Use Of Immune Checkpoint Inhibitors Research Articles

Understanding the late immune checkpoint inhibitor (ICI) symptom experience using an electronic patient reported outcomes (ePRO) app-based platform: The immunowave study.

e24067 Background: Chronic toxicities of ICI cancer therapy remain largely uncharacterized. With increasing use of ICIs in early cancer stages, the number of cancer patients exposed to ICI therapy will continue to increase. We undertook a smartphone app-based ePRO pilot study to examine symptom experience of patients with prior or ongoing (≥ 6 months) treatment with ICIs. Methods: Eligible patients had a history of advanced skin cancer or kidney cancer treated with ICI therapy (adjuvant or metastatic setting) with ongoing, clinician-assessed cancer control. Patients may have completed a course of ICI therapy or continued on therapy if ≥ 6 months had passed since initiation. We conducted a single-center, observational, prospective cohort study where participants completed weekly ePRO assessments measuring 11 PRO-CTCAE symptoms over 12 weeks. We assessed the feasibility of this app-based ePRO monitoring strategy (defined as the fraction of weekly assessments completed) and described the prevalence and severity of symptoms in this population. Results: Forty-seven patients (77% melanoma, 15% renal cell carcinoma, 8% non-melanoma skin cancer) consented to the study. At enrollment, 70% were on active therapy while 30% had completed therapy. 38% received adjuvant therapy and 62% were treated in a metastatic setting. The majority (N = 43, 91%) completed ≥ 1 weekly ePRO assessment (median 8, IQR 5.5-10). These 43 patients were included in the analysis. 61% (317/516) of the scheduled ePRO symptom assessments were completed. The prevalence, severity, and persistence of symptoms are noted in the Table. Fatigue and joint pain were most commonly reported (85% and 66% of assessments, respectively) and most commonly Grade ≥ 3 symptoms (23%, 20%). More than half of the patients reported persistent (present ≥ 50% of a patient’s assessments completed) symptoms of fatigue, joint pain, muscle pain, itchiness, rash, depression, anxiety, and numbness. Conclusions: Weekly app-based ePRO monitoring allowed for longitudinal assessment of symptoms with reasonable completion rates. Patients reported frequent, persistent, and sometimes severe symptoms, most notably fatigue, mental health symptoms, and musculoskeletal symptoms. This study suggests that patients during and after ICI therapy may experience high symptom burden, warranting further study in a larger population with longer study duration to identify candidate symptoms for interventions. [Table: see text]

Impact of ethnicity and insurance on adverse effects and treatment outcomes related to immune checkpoint inhibitors at a safety net hospital.

e18538 Background: Clinical trials have shown efficacy and safety of immune checkpoint inhibitors (ICI) in the treatment of various malignancies. However, trial populations often do not adequately represent patient populations in the real-world. We report immune related adverse effects (IRAEs) among patients with various malignancies, diverse ethnicities, and government sponsored insurance or uninsured, as well as treatment outcomes of ICIs in metastatic non-small cell lung cancer (mNSCLC). Methods: A retrospective study of adult patients with malignancy, who received ICI or ICI plus chemotherapy from January 1, 2015 to January 1, 2020 was conducted at a safety net hospital. Data was collected from electronic medical records with IRB approval. IRAEs were identified and categorized according to CTCAE v5.0. 1-year overall survival (OS) and median duration of ICI therapy (mDT) were calculated for mNSCLC patients. Results: We reviewed 121 patients: 49% were African American (AA), 40% were white and 11% were other ethnicities. Medicaid/Medicare (M/M) was the primary insurance for 83% of patients, 6% had commercial insurance and 11% were uninsured. The median duration of follow-up was two years. IRAEs occurred in 37% of patients; hypothyroidism was the most common (7.5%), and none led to death. The incidence of grade 2 or higher IRAEs was lower in AA (25.4%) compared to in whites (32.6%), with treatment discontinuation rates of 5% in AA versus 16% in whites. Among mNSCLC patients, AA and other ethnicities had a decreased 1-year OS of 37% and 22% respectively, compared to 48% in whites. The mDT was 8.3 months for AA and 3 months for other ethnicities, compared to 13.2 months for whites. 40% of M/M patients with mNSCLC were alive at 1 year; none of the uninsured patients were alive at 1 year. The mDT was higher in M/M patients (6 months) than uninsured patients (3.5 months). Conclusions: Ethnicity and insurance coverage may influence the incidence of IRAEs and treatment outcomes with ICI. AA had a lower incidence of IRAEs compared to whites. However, minority populations with mNSCLC had decreased survival compared to whites. mNSCLC patients with M/M had better OS than uninsured patients. Minorities and uninsured patients spent less time on ICI compared to other patients. IRAEs are a significant burden and further study of the use of ICIs in diverse populations is warranted.[Table: see text]

