs) were analyzed.ResultsThe median OS and PFS were 30.4 months (95% confidence interval [CI] 15.1–45.7 months) and 15.3 months (95% CI 12.8–17.8 months), respectively. Univariate and multivariate analysis showed that the number of ICI cycles, the intervention of radiotherapy and dysphagia were independent factors affecting OS (Hazard ratio [HR] = 0.39, 2.043 and 0.365, respectively; P = 0.018, 0.001 and 0.032, respectively). The intervention of radiotherapy was an independent factor for PFS (hazard ratio [HR] = 18.149, P = 0.013). The median OS and PFS for patients who had complete response and partial response (Objective response, ORR) were 50.8 months (95% CI 25.8–75.7 months) and 20.5 months (95% CI 14.1–27.0), respectively, which were significantly higher than those in the non-ORR group (OSnon-ORR:17.5 months, 95% CI 14.0–21.0; χ2 = 13.881, P < 0.001; PFSnon-ORR: 12.1 months, 95% CI 10.1–14.1, χ2 = 10.676, P = 0.001). The intervention of radiotherapy could improve treatment response (χ2 = 47.725, P = 0.000). In entire study population, 83 patients (41.9%) had ≥ grade 2 trAEs.ConclusionsICIs combined with radiotherapy/chemotherapy are safe and effective in LA/RM ESCC patients. Intervention of radiotherapy, the number of immunotherapy cycles and occurrence of dysphagia affecting the overall survival of LR/RM ESCC patients. Intervention of radiotherapy was an independent prognosis factor for OS and PFS and associated with better treatment response.

#3880 REDUCED EGFR IS ASSOCIATED WITH IMPROVED SURVIVAL IN PATIENTS WITH RENAL CANCER WHO RECEIVED TARGETED SYSTEMIC ANTI-CANCER THERAPY

Abstract Background and Aims Treatment with vascular endothelial growth factor signalling pathway inhibitors (VSPI) and immune checkpoint inhibitors (ICI) has transformed outcomes in advanced renal cancer. A significant proportion of people with renal cancer have co-existing chronic kidney disease (CKD) and concerns persist about the usage of these agents in patients with CKD. We sought to analyse the effect of reduced kidney function on the survival of patients with renal cancer treated with VSPI or ICI. Methods The ChemoCare and NHS West of Scotland SafeHaven databases were linked (data collection spanning 2008–2020), to identify adults from the Greater Glasgow and Clyde Health board who had received either a VSPI or ICI as an anti-cancer therapy. We included participants with two available serum creatinine values (at least 3 months apart) before the date of initiation of treatment. The estimated glomerular filtration rate (eGFR) was calculated using CKD-EPI (2009), the average of the two eGFR results (at least 3 months apart) was included in the analyses. Proteinuria was defined as any positive urine albumin: creatinine (&amp;gt;3 mg/mmol) or protein:creatinine (&amp;gt;15 mg/mmol) ratio before treatment. Factors associated with all-cause mortality were analysed using Cox proportional hazards models with R Software. Results We identified 349 patients with renal cancer who received at least one cycle of ICI and/or VSPI. Sufficient serum creatinine results were available for analysis in 337 of these patients. The average age at first treatment was 63.0 (IQR 55-71) years, 62.5% were male and the median BMI was 28.2kg/m2 (IQR 23.9-31.6). Proteinuria results were recorded in 125 patients and 149 patients had nephrectomy prior to treatment. The majority of patients received VSPI (88.7%). Over a median follow-up of 335 days (IQR 131 days – 840 days), 281 patients died (Table 1). On univariable analysis, lower baseline eGFR (per 10mL/min/1.73 m2 decline in eGFR: HR 0.89, CI 0.84-0.95, p = &amp;lt;0.001) and prior nephrectomy (HR 0.65, CI 0.52-0.83, p= &amp;lt;0.001) were associated with a higher hazards of death. Age (HR 0.99, CI 0.98-1.00, p = 0.245), sex (HR 0.93, CI 0.74-1.18, p = 0.570), BMI (HR 0.99, CI 0.96-1.03, P = .775) and treatment class (HR 0.76, CI 0.51-1.14, p = 0.253) were not associated with higher hazards of death. After adjustment for age, sex and prior nephrectomy, lower eGFR was associated with lower hazards of death (per 10mL/min/1.73 m2 decline in eGFR: HR 0.91, CI 0.84-0.97, p= 0.007). In a sensitivity analysis in people who had complete eGFR and proteinuria data available, the presence of proteinuria was associated with greater hazards of death (HR 1.63, CI 1.05-2.12, p= 0.029) after adjustment for age, sex, eGFR and nephrectomy (Figure 1). Conclusion Lower baseline eGFR before treatment was associated with reduced hazards of death. This finding was not fully explained by the association of prior nephrectomy with better cancer outcomes. This suggests that other factors may contribute to these discrepancies, such as underlying selection bias of patients for treatment, or bias from the marker used to estimate GFR in this group of patients. The presence of proteinuria was associated with an increased hazards of death and maybe a better marker of renal-associated risk in this group than eGFR and warrants further investigation.

