Administration Of ICI Research Articles

Immune checkpoint inhibitor-related type 1 diabetes incidence, risk, and survival association.

Although immune checkpoint inhibitor-related type 1 diabetes mellitus (ICI-T1DM) is a rare condition, it is of significant concern globally. We aimed to elucidate the precise incidence, risk factors, and impact of ICI-T1DM on survival outcomes. The study is a large retrospective cohort study, performed using the DeSC Japanese administrative claims database comprising 11 million patients. The database population is reportedly similar to the entire population of Japan. Patients administered ICI between 2014 and 2022 were enrolled in the study, including 21,121 patients. The risk factors for ICI-T1DM development and their characteristics were evaluated by logistic regression analysis. Development of a new irAE after the day following the first administration of ICI was set as the study outcome. ICI-T1DM was observed in 102 (0.48%) of the 21,121 patients after ICI initiation. PD-(L)1 and CTLA-4 combination therapy was associated with an increased risk of ICI-T1DM compared with PD-1 monotherapy (odds ratio [OR], 2.36; 95% confidence interval [CI], 1.21-4.58; P = 0.01). Patients with a prior diagnosis of diabetes mellitus (OR, 1.59; 95% CI, 1.03-2.46; P = 0.04) or hypothyroidism (OR, 2.48; 95% CI, 1.39-4.43; P < 0.01) also exhibited an increased risk of ICI-T1DM. The Kaplan-Meier analysis revealed that patients with ICI-T1DM showed higher survival rates than those without (log-lank test, P < 0.01). Multivariable Cox regression analysis demonstrated that ICI-T1DM development was associated with lower mortality (hazard ratio, 0.60; 95% CI, 0.37-0.99; P = 0.04). Collectively, the results of this study demonstrate the precise incidence and risk factors of ICI-T1DM. The development of ICI-T1DM, like other irAEs, is associated with higher survival rates.

Comparison of Magnetic Resonance Imaging Features Between Programmed Cell Death 1/Programmed Cell Death Ligand 1 Inhibitor-Induced Hypopituitarism and Idiopathic Hypopituitarism in Japanese Subjects.

Objective Immune checkpoint inhibitor-associated hypopituitarism (ICI-HP) is a rare immune-related adverse event (irAE) of ICIs. This study aimed to identify characteristic pituitary findings on magnetic resonance imaging (MRI) in ICI-HP. Methods This study is a single-center, retrospective, observational study. Among 95 patients admitted to our hospital for examination of hypopituitarism between January 2010 and December 2022, 26 patients with normal pituitary function (NPF), 13 patients with ICI-HP, and 13 patients with idiopathic hypopituitarism (IHP) were included and analyzed. Results For participants with ICI-HP, the time from ICI administration to ICI-HP diagnosis was 125 (56-212) days. Compared to the NPF, participants in the ICI-HP and IHP were significantly older (p<0.01) - the highest number of patients presented with isolated adrenocorticotropic hormone deficiency in both ICI-HP and IHP. Pituitary volume was not significantly different among the three groups (p=0.68). The width of the pituitary stalk was 1.8 (1.5-2.0) mm in NPF and 1.8 (1.7-2.2) mm in IHP, whereas it was 2.4 (2.4-2.7) mm in ICI-HP and was significantly larger compared to the other groups (p<0.01). Conclusion This study identified no pituitary enlargement in ICI-HP compared to NPF or IHP. However, the pituitary stalk was significantly thickened in ICI-HP compared to the other groups. Pituitary stalk enlargement may be a characteristic MRI findingof ICI-HP.

Clinical and electrocardiographic characteristics of immune checkpoint inhibitor-related myocarditis

BackgroundImmune checkpoint inhibitor (ICI) has become a major breakthrough in the field of tumor therapy, leading to improved survival. This study evaluated the clinical and electrocardiographic characteristics of patients with ICI-related myocarditis. MethodsPatients with ICI-related myocarditis were enrolled from 4 centers in China until September 2023. Demographic data (age, sex, comorbidity), types of ICI, clinical manifestations, electrocardiogram (ECG) and treatment were analyzed retrospectively. Arrhythmia and characteristics of ECG were compared according to prognosis and grading. ResultsA total of 29 participants (13 females with a median age of 63.25 years) with ICI-related myocarditis were enrolled. Lung cancer was the most, with a proportion of 31.03 % (9/29). The median time from the first administration of ICI to the diagnosis of myocarditis was 50 days. Camrelizumab was the main type of ICI (9/29). Most patients had non-specific symptoms, dyspnea (n = 16) and palpitation (n = 9) were common. The overall mortality rate was 37.93 % (11/29) with a median follow-up of 9(4,11) days. Compared with the survivors, P-wave abnormality was more common in participants who were dead (24.14 %vs6.90 %, p = 0.010). A total of 19 patients with severe ICI-related myocarditis were included in this study. The proportions of sinus tachycardia (34.48 %vs0.00 %, p = 0.005), premature ventricular complex (27.59 %vs0.00 %, p = 0.027) and atrioventricular block (34.48 %vs3.45 %, p = 0.044) were higher in severe ICI-related myocarditis. ConclusionsClinical manifestations of ICI-related myocarditis usually lacked specificity. ECGs can be manifested as new-onset arrhythmias, ST-T segment changes, fragmented QRS complex, abnormal P wave, prolonged QTc interval and multi‑lead low voltage.