Retrospective analysis on association of ABO blood type and immune checkpoint inhibitor response.

2596 Background: The presence or lack of a collection of antigenic cell surface markers on red blood cells makes up the ABO blood groups that contribute to various immunogenic neoantigens. Variations in the T-cell diversity and HLA haplotype with different blood types might affect a patient's response to Immune checkpoint inhibitors (ICIs). However, the association between the ABO blood type and ICIs is not well studied. Methods: We did a retrospective observational study to investigate the influence of ABO blood groups on patients receiving ICIs at the University of Vermont Cancer Centre. We examined the medical records of people who received ICIs as first-line therapy between January 2017 and June 2022 and collected demographic data, including age, sex, ethnicity, cancer stage, type and metastasis. We looked at overall survival and the occurrence of immune-related adverse events (irAEs) in different blood type subgroups and calculated relative risks. Results: A total of 288 cases were identified, out of which 169 had documented blood type, including 75 with A, 19 with B, 72 with O and 3 with AB blood type. The mean age was 63.71 years (Standard deviation (SD): 11.52), 58.6% were males, and ethnicity was 94.7% White, 1.2% Asian and 0.6% Hispanic. Lung cancer was most commonly identified at 41%, and 60% of total cancers were stage 4. The median ECOG status was 1 and the Charlson comorbidity index was 6. 36% of cases developed irAEs, whereas mortality was 39% during the study period. The relative risk of irAEs with blood type A and B compared to O was 0.89 and 0.83, respectively but wasn't statistically significant. The relative risk of irAEs of AB compared to O blood type was statistically significant at 2.63 (CI: 1.95-3.54). The relative risk of death in A and B blood types compared to O wasn't statistically significant. No patients in the AB blood group died. Conclusions: Clinically significant association wasn't found between different blood types and irAEs or mortality except for the increased risk of irAEs with AB compared to O. With the rapidly growing use of ICIs, prospective trials are needed to better understand the true risk of developing irAEs in patients with AB blood type. [Table: see text]

Pretreatment radiomic biomarker for immunotherapy responder prediction in IB-IV stage NSCLC: A multi-center retrospective study.