Safety and efficacy of immune checkpoint inhibitors (ICIs) in patients (pts) with cardiac metastases (mets) from solid tumors.

2653 Background: Given underlying differences in the tumor microenvironment across metastatic sites, ICIs demonstrate variable efficacy depending on sites of met involvement. Data on the safety and outcomes of pts on ICIs with cardiac mets are limited. Methods: In an international multi-center retrospective study, pts with solid tumors and baseline mets to the heart who had received ≥1 cycle of ICIs were included. Immune-related adverse events (irAEs) were graded per CTCAE v5.0. Objective response rates (ORR) were evaluated by RECIST1.1 when available. Median overall survival (mOS) and median progression-free survival (mPFS) were calculated from time of ICI initiation using the Kaplan-Meier method. Results: 110 pts across 20 institutions were identified with a median follow-up of 36 (95% CI 26-51) months. Melanoma (38%, n=42) and non-small cell lung cancer (NSCLC, 24%, n=26) were the most common cancers. Median age at ICI initiation was 65 (IQR: 59-75) years and 29% (n=26) received combination ICI therapy with anti-PD1 and anti-CTLA4. Overall, 62% (n=68) received ICIs as 1st line. The mets were mostly located in the atria (37%, n=41) and ventricles (35%, n=39). At ICI initiation, 21% (n=23) had a cardiac thrombus. Of 78 pts with available echocardiographic data at time of ICI initiation, the mean ejection fraction was 61+/- 7.1%. Cardiology referrals and cardiac MRIs since time of cancer diagnosis were completed on 53% (n=58) and 47% (n=52) of pts, respectively. Overall, 36.4% (n=40) of pts had cardiac complications from the mets, including arrhythmias (13%, n=14), arterial/venous emboli (3.6%, n=4), and cardiac tamponade (2.7%, n=3). For NSCLC, ORR, mPFS (95% CI), and mOS (95% CI) were 23%, 4.4 months (3.0-7.5), and 9.9 months (5.9-14.7), respectively. For melanoma, ORR, mPFS, and mOS were 35.7%, 9.1 months (5.2-20), and 29 months (14-58), respectively. Cardiac met ORRs for NSCLC and melanoma were 27% and 43%, respectively. 74% (N=71/96) of pts with evaluable response data had concordant response in the burden of overall disease and cardiac disease. IrAEs are shown. Conclusions: Although cardiac mets are frequently associated with cardiac complications, ICIs demonstrate meaningful efficacy with no overtly concerning safety signals. Close to three-quarter of pts have concordant response in the overall disease and cardiac disease burden. Multi-disciplinary approach involving cardiologists and oncologists need to be implemented to appropriately manage pts with cardiac mets. [Table: see text]

Efficacy and safety of radiation therapy combined with anti-angiogenic agentsand immunotherapy for MSS/pMMR metastatic colorectal cancer: A real-world study.

e15559 Background: The combination of anti-angiogenic drugs and immune checkpoint inhibitors (ICIs) can reshape tumor microenvironment, and their effectiveness has been demonstrated in pattients with microsatellite stable (MSS) or mismatch repair profificient (pMMR) metastatic colorectal cancer (mCRC). Radiotherapy (RT) can induce tumor immunogenic cell death, increase infiltration of tumor-infiltrating T lymphocytes and enhance neoantigen expression. Whether the application of RT can further improve the prognosis of pts with MSS/pMMR mCRC receiving anti-vascular drugs and immunotherapy remains to be explored. Methods: We retrospectively identified data on mCRC pts who received anti-angiogenic targeted agents and ICIs after failure of standard therapy at our institution from January 2015 to September 2022. Pts either received RT (RT+TT+IT group) or did not (TT+IT group) during the course of the disease. Baseline characteristics of the groups were compared with the Chi-squared, Fisher's exact, or the independent sample t-test as appropriate. Progression-free survival (PFS) and overall survival (OS) were examined by the Kaplan-Meier method with a log-rank test. Univariate and multivariate Cox regression analysis was conducted to identify prognostic factors for PFS and OS. Results: Of the 89 pts who received anti-angiogenic targeted therapy in combination with ICIs, 43 (48.3%) received RT and 46 (51.7%) did not. All pts were MSS/pMMR. The objective response rate (ORR) of the RT+TT+IT and TT+IT groups was 18.6% (8/43) and 10.9% (5/46) and the disease control rate (DCR) was 83.7% (36/43) and 67.4% (31/46) (both p &gt; 0.05), respectively. The median PFS time was slightly higher in the RT+TT+IT group than in the TT+IT group (5.0 vs. 4.3 months, p = 0.065). In addition, the PFS of RT sequential/simultaneous TT+IT was superior to TT+IT sequential radiotherapy (RT→IT+TT vs. RT-IT+TT vs. IT+TT→RT: median 7.5 vs. 6.1 v.s 3.8 months, p = 0.004). The median OS of RT+TT+IT group was significantly better than that of TT+IT group (15.2 vs. 7.2 months, p = 0.026). Application of RT appeared to be most benefificial in pts aged 56 or younger, advanced stage of initial diagnosis, metastatic lesions involving ≥2 organs, primary lesion not resected, RAS mutations. Cox multivariate regression analysis showed that the number of anti-angiogenic agents plus ICIs cycles &gt; 4 was an independent prognostic factor for OS. No treatment-related deaths were reported, and radiation pneumonia occurred in one patient in the combined radiotherapy group in a manageable manner. Conclusions: The addition of RT during the course of disease can significantly improve the survival benefit of MSS/pMMR mCRC pts treated with anti-angiogenic drugs combined with ICIs posterior line therapy.

