Administration Of Immune Checkpoint Inhibitors Research Articles

Endocrine Side Effects in Patients Treated with Immune Checkpoint Inhibitors: A Narrative Review.

Checkpoint inhibitors are monoclonal antibodies that elicit an anti-tumor response by stimulating immune system. Their use has improved the treatment of different types of cancer such as melanoma, breast carcinoma, lung, stomach, colon, liver, renal cell carcinoma, and Hodgkin's lymphoma, but several adverse events have been reported. Although the etiology of these effects is not completely understood, an uncontrolled activation of the immune system has been postulated. Indeed, some studies showed a cross reactivity of T cells, which acted against tumor antigens as well as antigens in the tissues of patients who developed immune-related adverse events. Despite the known possibility of developing immune-related adverse events, early diagnosis, monitoring during therapy, and treatment are fundamental for the best supportive care and administration of immune checkpoint inhibitors. The aim of this review is to guide the clinician in early diagnosis, management, and treatment of the endocrinological adverse effects in the major endocrine glands (thyroid, pituitary, adrenal, endocrine pancreas, and parathyroid).

BSBM-11 COMBINING IMMUNOTHERAPY AND WHOLE-BRAIN RADIATION THERAPY IN A NOVEL SYNGENEIC LUNG CANCER BRAIN METASTASIS PRECLINICAL MODEL: DOES TIMING OF ADMINISTRATION MATTER?

Abstract Approximately 50% of all brain metastasis cases originate from primary lung tumors. Whole-brain radiation therapy (WBRT) is a common treatment for patients with multiple brain metastases, but patients rarely survive longer than one year after diagnosis. Recent studies demonstrate improved outcomes with combinatorial radiotherapy and immunotherapy, but the optimal timing of immunotherapy administration is unclear. Eliciting a robust immune response post-immunotherapy is vital for therapeutic efficacy. Our work shows that the BBB is disrupted and proinflammatory cytokines are increased in the brain 12 hours post-WBRT in immunocompetent but not immunocompromised mice. Additionally, efflux transporter activity is decreased at this time point. This study utilizes a novel Lewis Lung Carcinoma cell line, LLC-Br, which was developed in our laboratory to preferentially metastasize to the brain. Mice were treated with immune checkpoint inhibitors (ICIs) before or after WBRT then we evaluated tumor progression, survival, and blood-tumor barrier (BTB) permeability. We hypothesized administration of ICI following WBRT would increase survival, decrease tumor burden, and increase BTB permeability in our preclinical syngeneic lung cancer brain metastasis model.

Effect of spatial transcriptomics on tumor immune microenvironment resistant to immune checkpoint inhibitors in metastatic urothelial carcinoma.

68 Background: Immune checkpoint inhibitors (ICBs) for metastatic urothelial carcinoma (mUC) are widely used, but their response rates are inadequate, around 20%. Currently, analyzing samples prior to ICB administration has accumulated so far; thereby predicting response to ICBs by high tumor mutation burden levels and PD-L1 positivity. However, little is known about what kind of tumor microenvironment is formed in recurrent or residual tumors post ICBs, and how it contributes to ICB resistance. Therefore, we applied large datasets of spatial transcriptome analysis to mUC samples post ICBs in order to reveal the diversity of the tumor microenvironment after ICB administration. Methods: The Visium spatial transcriptome analysis was performed on FFPE samples from 12 mUC patients with viable tumor resection after ICB administration. Further, 4 FFPE samples of non-metastatic UC treated-surgically were subjected to spatial transcriptome analysis and were used as ICB-naïve tumor controls. First, the tumor and stromal regions were pathologically annotated. We then identified CD4-positive, CD8A-positive, and FOXP3-positive spots in both tumor and stromal regions, respectively, and analyzed changes in differentially expressed genes (DEGs) and pathways in the tumor space where cancer cells survive after ICB treatment. Results: For DEGs and pathway analysis, 8082 spots in the tumor region and 10964 spots in the stromal region were used. In the tumor and stromal areas, 15.4% and 15.1% were CD4 positive, 6.5% and 6.3% were CD8A positive, and 2.9% and 2.0% were FOXP3 positive, respectively. In tumor regions of ICB-treated specimens, the expression of SULF1, an extracellular matrix-related gene, was increased in all CD4-, CD8A-, and FOXP3-positive spots compared to negative spots. In addition, the expression of complement-related genes such as C1QB, C1QC, and C1R was upregulated in CD8A-positive spots in the tumor regions after ICB. Pathway analysis revealed that oxidative phosphorylation was enriched in CD8A-positive spots in tumor regions prior to ICB, while angiogenesis was enriched in CD8A-positive spots after ICB. Conclusions: Spatial transcriptome analysis of a large dataset of UC samples showed distinct features of immune infiltration involved in therapeutic resistance in the tumor microenvironment under immunotherapy. Notably, T-cells may be exhausted by metabolic changes in CD8A-positive spots in ICB-refractory tumor environment spaces.