e21060 Background: The current biomarker of immune checkpoint inhibitors (ICIs) efficacy is not sufficient. This study investigated the correlation between radiomic biomarker and immunotherapy responder in patients with IB-IV stage non-small-cell lung cancer (NSCLC), including its biological explanation for ICIs treatment response prediction. Methods: CT images from 319 pretreatment NSCLC patients receiving immunotherapy between January, 2015 and November, 2021 were retrospectively collected and were distributed into a discovery (n = 214), independent validation (n = 54), and external test cohort (n = 51). 851 features were extracted from both tumoral and each peri-tumoral VOIs. The reference standard is the durable clinical benefit (DCB) and the crucial exclusion criteria are missing pretreatment CT scans. The predictive value of combined radiomic signature (CRS) was assessed in a cohort of 98 resectable NSCLC patients receiving ICIs. The association of radiomic features and tumor immune landscape on the online dataset (n = 60) was also evaluated. A clinical model was constructed and incorporated with radiomic signature to improve performance further. Results: CRS discriminated between DCB and non-DCB patients in the training cohort (area under the curve (AUC): 0.82, 95% CI: 0.75 to 0.88)) and independent cohort (AUC: 0.75, 95%CI: 0.62 to 0.88). In this study, the predictive value of CRS was better than PD-L1 expression (AUC of PD-L1 subset: 0.59, 95%CI: 0.50 to 0.69) or clinical model (AUC of validation cohort: 0.66, 95%CI: 0.51 to 0.81). When predicting pathological response, CRS divided patients into a major pathological response (MPR) and non-MPR group (AUC: 0.76, 95%CI: 0.67 to 0.81). Moreover, CRS showed a promising stratified ability on overall survival (OS; HR: 0.48, 95%CI: 0.27 to 0.89; p = 0.020) and progression-free survival (PFS; HR: 0.43, 95%CI: 0.26 to 0.74; p = 0.002). Biological pathway analysis on online dataset revealed that dysregulation of Hedgehog and Hippo signaling pathways got involved in the prediction of radiomic features. Conclusions: By analyzing both tumoral and peri-tumoral regions of CT images in a radiomic strategy, we developed a non-invasive biomarker distinguishing responder from ICIs therapy, which might inform clinical decisions on the use of ICIs in advanced as well as resectable NSCLC patients.

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 Additional Exclusions of ROS1 Fusions (In Addition to EGFR Mutation and ALK Fusions) in the Cemiplimab NSCLC FDA Indication (EMPOWER-Lung 1 and -Lung 3). Catching Up with Current Scientific View of Immunotherapy in Never-Smoker Predominant Actionable Driver Mutation Positive NSCLC?

Cemiplimab is one of seven immune checkpoint inhibitors (ICIs) approved for the first-line (1L) treatment of advanced NSCLC in the US based on EMPOWER-Lung 1 and -Lung 3 trials. In addition to exclusion of NSCLC patients harboring EGFR mutations and ALK fusion from 1L treatment with ICIs, exclusion of ROS1 fusion is an additional unique exclusion the use of criterion for cemiplimab in the US FDA indication based on the design of the EMPOWER lung trials. We review the effectiveness of ICIs in never-smoker predominant NSCLC with driver mutations (EGFR, ALK, ROS1, RET, HER2) and question whether exclusion of ROS1 fusion would put cemiplimab at a competitive disadvantage given the requirement for insurance to prove ROS1 fusion negativity. We further discuss whether the US FDA as a regulatory authority has the right and responsibility to harmonize the use of ICIs in these actionable driver mutations to standardize community practice for the benefit of patients and to advance the development of next-generation treatment for these driver mutations.

Effects of treatment and patterns of metastases in upper tract and bladder urothelial cancer and non-urothelial cancer based on the national cancer database (NCDB) analysis.