Interaction between gut microbiome and immune checkpoint inhibitor treatment in lymphoma patients: Final results of the MICRO‐LINF study

Introduction: Over the last decades, a revolution has occurred in oncology with the development of immune checkpoint inhibitors (ICIs). Following tremendous successes in solid tumors, interest has risen to explore these inhibitors also in hematologic malignancies, especially lymphomas. Biomarkers for ICIs response and resistance include PD-L1 expression and other environmental factors, among which the gut microbiome (GM) is gaining increasing interest. Several studies have demonstrated a connection between GM compositional and functional patterns and ICIs efficacy in solid tumors, but no data in lymphomas have yet been published. We hypothesize that GM dynamics in lymphoma patients during ICIs therapy correlate with treatment response and toxicities. Methods: We enrolled 20 patients (15 with classical Hodgkin lymphoma [cHL] and 5 with primary mediastinal B-cell lymphoma [PMBCL]) treated with ICIs due to relapsed/refractory (R/R) disease. Feces were collected at baseline, before each therapy cycle and at response assessment, and profiled through Illumina sequencing. Sequencing data were processed using a bioinformatics pipeline combining PANDASEQ and QIIME 2. At each time point, patients compiled a 7-day weighted food intake record that was analyzed by MètaDieta (METEDA). All statistical analysis was performed in R (4.4.2). Results: The two groups of patients did not differ for baseline characteristics, thus both clinical outcomes and GM results are reported as pooled. Nineteen patients were refractory to last therapy, with a median of previous treatments of 3 (range 2–8). The median number of ICIs cycles was 14 (1–39). The overall response rate (ORR) was 30.5%, with a median progression-free survival of 11 months and a median disease survival not reached, at a median follow-up of 28.9 months. No association was found between clinical characteristics and response/survival outcomes. Three patients developed 6 hematological toxicities and 18 patients developed 58 extra-hematological toxicities; 4 patients had SAE, of which 2 were judged as drug related. As for GM (Figure 1), responding patients showed a peculiar enrichment of Lachnospira at baseline (p = 0.013). The relative abundance of this taxon negatively correlated with dietary intake of Omega-6 (p = 0.038). On the other hand, non-responders showed higher basal levels of Enterobacteriaceae (p = 0.041). These features were also maintained at the end of the treatment, even if only as trends (p < 0.1). Keywords: Diagnostic and Prognostic Biomarkers, Immunotherapy No conflicts of interests pertinent to the abstract.

The prognostic value of [18F]FDG PET/CT based response monitoring in metastatic melanoma patients undergoing immunotherapy: comparison of different metabolic criteria

PurposeTo investigate the prognostic value of [18F]FDG PET/CT as part of response monitoring in metastatic melanoma patients treated with immune checkpoint inhibitors (ICIs).MethodsSixty-seven patients underwent [18F]FDG PET/CT before start of treatment (baseline PET/CT), after two cycles (interim PET/CT) and after four cycles of ICIs administration (late PET/CT). Metabolic response evaluation was based on the conventional EORTC and PERCIST criteria, as well as the newly introduced, immunotherapy-modified PERCIMT, imPERCIST5 and iPERCIST criteria. Metabolic response to immunotherapy was classified according to four response groups (complete metabolic response [CMR], partial metabolic response [PMR], stable metabolic disease [SMD], progressive metabolic disease [PMD]), and further dichotomized by response rate (responders = [CMR] + [PMR] vs. non-responders = [PMD] + [SMD]), and disease control rate (disease control = [CMR] + [PMR] + [SMD] vs. [PMD]). The spleen-to-liver SUV ratios (SLRmean, SLRmax) and bone marrow-to-liver SUV ratios (BLRmean, BLRmax) were also calculated. The results of PET/CT were correlated with patients’ overall survival (OS).ResultsMedian patient follow up [95% CI] was 61.5 months [45.3 – 66.7 months]. On interim PET/CT, the application of the novel PERCIMT demonstrated significantly longer survival for metabolic responders, while the rest criteria revealed no significant survival differences between the different response groups. Respectively on late PET/CT, both a trend for longer OS and significantly longer OS were observed in patients responding to ICIs with metabolic response and disease control after application of various criteria, both conventional and immunotherapy-modified. Moreover, patients with lower SLRmean values demonstrated significantly longer OS.ConclusionIn patients with metastatic melanoma PET/CT-based response assessment after four ICIs cycles is significantly associated with OS after application of different metabolic criteria. The prognostic performance of the modality is also high after the first two ICIs cycles, especially with employment of novel criteria. In addition, investigation of spleen glucose metabolism may provide further prognostic information.