Immune checkpoint inhibitors induced side effects of the peripheral nervous system.

This review highlights recent knowledge on the diagnosis and treatment of immune checkpoint inhibitor-induced neurological side effects (irNAE) focussing on the neuromuscular system. irNAEs mainly resemble sporadic neuromuscular autoimmune diseases and paraneoplastic neurological syndromes. However, neurological symptoms may be unspecific (muscle weakness, fatigue) in the oncological setting and carry the risk of misdiagnosis and delayed therapeutic intervention. The role of disease-specific neuromuscular autoantibodies in the diagnosis is controversial as preexisting autoantibodies may otherwise be present before immune checkpoint inhibitor (ICI) treatment without clinical symptoms and may not develop in case of irNAE manifestation. A new necrotising form of myositis (irMyositis) has been described presenting with facial weakness and ptosis mimicking myasthenia gravis. It comes along with a high rate of severe myocarditis accounting for a triad overlap syndrome (myasthenia/myositis/myocarditis). The role of modern biologicals in the treatment of irNAEs has to be determined. irNAEs are rare but carry the risk of permanent morbidity and mortality. Early suspicion and diagnosis are key to prevent neurological sequelae. Beyond interruption of ICI administration, treatment corresponds to sporadic autoimmune diseases. The myasthenia/myositis/myocarditis overlap syndrome deserves special attention as it carries the highest risk of mortality. The role of neurotoxic pretreatment regimens, preexisting subclinical neurological autoimmune diseases and the risk of ICI-re-challenge after irNAEs has to be further investigated.

Immunogenicity and safety of influenza vaccine in patients with lung cancer receiving immune checkpoint inhibitors: A single-center prospective cohort study

IntroductionPatients with lung cancer have a high risk of influenza complications. International guidelines recommend annual influenza vaccination for patients with cancer. Immune checkpoint inhibitors (ICIs) are progressively used to treat lung cancer. Data regarding immunogenicity and safety of influenza vaccine are limited in patients with lung cancer receiving ICIs; therefore, we conducted this single-center, prospective observational study in the Japanese population. MethodsPatients with lung cancer receiving ICIs and influenza immunization were enrolled. Blood samples were collected from patients for serum antibody titer measurement pre- and 4 ± 1 weeks post-vaccination. The primary endpoint was seroprotection rate (sP) at 4 ± 1 weeks post-vaccination. The secondary endpoints were geometric mean titer (GMT), mean fold rise, seroresponse rate (sR), seroconversion rate (sC), and immune-related adverse events (irAEs), defined as adverse effects caused by ICI administration, 6 months post-vaccination. ResultsInfluenza vaccination in the 23 patients included in the immunogenicity analyses significantly increased GMT for all strains, and sP, sR, and sC were 52%–91%, 26%–39%, and 26%–35%, respectively. In the 24 patients included in the safety analyses, 7 (29%) and 5 (21%) patients exhibited systemic and local reactions, respectively. Only one patient (4%) (hypothyroidism, grade 2) showed post-vaccination irAEs. ConclusionsOverall, influenza vaccination in patients with lung cancer receiving ICIs showed acceptable immunogenicity and safety, thus supporting annual influenza vaccination in this population.

Real-world evidence of incidence and outcomes of aplastic anaemia following administration of immune checkpoint inhibitors.

Aplastic anaemia (AA) is a rare immune-related adverse events (irAEs) after immune checkpoint inhibitors (ICIs) administration with poorly understood incidence and outcomes. We analysed an electronic health record database of 52 303 ICI-treated patients and found 77 (0.15%) cases of AA, with a median onset of 126 days (interquartile range, 58-363 days). The most used treatment for AA was systemic glucocorticoids 60 (77.9%) and 32 (41.6%) patients were able to resume ICI within 1 year. Patients diagnosed with AA had a steep decline in overall survival (OS) within the first 120 days; when compared to propensity score-matched patients without AA, they had a significantly worse OS (hazard ratio 1.72, 95% confidence interval 1.19-2.50; p = 0.003).