e16571 Background: Upper tract Urothelial cancer (UTUC) and bladder urothelial and non-urothelial cancers can have varying patterns of metastases and response to treatment. Given worse response of visceral metastases to current immune checkpoint inhibitors (ICI) and worse outcomes of non-urothelial cancers, understanding the incidence, characteristics and survival for different metastatic presentation would be informative. Methods: The primary objective is to describe characteristics, treatment patterns, evaluate trends and differences in metastatic presentation and survival according to NCDB between upper tract urothelial cancers (UTUC) versus non-urothelial (nUTUC) histologies (squamous, sarcomatoid, small cell or neuroendocrine, adenocarcinoma) and bladder urothelial cancer (UC) and bladder non-urothelial cancer (nUC). Results: Extraction of data from diagnosis between year 2004 – 2017 from the NCDB was performed. A total of 649939 cases of whom UC = 630423 and nUC = 19516 for both bladder and upper tract cancers, respectively, were identified. Median age was 71.4 years (UC) and 70.1 years (nUC), with majority made up of men (62% of UTUC and 75% of bladder UC). Stage distribution at diagnosis was higher in nUC with Stage III at 1711 (8.8%, nUC) compared to 15725 (2.5%, UC) and Stage IV the nUC group (21.9%) compared to UC at 4.6%. Overall survival (OS) was worse with nUC for stage IV cancers with median OS (mOS) of 6.14 mos (95% CI 5.78-6.47) for nUC vs 7.92 mos (95% CI 7.75-8.08) for UC; logrank p < 0.001. Metastatic sites evaluated included bone, brain, liver, lung, and distant lymph nodes. mOS of Patients with visceral metastatic sites of disease are as follows: distant lymph nodes: UC: 7.59 mos (95% CI 6.6- 8.8); nUC: 5.62 mos (95% CI 4.1-7); log-rank p = 0.0372; liver: UC: 3.5 mos (95% CI 2.89-4.1); nUC: 4.1 mos (95% CI 2.6-6.83); p = 0.1874; lung: UC: 5.7 mos (95% CI 5.09-6.37); nUC: 4.27 mos (95% CI 2.99-6.74); p = 0.1567; Brain: UC: 3.06 mos (95% CI 2.1-4.24); nUC: 2.34 (95% CI 1.1-5.3), p = 0.5464. Use of chemotherapy resulted in improved OS in the UC group with mOS of 73.53 mos (95% CI 72.61-74.41) compared to nUC at 17.28 mos (95% CI 16.59-17.87), p < 0.0001 and use of ICI similarly yielded improvement in the UC group with mOS of 115.98 mos (95% CI 114.33-117.65) compared to nUC at 64.49 mos (95% CI 45.67-88.51); p < 0.0001 although radiation therapy resulted in less profound treatment effect with UC at 16.39 mos (95% CI 16.07-16.69) and nUC: 13.01 (95% CI 12.32-13.63); p < 0.0001. Conclusions: While treatment using chemotherapy and ICI has led to improvement in OS in higher stages of disease, patterns of metastases reveals visceral presentation portends a poor prognosis in both urothelial and non-urothelial cancers with slightly better mOS in those with distant lymph nodes as main presentation of metastases.

Tumor mutational burden (TMB) in real-world patients with pancreatic ductal adenocarcinoma (PDAC): Differences in genomic alterations (GA) and predictive value for immune checkpoint inhibitor (ICI) effectiveness.

4146 Background: Currently, ICI therapy is recommended for patients with metastatic PDAC whose tumors exhibit dMMR, MSI-H, or high TMB (≥10 mutations/Mb). However, due to the low prevalence of high TMB in PDAC (~1%), few studies have evaluated the role of ICI therapy in this subpopulation. This study aimed to compare GA between PDAC patients with high TMB and low TMB ( < 10 mutations/Mb) and to evaluate the effectiveness of ICIs in real-world PDAC patients by TMB status. Methods: This study included PDAC patients who underwent genomic testing using Foundation Medicine tissue comprehensive genomic profiling (CGP) assays. GA were compared between tissue specimens with high and low TMB by chi-squared, adjusted for multiple comparisons. Patient clinical data was obtained by the US-wide de-identified Flatiron Health and Foundation Medicine real-world clinicogenomic pancreatic database (CGDB), originated from ~280 US cancer clinics between 01/2011 and 09/2022. Real-world overall survival (OS) and time to treatment discontinuation (TTD) were compared between patients receiving an ICI (high TMB versus low TMB) and between patients with high TMB (ICI versus other therapies) by Cox models. Results: We included 21,932 patients with PDAC with tissue CGP data available; 98.7% with low TMB and 1.3% with high TMB. Among actionable alterations, patients with high TMB had higher prevalence of mutations in BRCA2 (p < 0.0001), BRAF (p < 0.0001), PALB2 (p < 0.0001), and genes of the mismatch repair pathway ( MSH2, MSH6, MLH1, and PMS2, p < 0.0001), but lower prevalence of KRAS mutations (p < 0.0001). The most common KRAS mutation in both groups of patients was G12D. In CGDB, 51 patients received an ICI (10 with high TMB and 41 with low TMB) and 17 patients with high TMB received other therapies. Among patients receiving an ICI, those with high TMB had more favorable median OS compared to those with low TMB (25.7 versus 5.2 months, hazard ratio (HR) 0.27, 95% confidence interval (CI) 0.09 - 0.76, p = 0.01) and median TTD (20.7 versus 3.0 months, HR 0.33, 95% CI 0.13 - 0.82, p = 0.02). Among patients with high TMB, those receiving an ICI had more favorable OS compared to those receiving other therapies (25.7 versus 6.6 months, HR 0.31, 95% CI 0.10-0.96, p = 0.043), nominally favoring ICI use in this small cohort (n = 10 versus 17). Conclusions: There is no randomized clinical trial evaluating ICI versus other therapies in PDAC. To our knowledge, this is the largest cohort to date comparing ICI effectiveness in PDAC. We observed more favorable OS among PDAC patients with high TMB receiving ICI versus those with low TMB who received an ICI and more favorable to those with high TMB receiving other therapies. This study supports the FDA-approved use of ICIs in patients with PDAC and high TMB and demonstrates the importance of TMB assessment for patients with PDAC.