PD24-05 COMPLETE PATHOLOGICAL RESPONSE IN PATIENTS UNDERGOING NEPHRECTOMY FOR RENAL CELL CARCINOMA FOLLOWING IMMUNE CHECKPOINT INHIBITOR THERAPY: A MULTICENTER STUDY

You have accessJournal of UrologyCME1 Apr 2023PD24-05 COMPLETE PATHOLOGICAL RESPONSE IN PATIENTS UNDERGOING NEPHRECTOMY FOR RENAL CELL CARCINOMA FOLLOWING IMMUNE CHECKPOINT INHIBITOR THERAPY: A MULTICENTER STUDY Alireza Ghoreifi, Thomas Gerald, Joseph Cheaib, Anirudh Yerrapragada, Jie Cai, Vinay Duddalwar, Inderbir Gill, Nirmish Singla, Vitaly Margulis, and Hooman Djaladat Alireza GhoreifiAlireza Ghoreifi More articles by this author , Thomas GeraldThomas Gerald More articles by this author , Joseph CheaibJoseph Cheaib More articles by this author , Anirudh YerrapragadaAnirudh Yerrapragada More articles by this author , Jie CaiJie Cai More articles by this author , Vinay DuddalwarVinay Duddalwar More articles by this author , Inderbir GillInderbir Gill More articles by this author , Nirmish SinglaNirmish Singla More articles by this author , Vitaly MargulisVitaly Margulis More articles by this author , and Hooman DjaladatHooman Djaladat More articles by this author View All Author Informationhttps://doi.org/10.1097/JU.0000000000003302.05AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookLinked InTwitterEmail Abstract INTRODUCTION AND OBJECTIVE: Immune checkpoint inhibitors (ICI) are now among frontline treatments for advanced renal cell carcinoma (RCC). The aim of this study is to evaluate predictors and outcomes of patients with complete pathologic response in the primary tumor following ICI therapy. METHODS: Patients with RCC undergoing nephrectomy following ICI therapy were evaluated in three high-volume US academic centers. Available pre-ICI and preoperative computed tomography imaging were reviewed by expert radiologists. Radiological data, clinical features, and outcomes of patients with and without complete pathological response were compared. RESULTS: A total of 92 patients with a median (IQR) age of 63 (56-69) years were included. Among patients with available data, ICI regimens (median cycles=3) were Nivolumab±Ipilimumab (n=76), and Pembrolizumab±Axitinib (n=12). Clinical, radiological, and pathological features of the patients are shown in Table 1. Among all patients, 90 (98%) underwent radical and 2 (2%) partial nephrectomy; 40 (43.5%) open, 40 (43.5%) robotic and 12 (13%) laparoscopic. Median operative time, estimated blood loss, and length of stay were 3 hours, 200 mL, and 3 days, respectively. Eight patients (9%) showed complete pathological response in the kidney. Complete pathological response was marginally associated with higher number of ICI cycles (> 3 vs. ≤3 cycles: 16% vs. 4%, p=0.06), and with no other clinical or pretreatment radiologic variable. 3-year overall and progression-free survivals in patients with complete pathological response were 100%; however, the same outcomes in other patients were 89% and 53%, respectively (Figure 1). CONCLUSIONS: In our cohort, 9% of patients who underwent nephrectomy following immune checkpoint inhibitors for advanced RCC showed complete pathological response in nephrectomy specimen. These patients demonstrated more favorable overall and progression-free survivals compared to those with residual tumor in the final specimen. Source of Funding: None © 2023 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 209Issue Supplement 4April 2023Page: e723 Advertisement Copyright & Permissions© 2023 by American Urological Association Education and Research, Inc.MetricsAuthor Information Alireza Ghoreifi More articles by this author Thomas Gerald More articles by this author Joseph Cheaib More articles by this author Anirudh Yerrapragada More articles by this author Jie Cai More articles by this author Vinay Duddalwar More articles by this author Inderbir Gill More articles by this author Nirmish Singla More articles by this author Vitaly Margulis More articles by this author Hooman Djaladat More articles by this author Expand All Advertisement PDF downloadLoading ...

Biomarkers for Outcome in Metastatic Melanoma in First Line Treatment with Immune Checkpoint Inhibitors.