Assessments of therapeutic effects according to timings for combined therapy with axitinib and immune check point inhibitor in a mouse renal cell carcinoma model

Recently, several types of systemic therapy using tyrosine kinase inhibitor (TKI) and immune checkpoint inhibitor (ICI) have been performed for advanced renal cell carcinoma (aRCC) patients; however, the optimal strategy of sequential treatment with these agents has not been well established. The objective of this study was to determine the differences of therapeutic effects according to timing for the introduction of TKI and ICI using a mouse RCC, RenCa model. The effects of combined treatment of TKI and/or ICI with axitinib, anti-mouse programmed death (PD)-1, or PD-ligand 1 (PD-L1) antibody on tumor growth and survival after subcutaneous and intravenous injection of RenCa cells, respectively, were compared according to three different treatment schedules: simultaneous administration, initial axitinib administration, and initial ICI administration. Infiltrating patterns of lymphocytes into tumors after combined treatments were evaluated by immunohistochemical staining. In mice treated with anti-PD-1 and anti-PD-L1 antibodies, significantly marked inhibitory effects on subcutaneous growth of tumors were observed in the simultaneous and initial ICI treatment groups, but not the group with the initial axitinib administration, compared to controls without treatment. Survival intervals of mice after intravenous injection of RenCa cells were significantly longer in the simultaneous and initial ICI administration, but not the initial axitinib administration, compared to the control. Furthermore, both CD8+ to CD3+ and CD8+ to CD11b+ T-lymphocyte ratios in subcutaneous RenCa tumors were significantly higher in the simultaneous and initial ICI administration, but not the initial axitinib administration, compared to the control. Favorable control against aRCC progression may be achieved by administering TKI and ICI simultaneously or ICI followed by TKI.

Association Between the Severity of Immune-related Adverse Events and the Prognosis in Patients With Non-small Cell Lung Cancer Receiving Treatment With Immune Checkpoint Inhibitors.

Among patients with non-small cell lung cancer (NSCLC) treated with immune checkpoint inhibitors (ICI), survival is reported to be longer in those experiencing immune-related adverse events (irAEs). We evaluated the progression-free survival (PFS) in the absence of further treatment after ICI therapy was discontinued because of the emergence of irAEs in patients with NSCLC. Data from patients with NSCLC in whom ICI therapy was discontinued because of the development of irAEs were retrospectively analyzed. The primary endpoint was the PFS from the last day of administration of ICIs, in the absence of any further treatment. A total of 162 patients with NSCLC received treatment with ICIs between January 2016 and December 2021. Among them, ICI therapy was discontinued in 33 patients because of the appearance of irAEs. The median (95% confidence interval) PFS in the absence of any treatment after the last administration of ICIs was 7.2 (4.2-12.3) months. According to the Common Terminology Criteria for Adverse Events, the Cox proportional hazards model was used to identify the severity of irAEs, which were determined to be significantly associated with the PFS in the absence of any further treatment after the last administration of ICI therapy. Although the present study showed that the PFS in patients with NSCLC was relatively long in the absence of any further treatment after the last administration of ICIs, the PFS was associated with the severity of the irAEs, and some patients showed early disease progression or death.

Paraneoplastic Neurologic Syndromes

Paraneoplastic neurologic syndromes (PNS) are a group of neurological disorders that are possibly caused by immunological mechanisms triggered by an underlying tumor that involves every part of the nervous system. Autoantibodies were categorized according to the risk of cancer association. Antibodies against intracellular proteins are excellent markers for tumor detection, however, without functional roles in neuronal loss, the direct effector of neuronal damage is thought to be cytotoxic T cells. The frequently associated symptoms include limbic encephalitis, cerebellar ataxia and sensory neuronopathy. The associated tumors are mainly small-cell lung cancer, breast/ovarian/uterine cancers, and thymoma. Timely diagnosis, prompt immunotherapy, and treatment of the underlying tumor are essential for managing PNS. However, we need to be cautious about the high frequency of false-positive/negative results of antibodies using commercial antibody tests. This highlight the importance of the careful evaluation of clinical features. Recently, PNS emerged after immune check point inhibitor administration, and this became a subject of attention exploring its pathogenesis. Other basic studies to understand the immunological background of PNS have been progressing.