Tumor necrosis factor inhibitors enhance corticosteroid therapy for Stevens-Johnson syndrome and toxic epidermal necrolysis linked to immune checkpoint inhibitors: a prospective study.

Immune-related epidermal necrolysis (irEN), including Stevens-Johnson Syndrome (SJS) and toxic epidermal necrolysis (TEN), represents a potentially lethal reaction to immune checkpoint inhibitors. An optimal treatment strategy remains undefined. This study evaluates the effectiveness and safety of combination therapy with corticosteroids and tumor necrosis factor inhibitors (TNFi) in treating irEN patients. In this single-center, prospective, observational study, patients with irEN received either corticosteroid monotherapy or a combination therapy of corticosteroids and TNFi (etanercept for SJS, infliximab for TEN). The primary endpoint was re-epithelization time, with secondary endpoints including corticosteroid exposure, major adverse event incidence, acute mortality rates, and biomarkers indicating disease activity and prognosis. The study was registered at the Chinese Clinical Trial Registry (ChiCTR2100051052). Thirty-two patients were enrolled (21 SJS, 11 TEN); 14 received combination therapy and 18 received corticosteroid monotherapy. IrEN typically occurred after 1 cycle of ICI administration, with a median latency of 16 days. Despite higher SCORTEN scores in the combination group (3 vs. 2, p = 0.008), these patients experienced faster re-epithelization (14 vs. 21 days; p < 0.001), shorter corticosteroid treatment duration (22 vs. 32 days; p = 0.005), and lower prednisone cumulative dose (1177 mg vs. 1594 mg; p = 0.073). Major adverse event rates were similar between groups. Three deaths occurred due to lung infection or disseminated intravascular coagulation, with mortality rates for both groups lower than predicted. Potential risk factors for increased mortality included continuous reduction in lymphocyte subset counts (CD4+ T cells, CD8+ T cells, natural killer cells) and consistent rises in inflammatory markers (serum ferritin, interleukin-6, TNF-α). Re-epithelization time negatively correlated with body mass index and positively correlated with epidermal detachment area and serum levels of interleukin-6 and TNF-α. Corticosteroids combined with TNFi markedly promote re-epithelization, reduce corticosteroid use, and decrease acute mortality in irEN patients without increasing major adverse events, offering a superior alternative to corticosteroid monotherapy. Inflammatory markers and lymphocyte subsets are valuable for assessing disease activity and prognosis.

Cost-effectiveness study of atezolizumab (ATZ) vs. durvalumab (DUR): Real-world data (RWD) on first-line chemotherapy combined with immune-checkpoint inhibitors (Chemo-ICIs) for extensive disease small-cell lung cancer (ED-SCLC).

8097 Background: Chemo-ICI is the standard of care in first-line therapy for ED-SCLC. Although there is no comparative data on ATZ vs. DUR, their efficacies appear to be equivalent based on results from IMpower133 and CASPIAN trials. On the other hand, the drug price of DUR is higher than that of ATZ, suggesting a different cost-effectiveness. Methods: This is a multicenter retrospective study of RWD. Clinical outcomes and safety information of ED-SCLC patients (pts) who had received Chemo-ICIs were collected from electronic medical records, and the total cost incurred during ICIs was obtained from the receipts of each hospital. Propensity score matching (PSM) was performed to adjust difference of pts' backgrounds of two groups (ATZ-G vs. DUR-G). The total monthly medical costs incurred during ICI administration for both groups were compared by cost minimization analysis to evaluate cost-effectiveness. Results: From August 2018 to December 2022, 274 pts (ATZ/DUR: 176/98) were extracted from 8 hospitals in Japan. After PSM and exclusion of cisplatin-treated pts, total 128 pts: 64 pts in each group were evaluated. The mean total medical costs per month during ICIs were 1,003,922 (±310,192) JPY (6,783 USD) in the ATZ-G and 1,596,511 (±371,405) JPY (10,787 USD) in the DUR-G (Wilcoxon rank sum test: p &lt; 0.001). Mean ICI drug costs per month during ICIs were 799,079 (±89,555) JPY (5,399 USD) in the ATZ-G and 1,570,744 (±371,405) JPY (10,163 USD) in the DUR-G (p &lt; 0.001). Response rate was 73.4% for ATZ-G and 75.0% for DUR-G. Median overall survivals (OSs) of ATZ-G vs. DUR-G were 13.9 (95% confidence interval [CI]: 11.7-17.5) vs. 13.6 (95% CI: 11.0-20.0) months, respectively (p = 0.919). Median progression-free survivals of ATZ-G vs. DUR-G were 4.9 (95% CI: 4.4-5.6) vs. 5.6 (95% CI: 5.0-6.7) months, respectively (p = 0.060). Cox-proportional hazard model identified poor performance status (hazard ratio [HR]: 5.5, p &lt; 0.001) and bone metastases (HR: 1.8, p = 0.029) as significant factors for shorter OS, while ATZ vs. DUR was not significant. ATZ-G revealed lower incidences of immune-related adverse events (irAEs) ≥grade 2 (10.9 vs. 31.3%, p = 0.009) and any grade interstitial lung disease (ILD) (3.1 vs. 20.3%, p = 0.004) than DUR-G. Number of hospitalizations in ATZ-G (median 1, range 0-6) was lower than that in DUR-G (median 2, range 0-7) (p = 0.005). Conclusions: Our RWD demonstrated a superior cost-effectiveness of ATZ to that of DUR. Total efficacies were similar, whereas the safety profiles, including irAE and ILD were more favorable in ATZ-G. Further discussion is required regarding not only cost-effectiveness but also clinical practicality such as: dose schedule of 3 weeks vs. 4 weeks; regimen flexibility of carboplatin vs. cisplatin; and etoposide dose adjustment of 100 mg/m2 vs. 80 mg/m2. Clinical trial information: 000053483.