A high proportion of metastatic melanoma patients do not respond to immune checkpoint inhibitors (ICI), and until now, no validated biomarkers for response and survival have been known. We performed a retrospective analysis of outcomes in patients with metastatic melanoma treated with first-line ICI at the Institute of Oncology Ljubljana from January 2018 to December 2020. The immune-related adverse events (irAEs) and serum immune-inflammation parameters (neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio (LR), systemic immune-inflammation index (SII) and pan-immune-inflammation value (PIV)) were analyzed as potential biomarkers for response and survival. Survival rates were calculated using the Kaplan-Meier method and then compared with the log-rank test. Multivariate regression Cox analysis was used to determine independent prognostic factors for progression-free survival (PFS) and overall survival (OS). Median follow-up was 22.5 months. The estimated median progression-free survival (PFS) was 15 months (95% CI 3.3-26.2). The two-year survival rate (OS) was 66.6%. Among 129 treated patients, 24 (18.6%) achieved complete response, 28 (21.7%) achieved partial response, 26 (20.2%) had stable disease and 51 (39.5%) patients experienced a progressive disease. There was a higher response rate in patients with irAEs (p < 0.001) and high NLR before the second cycle of ICI (p = 0.052). Independent prognostic factors for PFS were irAE (HR 0.41 (95% CI 0.23-0.71)), SII before the first cycle of ICI (HR 1.94 (95% CI 1.09-3.45)) and PLR before the second cycle of ICI (HR 1.71 (95% CI 1.03-2.83)). The only independent prognostic factor for OS was SII before the first cycle of ICI (HR 2.60 (95% CI 0.91-7.50)). Patients with high pre-treatment levels of SII had a higher risk of progression and death; however, patients with irAEs in the high-SII group might respond well to ICI. Patients who develop irAEs and have high NLRs before the second ICI application have higher rates of CR and PR, which implicates their use as early biomarkers for responsiveness to ICI.

Safety and efficacy of immune checkpoint inhibitors (ICI) in advanced penile squamous cell carcinoma (PeCa): An international study from the Global Society of Rare Genitourinary Tumors (GSRGT).

5 Background: Management options for patients (pts) with advanced (locally advanced or metastatic) PeCa are limited. The GSRGT assembled an international cohort of pts with advanced PeCa treated with ICI to evaluate toxicity and clinical outcomes. Methods: We retrospectively collected data on pts with advanced PeCa receiving ≥1 cycle of ICI between 2015-2022 at 18 medical centers in the US, Europe, and Asia. Immune-related adverse events (irAE) were graded per the Common Terminology Criteria for Adverse Events v5.0. Overall survival (OS) and progression-free survival (PFS) were estimated by the Kaplan-Meier method. Objective response rate (ORR) was determined by the clinical investigator per RECIST 1.1 criteria, whenever feasible. Results: Among 72 pts with advanced PeCa treated with ICI, 24 (33%) were Hispanic and 7 (10%) were Black. 60 (83%) pts had metastases while the remainder had locally advanced disease. The median age was 64 (inter-quartile range (IQR): 54,70) years and 48 (67%) had ECOG performance status ≥1. Most pts (n=60, 83%) were treated in the ≥2nd line setting and received pembrolizumab (n=23), nivolumab (n=15), cemiplimab (n=15), nivolumab and ipilimumab (n=7), or other anti-PD1/L1-based therapies (n=12). Among 37 pts with available data on HPV status, 24 (65%) were HPV+. 3 (4%) pts were HIV+. irAE of any grade occurred in 18 (25%) pts, 7 (10%) were grade ≥3, 7 (10%) required steroids, 6 (9%) required hospitalization, and 8 (11%) led to treatment discontinuation. The median OS and 24-month OS and median PFS and 24-month PFS were 9.4 (95%CI: 6.8, 12.8) months and 19.3% (95%CI: 9.2, 32.1) and 2.8 (95%CI: 2.1, 3.9) months and 11.2 % (95%CI: 4.9, 20.2), respectively. Among 66 pts evaluable for response, ORR was 7/66 (11%) (2 with complete response, 5 with partial response), and 16 (24%) pts had stable disease for a disease control rate of 35%. The median duration of response was 7.9 (IQR: 3, not reached) months. Conclusions: In the largest retrospective cohort of ICI-treated advanced PeCa, ICI showed no new safety signals, however, overall anti-tumor activity was limited. Future translational studies are needed to identify pts that are more likely to derive clinical benefit from ICI.

A Novel Workflow to Create a Checkpoint Inhibitor Pneumonitis Patient Registry.

Background Despite being a groundbreaking cancer therapy, immune checkpoint inhibitors (ICI) can lead to potentially life-threatening toxicity with checkpoint inhibitor pneumonitis (CIP). While treatable, it is easy for clinicians to miss the symptoms of CIP, which can lead to a delay in diagnosis and worsening respiratory function. There is no consensus approach to systematically identifying patients at risk of developing CIP. Thus, we sought to create a workflow that could inform patient selection for ICI therapy based on previously reported risk factors for CIP development. Materials and methods We retrospectively identified 250 patients with lung cancer treated with at least one dose of an ICI over 20 months. Data were collected on comorbidities, cancer type and stage, performance status, ICI cycles, biomarkers, prior curative treatment, diagnostic evaluation, antibiotics, steroids, progression, and survival. A single-blinded radiologist characterized radiographic patterns of suspected CIP cases. Results Among 97 patients who received steroids while admitted to the hospital, 12 (6%) had at least one sign or symptom suggestive of CIP. Chronic obstructive pulmonary disease and non-small cell lung cancer subtypes correlated with suspicion of having CIP. CIP was confirmed in five patients (42%) and ruled out (mimics) in seven (58%).Median times until symptoms were 17 months and one month for confirmed and mimic cases, respectively.The median time to confirm or exclude CIP was 5 ± 4 days. Most suspected cases underwent thoracic imaging, blood cultures, and empiric antibiotics. Radiographic patterns in suspected cases included ground glass opacities, organizing pneumonia, acute interstitial pneumonia/acute respiratory distress syndrome, bronchiolitis, radiation recall pneumonitis, hypersensitivity pneumonitis, and post-radiation fibrotic changes. Conclusions CIP mimics are common in clinical practice; therefore, it is reasonable to empirically treat suspected cases with shorter courses of steroids until diagnostic clarity is achieved. This proof-of-concept study demonstrates that this novel workflow can identify the true incidence of CIP, inform treatment decisions, and lead to the development of implementation studies to improve patient care directly.