Frequency of delayed immune-related adverse events (irAEs) in hospitalized patients treated with immune checkpoint inhibitors (ICIs).

2652 Background: Across cancer types and indications, the use of ICIs is increasing. Guidelines indicate that most irAEs occur in the months immediately following receipt of ICI. Little is known about the frequency of delayed irAEs following ICI administration. Methods: Patients who received ICIs and were hospitalized following ICI initiation between January 2011 and October 2022 were identified using pharmacy and hospital admission databases. Patient demographics, and oncologic and irAE history were extracted from the medical record. All admissions were reviewed by two physicians to evaluate for irAEs, which were defined as suspected or confirmed using published disease-specific criteria. We examined the number of irAEs hospitalizations at < 6 months, 6-12 months, 1-2 years, 2-5 years, and >5 years from the first dose of the most recent line of ICI to date of admission. Results: Among the 930 patients hospitalized with irAEs, average age was 66.0 years (range 18.3 - 96.2) and 61.2% were male. Most common tumor types were melanoma (42.0%), lung (24.1%), and gastrointestinal (12.7%). Median time from start of last line of ICI to hospitalization was 98 days (IQR 37-244.3). One hundred sixty-six patients (19.4%) had been treated with >1 prior line of ICI and 102 (11.0%) were diagnosed with multiple irAEs during the same admission. Of all patients admitted, 147 (15.7%) presented 6 months – 1 year after start of ICI line, 79 (8.4%) presented after 1-2 years, 35 (3.7%) presented after 2-5 years, and 2 (0.2%) presented after >5 years. Rates of irAEs by time from start of ICI line are demonstrated. Conclusions: Although irAEs occur in a time-dependent fashion, delayed, serious irAEs in hospitalized patients are common (28% at 6+ months), with a subset presenting two years or more after start of ICI. Providers must remain vigilant for potential irAEs regardless of elapsed time from ICI, especially as patients live longer and ICIs become widely used in different settings. Future work is needed to define potential triggers of and patients at risk for delayed irAEs. [Table: see text]

The exploratory case-control study on prediction of immune checkpoint inhibitor-induced thyroiditis by human leukocyte antigen types.

2558 Background: Given the function of human leukocyte antigen (HLA) in immunity, variation of the HLA type could affect the development of immune-related adverse events (irAEs) that is induced by immune checkpoint inhibitors (ICIs). In this study, we examined whether HLA types of cancer patients could be a marker for the development of irAE thyroiditis. Methods: In the present case-control study, we randomly selected 20 cancer patients who received ICIs and developed thyroiditis (irAE thyroiditis group) and 51 who did not develop thyroiditis (No irAE thyroiditis group). The 51 patients were subdivided into 31 who did not develop any irAEs (No irAEs group) and 20 who developed irAEs other than thyroiditis (irAEs other than thyroiditis group). HLA types were classified at the amino acid sequence level (Field 2 resolution). Frequency of the HLA types of each group was compared. Results: There was no significant difference in HLA type prevalence, comparing the irAE thyroiditis group and the No irAE thyroiditis group. When comparing the irAE thyroiditis group with the No irAEs group, the irAE thyroiditis group had significantly higher HLA-X, HLA-Y, and HLA-Z (Tentative names are used here, and actual HLA types will be announced at the time of publication). This result suggested that irAEs other than thyroiditis in the control group could be noise. HLA-X had a specificity of 96.8% for the development of irAE thyroiditis. HLA-Y had a sensitivity of 80.0%. Patients carrying both HLA-X and HLA-Y had the highest specificity of 100.0%. There was a significant difference in frequency of HLA-Y between irAEs other than the thyroiditis group and the No irAEs group. HLA-Y may be a universal marker for any irAEs. On the other hand, HLA-X is a specific marker for thyroid irAE. The median time of onset of irAE thyroiditis in all patients was 72 days after ICI administration. Patients with both HLA-X and HLA-Y tended to have an earlier onset with a median onset time of 53 days. Conclusions: We found an association between specific HLA types and the development of irAE thyroiditis. The present study indicates that HLA types could be a predictive marker for the development of irAE thyroiditis.

Real-world outcomes of patients (pts) with malignant solid tumors treated with immune checkpoint inhibitors (ICI) in relation to smoking status: The SAKK 80/19 SMOKER study.