Objective response after immune checkpoint inhibitors in a chemotherapy-refractory pMMR/MSS metastatic rectal cancer patient primed with experimental AlloStim® immunotherapy

BackgroundImmune Checkpoint Inhibitor (ICI) immunotherapy is most effective in immune effector cell infiltrated ‘hot’ tumor lesions, such as occurs in deficient mismatch repair, microsatellite instability high (dMMR/MSI-H) colorectal cancer (CRC). However, most all metastatic CRC tumors are mismatch repair proficient/microsatellite stable (pMMR/MSS) ‘cold’ lesions, without significant immune cell infiltration, and are unresponsive to ICI. AlloStim®, is an experimental, allogeneic immunomodulatory cell therapy designed to convert ‘cold’ metastatic tumor lesions to ‘hot’ inflamed lesions. After AlloStim® immunotherapy, this cold to hot inflammatory mechanism can make it difficult to distinguish between pseudoprogression and actual progression on restaging CT scans, as inflamed metastatic lesions can appear larger and occult disease can appear as new small lesions.MethodsTo explore whether radiological progression after AlloStim® immunotherapy is due to immune-flare or disease progression, we administered a short course of a combination ICI therapy to a pMMR/MSS chemotherapy-refractory metastatic colorectal cancer patient enrolled in the StimVax Phase IIb clinical study that presented with radiological progression after AlloStim® immunotherapy. Our rationale was that an accelerated response to ICI should occur if the lesions were inflamed, while if the enlarged lesions were due to disease progression there would not be a response.ResultsHere we report a rapid, significant reduction in tumor burden in response to ICI administration in an AlloStim® primed pMMR/MSS mCRC patient with retroperitoneal and lung metastases.ConclusionThis rare objective response to ICIs in a pMMR/MSS mCRC patient supports further evaluation of the combination of AlloStim® with ICI immunotherapy in MSS mCRC and other cold or ICI refractory tumors.Trial registrationNational Library of Medicine (NLM) at the National Institutes of Health (NIH). Registered 22 June 2020, https://clinicaltrials.gov/study/NCT04444622.

THU353 Late Onset Of Immune Checkpoint Inhibitor-Related Diabetes After 3 Years

Abstract Disclosure: S. Avula: None. A. Ahmed: None. M. Salim: None. Z.J. Anderson: None. A. Kumar: None. A. Estrada: None. Background: Immune checkpoint inhibitor-induced diabetes mellitus (ICI-DM) is characterized by acute onset of dramatic hyperglycaemia with severe insulin deficiency following exposure to PD-1/PD-L1 inhibitors. The frequency of type 1 diabetes related to ICIs is estimated to be ∼3.5%. Endogenous insulin secretion is depleted within a few weeks of the clinical onset of diabetes. Moreover, the positive rate for islet-related autoantibodies varies from 5% to 50%. Case: 51-year-old male with a PMH of stage 4 adenocarcinoma of the lung with metastasis to brain, bone, and kidneys was sent to the ED for a POC BG above 700 mg/dl. He was diagnosed with stage 4 lung adenocarcinoma three years prior to the current presentation. He received stereotactic radiotherapy for the brain metastases, Carboplatin/pemetrexed/pembrolizumab x4 cycles, then continued maintenance therapy of pemetrexed/pembrolizumab with the last dose given 3 weeks prior. He had recent evidence of progression, so chemotherapy adjustment was planned, and he started dexamethasone 4mg on the day prior to presentation. Upon ED presentation, he reported new onset polyuria and polydipsia for 1 week accompanied by 10% weight loss over the last 3 months. His vitals were stable. Physical examination was unremarkable. Serum glucose level was found to be 726 mg/dl, Bicarbonate level 28 mEq/L (22-30), creatinine 1.99 mg/dl (baseline 1.2), venous blood PH was 7.29, Bicarbonate 24 mEq/L (24-28), anion gap 15 mEq/L (8-16), B-hydroxybutyrate 2.91 mmol/L (0.02-0.27), sodium 127 mEq/L(135-148) and HbA1c 6.3%. He received normal saline boluses and NPH insulin 15 units SQ, after which his repeat BG level was 426 mg/dl. Given prediabetic Hba1c with recent dexamethasone therapy he was thought to have steroid-induced hyperglycaemia. He was discharged on NPH 15 units daily with Novolog sliding scale. Upon clinic follow-up 1 week later, his BGs did not improve significantly despite stopping steroids. His C-peptide level was low at 0.22 ng/ml (1.10-4.40) with BG 443mg/dl, and GAD -65 antibodies were negative. He continued to have hyperglycaemia while on NPH /Novolog regimen, thus he was switched to Lantus and Novolog regimen with better glycaemic control. He continues to have significant insulin requirements 3 months later. Conclusion: Although the mean interval between the first ICI administration and T1DM development was found to be 201 ± 187 days, the development of type 1 DM may occur with longer intervals from initiating the ICI therapy. In our case, the patient developed new-onset diabetes with low C-peptide after 1,095 days from receiving the first dose of pembrolizumab. On the previous case reports, the presence of GAD-65 antibodies is typically associated with shortened intervals between receiving the ICI therapy and the development of DM. Presentation: Thursday, June 15, 2023