Immune-related hypophysitis: An analysis of a heterogeneous entity.

e14704 Background: Immune-checkpoint inhibitors (ICIs) have led to revolutionary breakthroughs in the management of many malignancies. With the increasing use of ICIs, immune-related adverse events (irAE) have emerged and led to significant challenges and limitations. Immune-related hypophysitis, a potentially life-threatening irAE, has limited data on its diagnosis, clinical findings, and management. This was our incentive to characterize our single-institution experience with immune-related hypophysitis over the past 5 years. Methods: We retrospectively studied a cohort of adult patients who received ICIs at the Cleveland Clinic Foundation between 2017-2022. Our search was done by utilizing an outpatient oncology pharmacy database. Analyzed ICIs included atezolizumab, nivolumab, pembrolizumab, ipilimumab, avelumab, and durvalumab. The occurrence of immune-related hypophysitis was as determined by an endocrinologist or oncologist. Results: 6,615 patients received ICIs from 2017-2022, of which 27 patients were diagnosed with hypophysitis. Immune-related hypophysitis occurred with ICI monotherapy in 44.4% and combined therapy (ipilimumab and nivolumab) in 55.5%. The most commonly implicated agents were ipilimumab (74%), followed by nivolumab (59.3%), pembrolizumab (18.5%), and durvalumab (3.7%). In patients receiving ipilimumab-nivolumab, hypophysitis was detected after a median duration of 65 days (range: 29-163 days) from ICI initiation, compared to 58 days (38-112) with ipilimumab alone and 155 days (8-294) with pembrolizumab. Hypophysitis was grade 1 in 18.5%, grade 2 in 29.6%, grade 3 in 37%, and grade 4 in 14.8% of all patients. No hypophysitis-related deaths occurred. Signs and symptoms included constitutional symptoms (fever, anorexia, myalgia) in 88.89%, severe/intractable headaches in 40.7%, gastrointestinal complaints in 29.6%, dermatologic findings in 7.4%, visual symptoms in 7.4%, and syncope in 3.7% of all patients. Lab findings included abnormalities of TSH in 77.78%, ACTH in 70.60%, FSH and/or LH in 52.63%, and a positive ACTH stimulation test in 69.3%. Imaging findings were present in 62.5% of patients, and most commonly revealed pituitary gland enlargement, enhancement, or stalk thickening on brain/pituitary MRI. Treatment included glucocorticoid replacement in 92.6%, thyroid replacement in 40.7%, and testosterone in 7.4% of patients. All patients remained on glucocorticoid therapy indefinitely after hypophysitis was diagnosed. ICIs were momentarily held in 22.2% and discontinued in 51.86% of patients, while 25.9% of patients did not experience treatment interruptions. Conclusions: Immune-related hypophysitis is an uncommon irAE that presents with variable clinical and diagnostic findings. Nonetheless it is a cause of permanent glucocorticoid dependence. Healthcare professionals should be aware of this entity so treatment can be promptly started.