6619 Background: ICIs are the standard of care for the treatment of different advanced solid organ tumors. Especially in advanced non-small-cell lung cancer, never-smokers were shown to have an inferior outcome when compared to ex-smokers/smokers, suggesting that the smoking status could be a predictive marker for survival benefits under ICI treatment. Methods: Pts within the Swiss Alpine Tumor Immunology Registry (AlpineTIR) treated with an ICI were differentiated by their smoking status (ex-smokers/smokers versus never-smokers). Overall survival (OS) and progression-free survival (PFS) from the start of the first ICI treatment were analyzed by smoking status. Further, subgroup analyses for OS and PFS were done for the most common disease entities. Results: A total of 702 pts were included, from which 455 pts (65%) were ex-smokers/smokers, 213 pts (30%) were never smokers, and 34 pts (5%) had an unknown smoking status. The median follow-up time from the administration of the first ICI to the statistical analysis was 2.7 years (95% CI: 2.3 to 3.2 years). The most frequent tumors were lung cancer (50%), melanoma (13%), renal cell cancer (7%), bladder cancer (6%), and others (24%). Across all indications, the median OS was 1.7 years (95% CI: 1.4 to 2.6 years) for never-smokers (n = 213) and 1.5 years (95% CI: 1.2 to 1.8 years) for smokers (n = 455) (HR: 1.10, 95% CI: 0.89 - 1.37). The median PFS was 6.3 months (95% CI: 4.4 to 8.3 months) for non-smokers and 6.2 months (95% CI: 5.2 to 7.0 months) for smokers (HR: 1.05, 95% CI: 0.87 - 1.27). In lung cancer pts, the median OS was 1.4 years (95% CI: 0.8 to 2.8 years) for never-smokers (n = 43) and 1.4 years (95% CI: 1.2 to 1.7 years) for smokers (n = 302) (HR: 1.02, 95% CI: 0.68 - 1.51). In melanoma pts, the median OS was 3.4 years (95% CI: 1.8 to not reached (NR) years) for never-smokers (n = 54) and 1.7 years (95% CI: 0.8 to NR years) for smokers (n = 34) (HR: 1.35, 95% CI: 0.72 - 2.53). In renal cell cancer pts, the median OS was 1.5 years (95% CI: 1.0 to 3.6 years) for never-smokers (n = 28) and 3.5 years (95% CI: 0.6 to NR years) for smokers (n= 17) (HR: 0.74, 95% CI: 0.31 - 1.78). In bladder cancer pts, the median OS was 1.8 years (95% CI: 0.6 to NR years) for never-smokers (n = 17) and 1.4 years (95% CI: 0.5 to NR years) for smokers (n = 26) (HR: 0.88, 95% CI: 0.39 - 1.99). Conclusions: No survival difference between smokers and non-smokers with metastatic solid organ tumors treated with ICIs could be detected. Interestingly, even in the subgroup of lung cancer pts, no difference was seen. Based on these data, the smoking status should not guide ICI treatment decisions.

Extracellular vesicle-based drug delivery in cancer immunotherapy.

Extracellular vesicles (EVs) are a group of nanoscale membrane-bound organelles including exosomes, microvesicles (MVs), membrane particles, and apoptotic bodies, which are released from almost all eukaryotic cells. Owing to their ingredients, EVs can be employed as biomarkers for human diseases. Interestingly, EVs show favorable features as candidates for targeted drug delivery and thus, they are suggested as ideal drug carriers as well as good vaccines for various human diseases including cancer. Among various drugs loaded in EVs for targeted drug delivery, immune checkpoint inhibitors (ICIs), including antibodies against programmed cell death-1 (PD-1), programmed death-ligand 1 (PD-L1), and cytotoxic-T-lymphocyte-associated protein 4 (CTLA-4), have attracted an increasing attention for cancer researchers and clinicians. Animal and clinical studies have shown combination of EVs and immunotherapy antibodies to improve the efficacy and reduce possible side effects in systemic administration of ICIs. In this review, we discuss the EVs and their significance in drug delivery with a focus on cancer immunotherapy agents.

Discontinuation of immunotherapy over 2 years for patients with non–small cell lung cancer (NSCLC): A search for predictors.