β2-AR inhibition enhances EGFR antibody efficacy hampering the oxidative stress response machinery

The β2-Adrenergic receptor (β2-ARs) is a cell membrane-spanning G protein-coupled receptors (GPCRs) physiologically involved in stress-related response. In many cancers, the β2-ARs signaling drives the tumor development and transformation, also promoting the resistance to the treatments. In HNSCC cell lines, the β2-AR selective inhibition synergistically amplifies the cytotoxic effect of the MEK 1/2 by affecting the p38/NF-kB oncogenic pathway and contemporary reducing the NRF-2 mediated antioxidant cell response. In this study, we aimed to validate the anti-tumor effect of β2-AR blockade and the synergism with MEK/ERK and EGFR pathway inhibition in a pre-clinical orthotopic mouse model of HNSCC. Interestingly, we found a strong β2-ARs expression in the tumors that were significantly reduced after prolonged treatment with β2-Ars inhibitor (ICI) and EGFR mAb Cetuximab (CTX) in combination. The β2-ARs down-regulation correlated in mice with a significant tumor growth delay, together with the MAPK signaling switch-off caused by the blockade of the MEK/ERK phosphorylation. We also demonstrated that the administration of ICI and CTX in combination unbalanced the cell ROS homeostasis by blocking the NRF-2 nuclear translocation with the relative down-regulation of the antioxidant enzyme expression. Our findings highlighted for the first time, in a pre-clinical in vivo model, the efficacy of the β2-ARs inhibition in the treatment of the HNSCC, remarkably in combination with CTX, which is the standard of care for unresectable HNSCC.

Abstract PD2-02: Longitudinal local and peripheral immunologic changes associated with checkpoint inhibition response in murine models of breast cancer

Abstract Immune checkpoint inhibitors (ICI) have significantly enhanced patient survival in some cancer types but yield limited success in breast cancer. ICIs activate anti-tumor immunity by overriding the inhibition of tumor infiltrating lymphocytes (TILs). Clinical trials in triple negative breast cancer (TNBC) patients, who are more likely to harbor TILs within tumor stroma, have demonstrated increased progression-free survival (IMpassion130) and pathologic complete response (KEYNOTE-522) to ICI. Consequently, combinations of ICI and chemotherapy have been FDA-approved for metastatic TNBC. However, the therapeutic benefit of ICIs is highly heterogeneous among breast cancer patients; as such, we sought to model ICI response in vivo to evaluate therapeutic resistance and response heterogeneity, as well as ascertain predictive biomarkers for favorable outcomes to ICI in breast cancer. We used an immunocompetent EMT6 orthotopic mammary tumor model to investigate the efficacy of ICI (anti-PD-L1). Analysis of the primary tumor immune landscape was performed by flow cytometry and single-cell RNA sequencing. Matched longitudinal samples of the tumor microenvironment (collected by fine-needle aspiration) and peripheral blood (PBMC) from mice were profiled by bulk RNA and T-cell receptor (TCR) sequencing to identify systemic genomic alterations and T-cell expansion, respectively. Single-agent ICI robustly suppressed primary tumor growth (p =0.0046) and extended survival (p&amp;lt; 0.0001) beyond the control group in the EMT6 model. The addition of chemotherapy (paclitaxel and/or doxorubicin) demonstrated moderate therapeutic efficacy but failed to enhance ICI benefit. Phenotypic profiling of the tumor microenvironment (TME) revealed increased T cells, dendritic cells, and NK cells in anti-PD-L1 only and chemotherapy combination groups. Despite using a genetically identical tumor model and murine host, we found that PD-L1 blockade induced heterogeneous responses, similar to clinical outcomes in breast cancer patients, ranging from complete response to intrinsic resistance. Analysis of the primary tumor microenvironment showed upregulated signatures of cytotoxic T cell response and activation, specifically inflammatory interferon signaling (both prior to and post ICI administration) that corresponded to favorable response to anti-PD-L1 in individual mice. Longitudinal analysis of the peripheral blood identified modest changes among mice at baseline that progressively deviated by response type (non responders-vs-responder mice). Moreover, mice harbored enriched myeloid signatures and clonal T cell expansion during therapy corresponding to ICI resistance and response, respectively. Further investigations of matched peripheral blood and the primary tumor microenvironment signatures may identify systemic biomarkers and tumor antigen-specific T cell clones to accurately predict ICI response in patients and uncover mechanisms for sensitizing tumors refractory to ICI. In conclusion, we identify a heterogeneously ICI-responsive in vivo model that emulates TNBC patient response to combinatorial ICI approaches. We describe host-specific signatures, specifically myeloid cell responses, that correlate with differential responses to immunotherapy, which may serve as a basis for tracking immunotherapy response in peripheral blood from breast cancer patients. Citation Format: Ann Hanna, Xiaopeng Sun, Quanhu Sheng, Melinda Sanders, Justin Balko. Longitudinal local and peripheral immunologic changes associated with checkpoint inhibition response in murine models of breast cancer [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr PD2-02.