Five-year survival outcomes in patients with melanoma with complete response to immunotherapy who discontinue therapy.

e21503 Background: Immune checkpoint inhibitor (ICI) therapy for advanced melanoma in the first-line setting often results in durable responses and prolonged overall survival (OS) after achieving a complete response (CR). While generally well-tolerated, there are financial toxicities and treatment related adverse events (TRAEs) associated with ICI use. There are limited data to inform the optimal duration of therapy after CR, and how specific patient factors may lead to variable OS in patients (pts) with CR. Methods: Pts with locally advanced stage III or stage IV melanoma who started first-line ICI therapy with pembrolizumab, nivolumab, or ipilimumab/nivolumab (ipi/nivo) and achieved CR were identified at a single institution under an Institutional Review Board approved protocol. Pts were only included in the sample if they had initiated treatment by 2013 and discontinued therapy by February of 2021 and had documented follow-up at least 1 year after discontinuing ICI therapy. Recurrence rates were determined by the presence of any recurrence after CR. Pts were analyzed by baseline stage (III vs IV), BRAF status, use of steroids for TRAEs, time from treatment start to CR, and total duration of therapy. OS was determined by time from treatment start to death or date of last follow-up. Results: 78 Pts with CRs from ICI therapy who discontinued treatment were identified at the University of Pennsylvania. Median follow-up time was 63 months from ICI treatment start. Median age at treatment start was 65 years (range 33-94). 51 Pts (68%) had an ECOG performance status (PS) of 0 vs 24 (32%) with ECOG PS of 1-2. 21 Pts (27%) had locally advanced stage III and 57 (73%) had stage IV disease. Of stage IV pts, 8 were M1a, 16 M1b, 22 M1c, and 11 M1d. 61 (78%) pts were treated with pembrolizumab, 5 (6%) nivolumab, 12 (15%) ipi/nivo. 34 pts (44%) were treated with steroids for TRAEs. Of the 78 total pts, 13 (16.7%) developed a recurrence after stopping treatment. The median time to recurrence was 57 months (range 9-110). Melanoma specific survival was 96%. Of the pts with recurrence, 3 died of melanoma, 9 are disease free after additional local and/or systemic treatment and one patient is alive with disease. There was no significant difference ( p < 0.05) in OS based on baseline stage, BRAF status, or use of steroids for TRAEs. Pts were treated for a median of 6 months (range 1 day to 24 months). Conclusions: With over 5 years median follow-up time, the majority of pts with advanced melanoma who attain a CR from first-line ICI therapy remain disease free after treatment discontinuation. Patient factors including stage at treatment initiation, BRAF status, and steroid usage during treatment were not associated with significant variation in OS in this cohort. Most pts with recurrences remain disease free after additional local and/or systemic treatment. Few melanoma specific deaths occurred in pts with a CR to ICI who discontinued treatment.

Hemophagocytic lymphohistiocytosis in patients treated with immune checkpoint inhibitors: A pharmacovigilance study from FDA Database.

e14684 Background: Immune checkpoint inhibitors (ICIs) are increasingly used to treat multiple cancers uncovering varieties of immune-related adverse events (irAEs). ICI-related haemophagocytic lymphohistiocytosis (HLH) is a rare hyperinflammatory syndrome caused by exaggerated activation of macrophages and cytotoxic T cells resulting in fatal hematological toxicity and multi-organ damage. Methods: We conducted a retrospective analysis of reported cases of HLH in patients treated with checkpoint inhibitors using data from the FDA's Adverse Event Reporting System (FAERS) database from 2018 to 2022. Patients aged 18 or older were included, and cases were classified using the Medical Dictionary for Regulatory Activities (MedDRA) terminology. Results: Of 2,317 patients with HLH reported in the FAERS, 13.6% (315) of patients were reported to receive commonly used ICIs. With nivolumab being 44.93%%, pembrolizumab 35.87%, Ipilimumab 30.43%, and atezolizumab 15.94%. HLH among these ICI use was most commonly reported in males (65.2%) with a median age of 65. Melanoma was the most common cancer reported in this sample population. Out of the reported cases, 26% died, and 72% were males. Death was observed more in combination ICI therapy (40.73%) than in single-agent use (29.04%). Even though the most commonly reported HLH was with Nivolumab, mortality was highest with Atezolizumab use (29.55%). Conclusions: Nearly half of the patients with a diagnosis of HLH received commonly used ICIs, which points towards ICIs being one of the important risk factors for developing HLH. However, several confounders should be considered, like a cancer diagnosis, infection, and antibiotics. Further studies on ICI-induced HLH are necessary to establish its causal relationship.