2661 Background: In advanced NSCLC, treatment completion at 24 months emerged in trials evaluating immune checkpoint inhibitors (ICI). Nevertheless, in clinical practice the question of the optimal treatment duration is under debate. Methods: We performed a retrospective study on advanced NSCLC treated with ICI (alone or with chemotherapy) at Gustave Roussy before 2021. Among patients still receiving ICI at 12 months, we analyzed the reasons for ICI discontinuation at 18 and 24 months. Results: Of the 682 patients treated with ICI (first-line for n=230, 33.7%), 159 (23.3%) received ICI for ≥ 12 months and 122 (17.9%) for ≥ 18 months. Between 18-24 months, 20 (57.1%) patients interrupted ICI for progressive disease (PD), 8 (22.8%) for toxicity and 7 (20.0%) after discussion with the patient. Out of the 88 (12.9%) patients who completed 2-years of ICI (median duration of treatment: 31.46 months, first-line for n=51), 22 (25.0%) patients discontinued ICI for PD and 40 (45.5%) without PD: 14 (15.9%) for toxicities, patient request or unknown causes and 26 (29.5%) for clinical decision before (n=16, 61.5%) or after (n=10, 38.5%) 30 months of treatment. Discontinuation according to phase III clinical trial design was supported by complete response (CR) by PET imaging +/- tissue biopsy of metabolically active lesions +/- ctDNA in 17 (65.4%) cases just before therapy discontinuation. After a median follow-up of 45.6 months since treatment discontinuation for these 26 patients, only two experienced PD at 4 and 6 months from ICI interruption, in both cases with no proof of CR at ICI discontinuation (p=0.111). The remaining 26 (29.5%) patients who continued ICI after 2 years, are on treatment based either on absence of CR at PET-CT +/- tissue biopsy of metabolically active lesions (n=20, 76.9%) or after discussion with the patients (n=6, 23.1%). After a median follow-up of 40.17 months from the of 24-months landmark, the median progression-free survival was unreached in both continuation and discontinuation groups. Conclusions: The patients who completed 2-years of ICI treatment usually continue to experience long‐term response after discontinuation. Considering that a subgroup of patients could still benefit from maintained ICI administration, PET imaging was considered to guide ICI cessation or continuation. Prospective studies specifically designed to investigate biomarkers of maintained responses or residual disease (imaging, ctDNA, multi-omics including microbiome) are required to establish the indication for ICI continuation or stop for each patient.

Sex differences in burden of adverse events in patients receiving immunotherapy.

2646 Background: The association between sex and the occurrence of immune-related adverse events (irAEs) in cancer patients who receive immune checkpoint inhibitors (ICIs) is an area of growing interest. Despite the collection of irAEs data in registrational studies, the impact of sex differentiation is rarely published, and comparative analyses using meta-analytic approaches of retrospective data has produced contrasting results. G-DEFINER is a multicentre project evaluating the irAEs inequalities between female (F) and male (M) cancer patients treated with ICIs. The project explored the sex and gender differences spanning from clinical to personal and lifestyle traits (including diet and quality of life). Gene-expression profiling for immune assessment, SNPs, cytokines (blood samples) and microbiota analyses (faecal samples) are also being performed to identify the features associated with irAEs development. Methods: irAE burden (B) was estimated as the sum of the average and worst grade of irAEs occurring at each time. The cumulative sum of time-specific Bs was used as irAE burden index (BI). Median BI (mBI) was modelled using quantile regression models. A univariable analysis (UA), 1st G≥2 irAE crude incidence curves (CCI) were estimated in a competing risks setting (competing event: deaths without irAE), and event-free survival (EFS) curves were estimated with the Kaplan-Meier method and compared with the log-rank test. Multivariable analysis (MA) of CCI and EFS was performed using Fine&Gray and Cox models, respectively. Results: At closing date (31st January 2023) the study has enrolled 256 patients. Our subgroup analysis includes 204 patients (86 F,118 M) with median follow-up of 13 months; IQR: 6.1-20 months). Patients’ age, previous oncologic treatments, cancer type (lung, melanoma, head&neck, colorectal MSI high, urogenital), PS ECOG, ICI type, concomitant chemotherapy (about 20%), and disease setting were well balanced in the two sex groups. F temporarily interrupted ICI administration more frequently than M (44 vs 29%, p=0.034) mainly due to irAEs (27 vs 11%); 83% F vs 71% M (p=0.069) contributed with 204 vs 240 any grade irAEs (significant differences: 36 vs 21% endocrine, p=0.016; 20% vs 9% hepatic, p=0.040). F more frequently developed G1 (64 vs 53%), G2 (49 vs 40%), G3 (24 vs 17%), G4 (6% vs 2%) irAEs. mBI was significantly higher in F both at UA (p=0.024) and MA (p=0.048). First G≥2 irAE6-(12) month estimates in F vs M were 55% vs 45% (65% vs 53%) (p=0.073 UA and 0.140 MA). EFS between group difference was not significant both at UA (p=0.206) and MA (p=0.729). Conclusions: F experience a higher irAE burden and require close monitoring in order to avoid ICI interruption. The results also underline the need of using a measure of irAE cumulative load to gain insights into between groups differences. Clinical trial information: NCT04435964 .