P361 Risk of persistent gastrointestinal inflammation after treatment with immune checkpoint inhibitors

Abstract Background Immune checkpoint inhibitors (ICI) can cause immune-mediated gastrointestinal toxicity, but the long-term persistence of this toxicity is unknown. We aimed to describe the characteristics of patients with gastrointestinal inflammation persisting more than six months after discontinuation of ICI. Methods We included consecutive patients treated between October 2010 and March 2022 for endoscopic or histological gastrointestinal inflammation persisting at least six months after the last administration of ICI. Results Among 178 patients treated for a gastrointestinal immune-mediated adverse event during ICI therapy, 14 (8%) patients had chronic lesions persisting more than 6 months after the last ICI administration. The median follow-up time was 13 months after discontinuation of ICI. The most common symptom was watery diarrhea (54%). Ten (77%) patients had colon involvement and three (21%) had ileal involvement. Ten patients (77%) had an inflammatory phenotype, while two (15%) had a penetrating and one had (8%) a stricturing phenotype. All patients had lymphoplasmacytic infiltrate and basal plasmacytosis, and s54%) had crypt distortion. Two (15%) patients underwent surgery and nine (69%) received specific treatment, including five treated with vedolizumab. Among the patients who were followed up for at least one year, endoscopic lesions persisted at 1 year after stopping ICI in 4/6 patients, and at 2 years in 3/4 patients. Conclusion Eight percent of patients who had gastrointestinal toxicity due to ICI develop chronic inflammatory bowel disease characterized by watery diarrhea, colitis and lymphoplasmacytic infiltrate.

Longitudinal Strain and Troponin I Elevation in Patients Undergoing Immune Checkpoint Inhibitor Therapy

BackgroundImmune checkpoint inhibitors (ICIs) are a central part of cancer therapy; however, cardiac complications, such as myocarditis, have the potential for significant morbidity and mortality. Within this population, the clinical significance of longitudinal strain (LS) remains unknown. ObjectivesThis study sought to define the changes in LS in ICI-treated patients, and their associations with high-sensitivity troponin I (hsTnI) and myocarditis. MethodsWe conducted a retrospective cohort study of patients who received ICIs at our hospital from April 2017 to September 2021. All patients underwent echocardiography and blood sampling at standardized time intervals. We measured the changes in global and regional LS before and after ICI administration. Age- and sex-adjusted Cox regression analysis was used to evaluate the association between LS and elevations in hsTnI and myocarditis. ResultsIn a cohort of 129 patients with a median follow-up period of 170 (IQR: 62-365) days; 6 and 18 patients had myocarditis and hsTnI elevation, respectively. In an age- and sex-adjusted Cox proportional hazards model, an early relative worsening of ≥10% in the basal and mid LS and ≥15% in global LS was associated with hsTnI elevation. Relative reductions in LS were not significantly associated with myocarditis; however, 4 of the 6 patients with myocarditis had relative reduction of ≥10% in the basal LS. ConclusionsAn early worsening in the global and regional LS was associated with increased hsTnI in patients receiving ICIs. Assessment of LS early after ICI administration should be further studied as a strategy for risk stratification of ICI-treated patients.

Clinical significance of interstitial lung abnormalities and immune checkpoint inhibitor-induced interstitial lung disease in patients with non-small cell lung cancer.

Interstitial lung abnormalities (ILAs) are known to be a risk of drug-induced pneumonitis. However, there are few reports on the relationship between ILAs and immune checkpoint inhibitor-related interstitial lung disease (ICI-ILD). We retrospectively investigated the clinical significance of ILAs in patients with non-small cell lung cancer (NSCLC) receiving ICIs. We defined ILAs as nondependent abnormalities affecting more than 5% of any lung zone, including ground-glass or diffuse centrilobular nodularities, traction bronchiectasis, honeycombing, and nonemphysematous cysts. Early-onset ICI-ILD was defined as developing within 3months after the initiation of ICI administration. Of 264 patients with advanced NSCLC, 57 patients (21.6%) had ILAs (43 fibrotic and 14 nonfibrotic ILAs). The difference between the incidence of ICI-ILD in patients with or without ILAs was not significant. Of 193 patients treated by ICI monotherapy, 18 (9.3%) developed early-onset ICI-ILD. Among patients receiving ICI monotherapy, the incidence of early-onset ICI-ILD was significantly higher in patients with than in patients without nonfibrotic ILAs. The presence of nonfibrotic ILAs is a significant risk for early-onset ICI-ILD in patients with NSCLC undergoing ICI monotherapy. Clinicians should be aware of ILAs, especially nonfibrotic ILAs, before administering ICIs to lung cancer patients.