Development of a Novel Predictive-Prognostic Scoring Index for Immune Checkpoint Inhibitors in Advanced Non-small Cell Lung Cancer.

Immune checkpoint inhibitors (ICIs) have become the standard of care for the treatment of patients with driver mutation absent advanced non-small cell lung cancer (NSCLC). The present study aimed to develop a reliable, reproducible, and practical scoring system to prognosticate and predict response to ICI response in patients with advanced NSCLC. All patients who were diagnosed as having unresectable/advanced stage NSCLC and were treated with at least one cycle of ICIs at the Medical Oncology Departments of Dr. Burhan Nalbantoğlu State Hospital (Nicosia, Cyprus) and Near East University Hospital (Nicosia, Cyprus) were included in the study. The association between variables and OS was evaluated using a Cox proportional hazards regression model. Variables with a P-value less than 0.05 in the univariate analysis were included in the multivariate model. A prognostic scoring system was developed.  Survival estimates were calculated using the Kaplan-Meier method. The value of the Concordance index (C-index) and the area under the curve (AUC) was used to evaluate the discriminative ability of scoring systems. One hundred fifty consecutive patients with unresectable/metastatic NSCLC who received PD-1 inhibitors between March 2017 and November 2022 were included. In the multivariate Cox regression model, serum lactate dehydrogenase (LDH), C-reactive protein (CRP) levels, and Eastern Cooperative Oncology Group Performance Status (ECOG PS) were significantly associated with OS. We generated a new score using CRP ³1.0 mg/dL, ECOG PS ³2, and LDH level >ULN. Relative weight was based on the HRs of multivariate analyses (CRP ³1.0 mg/dL 2 points, ECOG PS ³2 2.5 points, and LDH level >ULN 1.5 points). The cohort was divided into three risk groups based on the sum of factors present: 0-2.5 (good risk), 3.5-4.5 (intermediate risk), or 6 (poor risk). The median OS was 18.9, 7.4, and 2.9 months for good, intermediate, and poor risk categories, respectively (log-rank test, p<0.001). The Harrell C-index of CEL to predict OS and PFS was 0.73 and 0.69, respectively, indicating significant predictability. The AUC of the scoring index for predicting the responses was 0.765 (95% CI: 0.685-0.845). The CEL score is a promising prognostic and predictive index consisting of serum CRP levels (C), ECOG PS (E), and serum LDH levels (L). This represents another step forward in the treatment of patients with advanced NSCLC.

Association between immune checkpoint inhibitors and vascular endothelial growth factor targeted therapy with cardiovascular events

Abstract 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.

Pharmacist's role in immune-related adverse events management: real-world incidence and risk evaluation from immunotherapy.

The challenge of using immune checkpoint inhibitors (ICI) is the immune-related adverse events (irAEs). Nonetheless, there is scarce evidence regarding the irAEs in Thailand. The primary aims of this study are to assess the incidence as well as risk factors of irAEs among cancer patients in Wattanosoth hospital. This was a cross-sectional retrospective chart review for the 3-year period (2017-2019). Data were collected after initiating the approved ICIs and patients were then followed for 12 months. The outcomes included incidences of irAEs, adverse events management, and tumor objective response. Bivariate analysis was performed for factors that might be associated with irAEs occurrences. Data from 91 patients was collected. There was a 49.5% overall irAEs incidence. The most frequent irAE to occur affected the endocrine system (29.85%). In addition, we identified that odds ratios of irAEs development increased in patients who had four or more ICI cycles or had a serum creatinine level higher than 1.2 mg/dl, (OR: 1.75; 95% CI 1.1611:2.6256, P = 0.0074) and (OR: 1.58; 95% CI: 1.0628:2.3574; P = 0.0238), respectively. The emergence of irAEs may be a sign of tumor objective responses (OR: 1.79; 95% CI 1.0035:3.1889; P = 0.0486). This study demonstrates that irAEs are common in patients treated with ICIs. In addition, our study identifies that number of cycles and serum creatinine influence the development of irAEs. Hence, prompt recognition and an adequate monitoring plan should be cautiously taken into consideration.

Pan-cancer (ca) analysis of the safety and efficacy of immune checkpoint inhibitors (ICI) in patients (pts) living with HIV (PLWH): Results from the international CATCH-IT consortium.