Association of immune checkpoint inhibitors (ICI) and venous thromboembolism (VTE) in non–small-cell lung cancer (NSCLC): A single healthcare system experience.

e14680 Background: NSCLC and chemotherapy are well-known predisposing factors for VTE. There are conflicting data regarding the association between ICI and VTE in patients with NSCLC. In a retrospective study by Khorana et al. in 2299 NSCLC patients, VTE incidence was numerically lower for patients receiving ICI than chemotherapy. In another study by Attia et al., in 514 patients with lung cancer, there was an increased incidence of VTE with ICI. We conducted a retrospective chart review to further assess the relationship between VTE and ICI in patients with NSCLC who were treated at our facility. Methods: All adult patients >18 years of age with NSCLC who received cancer treatment in our academic health system between January 2011- January 2021 were extracted from the tumor registry. Information was obtained about the type of cancer treatment, deep venous thrombosis (DVT) or pulmonary embolism (PE) occurrence, and associated comorbidities. Patients were divided into two groups – chemotherapy and combined ICI-chemotherapy. Fisher exact tests were used to compare categorical covariates by VTE status, while Wilcoxon rank-sum tests were used for continuous covariates. Multivariable logistic regression was performed to adjust for potential confounding. Results: 370 patients with NSCLC were included in the study. No statistically significant difference was found between VTE incidence and race, histology, or gender. There was a decreased VTE rate among non-advanced cancer (6.2% vs. 18.1%, p=.015) and squamous cell histology (7.5% vs. 28.1%, p=.009). Although the rate of VTE increases slightly in ICI/chemotherapy (17.4%, CI: 11.2%-25.8%) when compared to chemotherapy (15.3% %, CI: 11.2%-20.4%), this was not statistically significant (p=.645). After adjusting for sex, histology, and race, ICI/chemotherapy group had a statistically insignificant increase in odds of VTE events (adjusted OR = 1.24 95% CI = 0.67-2.3, p=.498) compared to the chemotherapy group. The odds of death were significantly lower in patients with ICI/chemotherapy (aOR=.33, 95% CI = .2-.54, p=.001). The median time between ICI use and VTE was 21 days (CI: 12.5-65), while the median time between chemotherapy and VTE was 65.5 days (CI=36.5-146.5). Conclusions: In patients with NSCLC who were treated at our facility, there was no significant VTE difference in patients related to race or gender identity. Likewise, there was no statistical difference in the incidence of VTE in the ICI/chemotherapy and chemotherapy groups. Multivariable logistic regression of various groups to the vital status of the patients shows a statistically significant decrease in death in ICI/chemotherapy group, which is a potential censoring event for VTE. Further studies, including meta-analyses, are required to evaluate the association further, given conflicting results on prior retrospective studies.

Immunologic constant of rejection as a predictive biomarker of immune checkpoint inhibitors efficacy in non-small cell lung cancer.