RF30 | PSAT177 A Case of Hypercalcemia Related to Immune Checkpoint Inhibitor-Induced Sarcoidosis-like Granuloma

Abstract Background Immune checkpoint inhibitor (ICI) is an essential part of the treatment of various advanced cancers, but its use can be associated with a number of side effects, including hypercalcemia. The mechanism through which hypercalcemia arises is not well established. One proposed mechanism is through sarcoidosis-like reactions. Here we present an illustrative case. Clinical Case A 75-year-old female with past medical history notable for stage IV endometrial adenocarcinoma treated with surgery plus adjuvant chemotherapy, presently on pembrolizumab for 9 months, hypertension, and diabetes was admitted with generalized fatigue, difficulty ambulating, slow movements, and slow speech. Stroke was ruled out with negative neurologic imaging. Blood work revealed elevated calcium 13.8 mg/dL (8.6-10.4 mg/dL) and ionized calcium 1.64 mmol/L (1.09-1.29 mmol/L). Additional workup showed suppressed PTH 7 pg/mL (11-51 pg/mL), 25-OH vitamin D 19 ng/mL (20-50 ng/mL), elevated 1,25(OH)2 vitamin D of 114 pg/mL (19.9-79.3 pg/mL), elevated angiotensin converting enzyme (ACE) level 90 U/L (12-69 U/L), and normal PTHrP, suggestive of PTH-independent hypercalcemia mediated by 1,25(OH)2D as seen in sarcoidosis. Two months prior to admission and seven months after starting pembrolizumab, surveillance CT found improvement in tumor burden but new intrathoracic lymphadenopathy. Lymph node biopsy via bronchoscopy identified non-caseating granulomas suggestive of a sarcoidosis-like reaction. The patient's moderate hypercalcemia was treated with intravenous fluids, calcitonin, and zoledronic acid 4 mg with normalization of calcium levels. Glucocorticoid therapy was initially deferred to avoid counteracting the effect of pembrolizumab, however prednisone 10 mg daily was started 1 month after discharge when calcium rose again to 11.1 mg/dL. Prednisone was tapered off over 8 weeks as her calcium and 1,25(OH)2D levels normalized. She then restarted pembrolizumb, but after the third month she had recurrence of hypercalcemia (calcium 10.8 mg/dL) with elevated 1,25(OH)2D (89.5 pg/mL). She was again treated with prednisone 10 mg daily which was tapered off over 6 weeks with resolution of hypercalcemia. Her calcium levels remained normal off pembrolizumab. The temporal correlation in our case strongly suggests that ICI administration caused sarcoidosis-like granulomas and hypercalcemia. Conclusion Immune checkpoint inhibitors are known to occasionally cause hypercalcemia, although the mechanisms are not well established. In our case, moderate hypercalcemia was likely caused by ICI-induced sarcoid-like granulomas that responded promptly to glucocorticoids and interruption of ICI-therapy. Presentation: Saturday, June 11, 2022 1:00 p.m. - 3:00 p.m., Monday, June 13, 2022 1:12 p.m. - 1:17 p.m.

LBODP108 Did You Follow Your Patient After ICI Cessation? A Case of Immune-Related Adverse Event 5 Months Following Completion Of Immunotherapy

Abstract Introduction Immune checkpoint inhibitors (ICI) have been approved for use in cancer therapy for malignant melanoma, non-small cell lung cancer, and renal cell carcinoma in the last decade. Since their inception, immune-related adverse events (irAEs) have been well documented. We present a patient who developed 2 irAEs - grade 1 irAE during therapy and grade 3 irAE five months after completion of anti-CTLA-4 (Ipilimumab) and anti-PD-1 antibody (Nivolumab) therapy. Case description Our patient is a 65-year-old woman who was diagnosed in 2019 with Melanoma over the left knee which was resected in her home country. During follow-up here, she was started on immunotherapy with Ipilimumab and Nivolumab for metastatic disease. Her baseline labs including TFTs were normal before initiation of therapy. During treatment after 4 infusions, she developed hypothyroidism. At that time she was tolerating treatment well. Levothyroxine was initiated for this grade 1 irAE with the continuation of immunotherapy. She decided to move to her home country with a plan to pursue further immunotherapy upon her return. 7 months after discontinuation of therapy, the patient presented to our hospital with nausea, vomiting, and dizziness for 2 months. She was hypotensive and minimally responsive to intravenous fluids. Labs drawn were remarkable for hypothyroidism. Further workup demonstrated adrenal insufficiency with morning cortisol of 0.1 μg/dL and ACTH of &amp;lt;1.5 pg/ml. Pituitary hormones were within normal range except for elevated prolactin. A contrast-enhanced MRI of the pituitary was negative for any enlargement or mass. She was diagnosed with secondary adrenal insufficiency and managed with stress-dose corticosteroids with a resolution of symptoms. We were able to ascertain that our patient developed grade 3 irAE almost 5 months after her last immunotherapy. Discussion Cancer immunotherapy is associated with endocrinopathies such as hypophysitis, hypothyroidism, and adrenal insufficiency. As per a review done by González-Rodríguez E et al it has been found that the median time of onset from initiation for endocrine AEs was 7 - 20 weeks due to Ipilimumab and 11 weeks due to Nivolumab. In patients who received combined therapy, as per a retrospective study done by Nguyen et al, the median time from ICI administration to the diagnosis of immune-related hypophysitis was 35.8 weeks. In 2019, Ohara N reported a case of a patient with lung adenocarcinoma who developed isolated ACTH deficiency 4 months after discontinuation of Nivolumab therapy. Our patient developed two irAEs - during and after completion of immunotherapy. Symptoms can often be generalized and overlap with those of cancer progression making it difficult to diagnose. Our case highlights the need for continued surveillance of these patients by physicians probably even months after completion. Presentation: No date and time listed