2649 Background: PLWH and ca are inadequately represented in clinical trials evaluating ICI especially in the setting of low CD4 counts (ct) and elevated HIV viral loads (VL). We assembled an international cohort of PLWH and ca treated with ICI to evaluate toxicity profiles and clinical outcomes. Methods: We retrospectively collected data on 204 PLWH and ca receiving ≥ 1 cycle of ICI between 2015-2021 at 14 academic medical centers in the US and Europe. Immune-related adverse events (irAEs) were graded per the Common Terminology Criteria for Adverse Events (CTCAE) V5.0. Baseline CD4 ct, CD8 ct and HIV VL were collected within 3 months (mo) of ICI initiation when available. Fisher’s exact test was performed to compare categorical variables. Median (med) Overall Survival (OS) and Objective Response Rate (ORR) were calculated for 186 pts treated in the metastatic (met) setting. Results: Among 204 PLWH treated with ICI, 174 (85%) were cis-gender males. 61 (31%) were Black and 34 (18%) were Hispanic/Latinx. Pts were treated with pembrolizumab (n=93), nivolumab (n=71), atezolizumab (n= 20), nivolumab and ipilimumab (n=13), durvalumab (n=6), or avelumab (n=1). Med number of prior lines of systemic therapy was 1 (range: 0-5). Among pts with available baseline data, 36/133 (27%) had CD4 ct &lt;200 cells/µL while 12/136 (9%) had VL ≥400 copies/mL. irAEs of any grade occurred in 43 (21%) pts and 13 (7%) were grade ≥3 while 19 (9%) required steroids. Pts with CD4 ct &lt;200 cells/µL experienced fewer irAEs than pts with CD4 ct ≥200 cells/µL (2/36 vs 26/97; p&lt;0.01). The incidence of any grade irAEs was similar between pts with CD4/CD8 ratio &lt;0.4 vs ≥0.4 (8/54 vs 18/72; p=0.16) and between pts with HIV VL ≥400 vs &lt;400 copies/mL (1/12 vs 28/124; p=0.46). Clinical outcomes are shown in the table below. Among 29 pts with met non-small cell lung ca (NSCLC) with available CD4 ct, the ORR of pts with CD4 ct &lt;200 cells/µL was 13% (95% CI:0-53) vs 38% (95% CI:18-62) in pts with CD4 ct ≥ 200 cells/µL (1/8 vs 8/21; p=0.38). Conclusions: In the largest dataset to our knowledge, we demonstrate tolerability and activity of ICI among PLWH regardless of CD4 ct and HIV VL levels. CD4 ct &lt;200 cells/µL may be associated with a lower incidence of irAEs. An analysis of a larger cohort is underway. [Table: see text]

Immuntherapien in der Uroonkologie

Immune checkpoint inhibitors (ICI) have been approved in uro-oncology for afew years. Real-world experience regarding benefits and risks with novel side effects are rare. In aretrospective analysis, all patients who received ICI therapy due to metastatic renal cell carcinoma (NCC) or urothelial carcinoma (UCA) were enrolled at two maximum care hospitals in Germany between July 2016 and May 2021. Radiologic response, progression-free survival (PFS), and adverse events leading to treatment interruption were collected. Oncologic response was compared to randomized controlled trials. In all, 1185 ICI cycles were administered to 145 patients (111 men [77%] and 34women [23%]): 64(44.1 %) patients with NCC and 81 (55.9%) patients with UCA received ICI therapy. Of 141 patients with radiological follow-up, an objective response was observed in 21.3% (n = 13) of patients with NCC and 20.0% (n = 16) with UCA (median duration of response 14.9 months [3.0-51.3]). Median PFS was 5.3months in patients with NCC and 4.8months with UCA. ICI-associated adverse events requiring treatment interruption were observed in 17.2% patients with NCC and 20.9% with UCA. These were most commonly renal (5.5%: nephritis) and gastrointestinal (4.8%: colitis, diarrhea) adverse events. Hospitalization was required for 22(15.1%) patients. This real-world experience may support patient-centered consultation in treatment decision-making. Further studies on prognostic factors are needed. Therapy interruptions are frequent and the spectrum of side effects requires interdisciplinary treatment.

De Ritis Ratio, Neutrophil-to-Lymphocyte Ratio, and Albumin Are Significant Prognostic Factors for Survival Even After Adjusted by the Treatment Duration in Metastatic Kidney and Bladder Cancer Treated With Immune-Checkpoint Inhibitors

Purpose: This study aimed to determine the prognostic roles of several immune-related laboratory parameters in patients with metastatic kidney and bladder cancer treated with immune checkpoint inhibitors (ICIs).Materials and Methods: Overall, 36 patients with either metastatic bladder (N=18) or kidney cancer (N=18) were enrolled retrospectively. Progression-free survival (PFS) and overall survival according to the pretherapeutic serum De Ritis ratio (DRR), neutrophil-to-lymphocyte ratio (NLR), and albumin level after ICI treatment, were analyzed. Treatment duration was adjusted using Contal and O’Quigley’s method to explore the cutoff and maximize the log-rank test statistic. Cox proportional hazards model was used to analyze the laboratory parameters.Results: A total of 9 patients received a combination therapy of multiple ICIs (N=9) and targeted agents (N=7). The median NLR, DRR, and albumin level at baseline were 1.7, 1.2, and 4.2 mg/dL, respectively. In the univariable analysis, combination of immunotherapies, total ICI cycles, baseline DRR, and albumin level were significant for PFS. Sex ratio, total ICI cycles, and baseline NLR and DRR were significant for cancer-specific survival (CSS). DRR and albumin levels, which were measured for up to 10 cycles, were significant in PFS and CSS. NLR was additionally significant in CSS. After adjusting total ICI cycles, DRR was significant in PFS and CSS, albumin level was significant only in PFS, and NLR was significant only in CSS in the multivariable analysis.Conclusions: NLR, DRR, and albumin level are significant factors associated with the survival of patients with metastatic kidney and bladder cancer treated with ICI.