Delayed immune toxicities in patients with breast cancer receiving immune checkpoint inhibitors.

e24091 Background: Immune checkpoint inhibitors (ICI) have improved outcomes in patients with breast cancer, however management of immune-related adverse events (irAE) remains a challenge. Delayed irAE after cessation of ICI have been observed. We sought to characterize delayed irAE occurring at our center. Methods: We identified patients with breast cancer who received ICI at UCSF using ICD codes specific to ICI administration between 2012-2018. After IRB approval, charts were reviewed for delayed irAE. Delayed irAE were defined as occurring >60 days after the last ICI dose; events were counted as irAE if provider notes indicated that the toxicity was/possibly was related to ICI. Data were securely stored using RedCap. Results: We reviewed 100 consecutive patients who underwent ICI (56 metastatic, 44 localized) of which 11 (2 (4%) with metastatic disease, 9 (20.5%) with localized disease) developed delayed irAE. Median age was 42. 3 patients had HR+ disease, 8 patients had triple negative disease. 10 patients received ICI on a clinical trial, including 9 on the neoadjuvant ISPY2 trial. 10 patients received pembrolizumab; 1 received durvalumab. Median number of ICI doses was 4, median follow-up time after last ICI infusion was 46 months. 14 incidences of delayed irAEs were identified (Table). 9 patients experienced both delayed and early irAE. 7 patients experienced 2 irAEs: 1) three dermatitis & delayed hypophysitis/adrenal insufficiency (AI) 2) one AI & delayed thyroiditis 3) one dermatitis and delayed colitis 4) one elevated transaminases & delayed colitis 5) one delayed elevated transaminases and delayed thyroiditis. One patient had 3 irAEs (thyroiditis, delayed AI & delayed arthralgia) and one patient had 4 irAE (colitis, dermatitis, delayed elevated transaminases & delayed neutropenia). Of the 9 patients with > 1 irAE, 3 experienced > 1 delayed irAE (thyroiditis + elevated transaminases; arthralgia + AI; elevated transaminases + neutropenia). All irAE either self-resolved, resolved with systemic steroids or indefinite hormone replacement. 6 irAEs required systemic steroids, not including hydrocortisone replacement for AI. Conclusions: Delayed irAE may occur months after ICI cessation and require awareness for identification. Patients who experience irAE may be more likely to develop additional irAE at either a delayed or earlier time point. Most patients with delayed irAE experienced an irAE at an early time point. Future directions include identifying risk factors for early and delayed irAEs to inform treatment decisions. [Table: see text]

Neutrophil-to-lymphocyte ratio as a predictor of immune checkpoint inhibitor therapy response in advanced bladder cancer.

e16586 Background: Immune checkpoint inhibitor (ICI) therapy is a novel and promising agent for treating muscle invasive bladder cancer (MIBC). However, there is a need for further understanding of which patient factors or biological markers can be used to help identify patients who will have a successful response to ICI therapy. We hypothesized that Neutrophil-to-Lymphocyte Ratio (NLR) could be predictive of response to ICI therapy as this ratio has previously been reported to correlate with a higher number of myeloid derived suppressor cells. Methods: A retrospective cohort analysis was performed on patients with advanced or metastatic bladder cancer who were treated with ICI therapy at a single institution between 2015-2020. Information on survival, disease recurrence, and patient characteristics was gathered. Neutrophil and lymphocyte numbers were recorded at time of ICI administration and a ratio of neutrophils to lymphocytes was calculated. The median of these values was calculated and used to divide the cohort into low NLR and high NLR. Tissue samples from a subset of these patients were collected and sent for multiplex immunohistochemistry with a myeloid and T cell staining panel. Results: In a cohort of 115 patients with advanced bladder cancer treated with ICI, the mean time to last follow up or event (death or disease progression) was 375.78 days (SD 41). 35 patients (30%) had either a complete or partial response to ICI therapy. A Kaplan Meier survival analysis shows a significant difference in survival between the low and high NLR group, with lower NLR having a longer event free survival (Wilcoxon rank p = 0.0156). Multiplex IHC showed variable tumor and adjacent microenvironmental distributions of myeloid and lymphoid marker positive populations in ICI responders and non-responders. Conclusions: In an effort to better predict which patients may benefit from ICI therapy, we have studied NLR at the time of ICI administration and its association with event free survival. Our results suggest that a lower NLR could be associated with a longer event free survival. Further research is being conducted to study the immune microenvironment as it relates to bladder cancer response to ICI therapy.