Utility of periodic medical questionnaires and examinations for immune-related adverse event screening: A prospective observational study.

Immune checkpoint inhibitors (ICIs) are associated with immune-related adverse events (irAEs) specific to the immunity-boosting activity of the drugs and may necessitate discontinuation of treatment depending on their severity. IrAEs may be difficult to diagnose in their early stages as they can occur in any organ. The present, prospective, observational study is the first to attempt to assess the utility of periodic medical questionnaires and laboratory, radiological, and physiological examinations in diagnosing irAEs. We analyzed 51 patients who received immunotherapy for metastatic renal or urothelial carcinoma at Tokyo Metropolitan Tama Medical Center between 2016 and 2020. A medical questionnaire consisting of 41 questions and laboratory tests were administered to the patients on the day of each ICI administration and 1 week afterwards. A significant complaint was defined as a complaint not addressed in the questionnaire immediately prior to the first ICI administration. Fifty-one patients with metastatic renal or urothelial carcinoma were enrolled. The mean age was 72.1 years (range: 54-88 years). The male: female ratio was 32: 19. Of the total cohort, 26 (51%) patients had renal carcinoma, and 25 (49%) had urothelial carcinoma. The median follow-up time was 2.6 (range: 0.4-40.7) months. Thirty-three patients (65%) experienced irAEs. In our cohort, periodic medical questionnaires and examinations were effective for early diagnosis and prompt treatment of irAEs. Although periodic examinations led to a high irAE diagnosis rate, the attendant medical cost was high. Further study is needed to find ways of addressing this issue.

Increased risk of incident diabetes after therapy with immune checkpoint inhibitor compared with conventional chemotherapy: A longitudinal trajectory analysis using a tertiary care hospital database

Aims/hypothesisImmune checkpoint inhibitor (ICI) has been emerged as a promising cancer treatment. However, ICI use induces immune-related adverse events, including diabetes mellitus. We compared the risk of new-onset diabetes between patients receiving an ICI and those receiving conventional chemotherapy (CC). MethodsUsing a tertiary care hospital database, we included cancer patients without a previous history of diabetes who were treated with either CC or an ICI. One-to-five nearest neighbor propensity matching was applied, and the risk of diabetes was estimated using a Cox proportional hazards model. Latent class growth modeling was performed with a trajectory approach to determine distinct clusters that followed similar glucose trajectory patterns over time. ResultsAmong 1326 subjects, 1105 received CC, and 221 received an ICI. The risk of new-onset diabetes was significantly higher in the ICI group than the CC group (adjusted hazard ratio 2.454, 95 % confidence interval 1.528–3.940; p < 0.001). The ICI group had a higher proportion of subjects in the trajectory cluster with an increasing glucose pattern than the CC group (10.4 % and 7.4 %, respectively). Within the ICI group, the subjects with an increasing glucose pattern were predominantly male and associated with enhanced lymphocytosis after ICI administration. ConclusionsICI therapy is associated with an increased risk of incident diabetes compared with CC. The glucose levels of patients treated with an ICI, especially males and those with prominent lymphocytosis after ICI treatment, need to be monitored regularly to detect ICI-associated diabetes as early as possible.

Efficacy and safety of amrubicin monotherapy after atezolizumab plus carboplatin and etoposide in patients with relapsed small-cell lung cancer

This study examined the activity and safety of amrubicin monotherapy among relapsed small-cell lung cancer (SCLC) patients who had previously been treated with atezolizumab plus carboplatin and etoposide (AteCE). This retrospective study evaluated patients with relapsed SCLC who were treated with previously AteCE combination therapy followed by amrubicin monotherapy between August 2019 and May 2021. Clinical efficacy and toxicity were analyzed. Overall, 40 patients were included: 12 and 28 patients had sensitive and refractory relapse, respectively. The response rate was 32.5% (25.0% in the sensitive group and 35.7% in the refractory group). The median progression-free survival (PFS) and overall survival (OS) from the first amrubicin treatment was 3.4 months (95% CI: 1.9–4.9 months) and 9.9 months (95% CI: 4.5–11.5 months), respectively. There was no significant between-group difference in median PFS (3.6 months vs. 3.2 months, p = 0.42) or median OS (11.2 months vs. 7.3 months, p = 0.78). Grade ≥ 3 hematological adverse events occurred as follows: decreased white blood cells in 52.5% of patients; decreased neutrophil count in 57.5%; and febrile neutropenia in 10.0%. Grade 3 pneumonitis was observed in one patient. There were no treatment-related deaths. Amrubicin is feasible and effective for relapsed SCLC patients previously treated with AteCE therapy. Although immune checkpoint inhibitor treatment (ICI) does not improve the effect of amrubicin, the toxicity is not increased, suggesting that amrubicin remains effective even after ICI administration. Thus, amrubicin after AteCE could be the preferred standard chemotherapeutic choice in patients with relapsed SCLC.