Immune Checkpoint Inhibitors-Associated Cardiotoxicity.

Simple SummaryWith nonspecific activation of the immune system, immune checkpoint inhibitors (ICIs) can lead to off-target immune-related adverse events (irAEs) to every organ system. Immune-related cardiotoxicity is rare but often fatal. Large population-based studies examining different ICI-associated cardiotoxicity across cancer types and agents are limited. Using data from a large network of health care organizations, this study aims to: (1) provide an estimate of the incidence of ICI-associated cardiotoxicity, (2) to determine patient and clinical characteristics associated with the risk of developing ICI-associated cardiotoxicity, and (3) to assess the overall survival of patients experiencing ICI-associated cardiotoxicity compared to patients who did not develop cardiotoxicity after ICI use.Large population-based studies examining differences in ICI-associated cardiotoxicity across cancer types and agents are limited. Data of 5518 cancer patients who received at least one cycle of ICIs were extracted from a large network of health care organizations. ICI treatment groups were classified by the first ICI agent(s) (ipilimumab, nivolumab, pembrolizumab, cemiplimab, avelumab, atezolizumab, or durvalumab) or its class (PD-1 inhibitors, PD-L1 inhibitors, CTLA4-inhibitors, or their combination (ipilimumab + nivolumab)). Time to first cardiac adverse event (CAE) (arrhythmia, acute myocardial infarction, myocarditis, cardiomyopathy, or pericarditis) developed within one year after ICI initiation was analyzed using a competing-risks regression model adjusting for ICI treatment groups, patient demographic and clinical characteristics, and cancer sites. By month 12, 12.5% developed cardiotoxicity. The most common cardiotoxicity was arrhythmia (9.3%) and 2.1% developed myocarditis. After adjusting for patient characteristics and cancer sites, patients who initiated on monotherapy with ipilimumab (adjusted Hazard Ratio (aHR): 2.00; 95% CI: 1.49–2.70; p < 0.001) or pembrolizumab (aHR: 1.21; 95% CI: 1.01–1.46; p = 0.040) had a higher risk of developing CAEs within one year compared to nivolumab monotherapy. Ipilimumab and pembrolizumab use may increase the risk of cardiotoxicity compared to other agents. Avelumab also estimated a highly elevated risk (aHR: 1.92; 95% CI: 0.85–4.34; p = 0.117) compared to nivolumab and other PD-L1 agents, although the estimate did not reach statistical significance, warranting future studies.

Dosimetric Risk Factors for Acute Radiation Pneumonitis in Patients With Prior Receipt of Immune Checkpoint Inhibitors.

PurposeDosimetric parameters (e.g., mean lung dose (MLD), V20, and V5) can predict radiation pneumonitis (RP). Constraints thereof were formulated before the era of combined immune checkpoint inhibitors (ICIs) and radiotherapy, which could amplify the RP risk. Dosimetric predictors of acute RP (aRP) in the context of ICIs are urgently needed because no data exist thus far.Methods and MaterialsAll included patients underwent thoracic intensity-modulated radiotherapy, previously received ICIs, and followed-up at least once. Logistic regression models examined predictors of aRP (including a priori evaluation of MLD, V20, and V5), and their discriminative capacity was assessed by receiver operating characteristic analysis.ResultsMedian follow-up of the 40 patients was 5.3 months. Cancers were lung (80%) or esophageal (20%). ICIs were PD-1 (85%) or PD-L1 (15%) inhibitors (median 4 cycles). Patients underwent definitive (n=19), consolidative (n=14), or palliative (n=7) radiotherapy; the median equivalent dose in 2 Gy fractions (EQD2) was 60 Gy (IQR, 51.8-64 Gy). Grades 1-5 aRP occurred in 25%, 17.5%, 15%, 2.5%, and 5%, respectively. The only variables associated with any-grade aRP were V20 (p=0.014) and MLD (p=0.026), and only V20 with grade ≥2 aRP (p=0.035). Neither the number of prior ICI cycles nor the delivery of concurrent systemic therapy significantly associated with aRP risk. Graphs were constructed showing the incrementally increasing risk of aRP based on V20 and MLD (continuous variables).ConclusionsThis is the first study illustrating that V20 and MLD may impact aRP in the setting of prior ICIs. However, these data should not be extrapolated to patients without pre-radiotherapy receipt of prior ICIs, or to evaluate the risk of chronic pulmonary effects. If these results are validated by larger studies with more homogeneous populations, the commonly accepted V20/MLD dose constraints could require revision if utilized in the setting of ICIs.