Kidney Disease Patient Representation in Trials of Combination Therapy With VEGF-Signaling Pathway Inhibitors and Immune Checkpoint Inhibitors: A Systematic Review

Kidney Disease Patient Representation in Trials of Combination Therapy With VEGF-Signaling Pathway Inhibitors and Immune Checkpoint Inhibitors: A Systematic Review

Anti-synthetase syndrome-associated interstitial lung disease possibly caused by atezolizumab in a patient with lung adenocarcinoma: a case report

BackgroundAnti-aminoacyl-tRNA synthetase (ARS) antibody-positive patients present with a variety of symptoms, including interstitial lung disease (ILD), which is termed anti-synthetase syndrome (ASS). But it is rare that ASS-ILD is considered an immune-related adverse event after the use of immune checkpoint inhibitors (ICIs).Case presentationA 47-year-old male with advanced lung adenocarcinoma was treated with platinum and ICI combination immunotherapy and was followed up as an outpatient. Nine months after the start of treatment, he developed a fever and cough, and imaging findings showed lung consolidations in the bilateral lower lung fields. The patient was positive for anti- ARS antibodies and was considered to have developed ASS-ILD due to ICIs remitted with steroid therapy. The patient was found to be positive for anti-ARS antibodies before ICI administration, and the antibody titer was elevated compared to that before ICI administration.ConclusionsThe examination of anti-ARS antibodies pior to the administration of ICIs may be useful in predicting the development of ASS-ILD.

Comparative efficacy and safety of multitarget angiogenesis inhibitor combined with immune checkpoint inhibitor and nivolumab monotherapy as second-line or beyond for advanced lung adenocarcinoma in driver-negative patients: a retrospective comparative cohort study.

The efficacy of immune monotherapy is not satisfactory in patients with advanced, treated non-small cell lung cancer (NSCLC). Combining antiangiogenic agents and immune checkpoint inhibitors (ICIs) can counteract the immunosuppression and confer synergistic therapeutic benefits. We explored the efficacy and safety of anlotinib and ICIs as a second- and subsequent-line treatment for advanced lung adenocarcinoma (LUAD) in patients without oncogenic driver alterations. We reviewed patients with driver-negative LUAD who had received anlotinib, a multityrosine kinase inhibitor affecting vascular endothelial growth factor receptor (VEGFR), fibroblast growth factor receptor (FGFR), platelet-derived growth factor receptor (PDGFR) and c-Kit, in combination with ICIs from October 2018 to July 2021 at Shanghai Chest Hospital as second- and subsequent-line treatment. Patients with advanced driver-negative LUAD who received nivolumab monotherapy as second-line treatment were included as a control group. In this study, 71 patients were included who had received anlotinib and programmed cell death-1 (PD-1) blockade combination therapy as second- and subsequent-line treatment, and 63 patients who had received nivolumab monotherapy as second-line therapy were included as controls, most of whom were male smokers at stage IV. The median progression-free survival (PFS) of the combination therapy and nivolumab monotherapy groups were 6.00 and 3.41 months, respectively (P<0.001). The median overall survival (OS) of the combination therapy and nivolumab monotherapy groups were 16.13 and 11.88 months, respectively (P=0.046). Twenty-nine patients (40.8%) in the combination group underwent previous immunotherapy (15 of whom were in first line), and they also achieved good survival (median OS: 25.67 months). The adverse reactions in the combination therapy group were mainly associated with either anlotinib or ICI administration, and there was a low incidence of grade 3 adverse events, all of which were resolved after intervention or discontinuation. The combination of the multitargeting tyrosine kinase inhibitor anlotinib and PD-1 blockade demonstrated significant benefits as the second- and subsequent-line treatment in driver-negative patients with advanced LUAD, even in those who underwent previous immunotherapy.