CDX2 downregulation in mouse mural trophectoderm during peri-implantation is heteronomous, dependent on the YAP-TEAD pathway and controlled by estrogen-induced factors.

PurposeTo investigate the transition of CDX2 expression patterns in mouse trophectoderm (TE) and its regulatory mechanisms during implantation.MethodsMouse E3.5–4.5 blastocysts were used to immunostain CDX2, YAP, TEAD4, and ESRRB. Endogenous estrogen signaling was perturbed by administrating estrogen receptor antagonist ICI 182,780 or ovariectomy followed by administration of progesterone and β‐estradiol to elucidate the relationship between the transition of CDX2 expression patterns and ovarian estrogen‐dependent change in the uterine environment.ResultsCDX2 expression was gradually downregulated in the mural TE from E4.0 in vivo, whereas CDX2 downregulation was not observed in blastocysts cultured in KSOM. Fetal bovine serum (FBS) supplementation in KSOM induced CDX2 downregulation independently of blastocyst attachment to dishes. CDX2 downregulation in the mural TE was repressed by administration of ICI 182,780 or by ovariectomy, and administration of β‐estradiol into ovariectomized mice retriggered CDX2 downregulation. Furthermore, Cdx2 expression in the mural TE might be controlled by the YAP‐TEAD pathway.ConclusionsCDX2 downregulation was induced heteronomously in the mural TE from E4.0 by uterus‐derived factors, the secretion of which was stimulated by ovarian estrogen.

Interleukin-6 blockade for prophylaxis and management of immune-related adverse events in cancer immunotherapy

BackgroundImmune checkpoint inhibitors (ICIs) have activity across many tumor types, but activation of the immune system may also lead to significant, often steroid-refractory immune-related adverse events (irAEs). We sought to determine the activity of tocilizumab, an anti-interleukin-6 receptor monoclonal antibody, in treatment or prevention of auto-immune irAE in ICI-treated patients. MethodsInstitutional databases from 2 melanoma centers were reviewed for patients treated with ICIs and tocilizumab. Longitudinal assessment of C-reactive protein (CRP) and assessment of clinical improvement or prevention of flare of pre-existing auto-immune conditions were utilised to evaluate the benefit of tocilizumab. ResultsTwenty-two patients were identified. Two were treated prophylactically. Twenty were treated for management of irAEs. Median time to irAE onset from ICI start was 48 days (range 8–786) and from irAE onset to tocilizumab 32 days (range 1–192). Median time to irAE resolution from tocilizumab was 6.5 days (range 1–93). Clinical improvement/benefit was demonstrated in 21/22 patients. Median CRP prior to ICI administration was 32 mg/l (range 0.3–99), at the onset of irAE 49.5 mg/L (range 0.3–251, P = 0.047) and after tocilizumab 18 mg/L (range 0.3–18, P = 0.0011). Tocilizumab was well tolerated with self-limiting and transient toxicities in 11 (50%) patients. From start of ICI, median progression-free survival was 6 months (range 3.9–18.8) and median overall survival was not reached. ConclusionsTocilizumab was a well-tolerated and effective steroid-sparing treatment for both management of irAEs, as well as prevention of flare of pre-existing auto-immune disorders. Prospective trials to evaluate its efficacy and impact on cancer outcomes compared with standard strategies are required.

Activation of G-protein coupled estradiol receptor 1 in the dorsolateral striatum attenuates preference for cocaine and saccharin in male but not female rats

There are sex differences in the response to psychomotor stimulants, where females exhibit a greater response than males, due to the presence of the gonadal hormone estradiol (E2). Extensive research has shown that E2 enhances drug-seeking and the rewarding properties of cocaine for females. The role of E2 in male drug-seeking, however, is not well understood. The current study investigated pharmacological manipulation of E2 receptors in the dorsolateral striatum (DLS) on preference for cocaine in gonad-intact male and female rats. In males, activation of G-protein coupled E2 receptor 1 (GPER1), via administration of ICI 182,780 or G1, attenuated conditioned place preference for 10 mg/kg cocaine, while inhibition of GPER1, via G15, enhanced preference at a 5 mg/kg cocaine dose. Similarly, GPER1 activation, via G1, prevented males from forming a preference for 0.1% saccharin (SACC) versus plain water. Surprisingly, activation of GPER1 did not alter preference for cocaine or SACC in females. These studies also examined the quantity of E2 receptor mRNA in the dorsal striatum, using qPCR. No sex differences in relative mRNA expression of ERα, ERβ, and GPER1 were observed. However, there was greater GPER1 mRNA, relative to ERα and ERβ, in both males and females. The results presented here indicate that E2, acting via GPER1, may be protective against drug preference in male rats.