e21162 Background: Immune checkpoint inhibitors (ICI) transformed non-small cell lung cancer (NSCLC) prognosis but response rate remains disappointing. Besides PDL1 expression, tumor mutational burden, quantification of tumor infiltrating lymphocytes or methylation profile failed to confirm their predictive role. The ICR (Immunologic Constant of Rejection) signature is defined as an immune phenotype quantifying the expression of 20 genes all involved in cancer immunity. Our first objective was the assessment of ICR signature predictive value and our secondary objectives were to compare ICR signature with other published immune signatures and to assess the prognostic value of ICR signature. Methods: Our series included 77 paraffin-embedded (FFPE) tumors derived from NSCLC patients treated with ICI as a single agent in at least the second line setting. We also collected clinical and biological data from 4 public data sets to expand and confront our local data. Transcriptomic analysis was performed using nCountertechnology Dx analysis by Nanostring based on microscopic imaging counting relative abundance of hundreds of transcripts using the “nCounter PanCancer Immune Profiling Panel” including the 20 ICR genes. Results: We applied the ICR classification to a series of 44 local tumor samples enhanced with 118 samples from public datasets. Hierarchical clustering on both local cohort and public datasets allowed us to distinguish the four ICR classes, from ICR 1 (“cold” tumors) to ICR 4 (“hot” tumors). Among the 5 datasets, we did not observe any significant difference between ICR groups for age, sex and smoking status. We observed a relative homogeneity in Durable Clinical Benefit (DCB) rate among ICR groups 2 to 4 (median DCB above 20%) unlike ICR group 1 (median DCB under 10%) leading us to consider ICR as a binary signature (ICR 1 vs ICR 2-4). ICR signature indeed showed a significant association with DCB among the 5 pooled datasets (OR = 4.40 [95% Confidence Interval 1.44-13.45] p = 0.950) with uniform distribution between them. Then, we conducted a logistic regression univariate analysis of DCB among various previously published immune signatures and ICR signature was the only one to show a significant association with DCB in this analysis ( p = 0.007). Conclusions: We identified a feasible transcriptomic signature with a promising signal of ICI efficacy prediction in the so far disappointing immune biomarkers field. In a near future, predict ICI efficacy will be a major challenge with three pivotal questions. When, balanced with the new data on ICI use in early-stage lung cancer or widely pretreated patients. How, assessing various techniques to develop composite signatures to better consider every driver of immune response. What, considering the amount of potential new therapeutic targets, starting by the 20 genes of ICR signature.

Real-world experience and outcomes of immune-checkpoint inhibitors (ICI) in hepatocellular carcinoma (HCC).

e16155 Background: Effective management of HCC needs concerted efforts of all the disciplines involved. ICI and its combinations have not improved the outcomes to the expected level outside clinical trials. This is a retrospective review of HCC patients treated with ICI in an academic institution. Methods: HCC patients who received at least one ICI dose between 1/1/2017 and 7/31/2021 at the Ohio State University were included in the study. The patient's baseline (BL) characteristics (at the first dose of ICI) were extracted with immune-related adverse events (irAE) details and survival outcomes. Descriptive statistics were used, Fisher exact test to compare categorical variables, log-rank test rank test for survival outcomes, and logistic regression model for categorical outcomes using JMP Pro 16 (SAS Institute Inc., Cary, NC). Results: Our cohort has 38 patients. The median age is 67 years (range 41-88), with 82% males and 90% Caucasians (7% African American and 3% other). Refer to the table for other BL characteristics. Median overall survival (OS) and progression-free survival were 6 months (m) (95% confidence interval [CI], 4-10) and 4m (95% CI, 3-6), respectively. The OS was better in patients with longer DoT (≤ 2m vs 3-6m vs ≥6m, 2m vs 5m vs 24m, p<0.001). Even though PFS was significantly better in patients with CP A-B9 (Vs B9-C, 6m vs 2.5m, p=0.03) and CP B (vs A vs C, 9m vs 5m vs 2m, p=0.02), OS was not different. Poor responders (<2 m vs ≥ 3m PFS) in this cohort had higher BL total bilirubin (TB) (p=0.03) and are more likely to have CPC (p=0.03) or CP B9-C (p=0.01) and BCLC D (p=0.04) patients. CP class (lower, p=0.0007), DoT (≥ 6m, p=0.0001), combination with bev (p=0.004), fewer liver lesions (≤2, < 0.001), no history of any LRT (p=0.01) or fewer LRTs (p=0.01), and non-metastatic disease (p< 0.001) are associated with better OS. PVTT, line of therapy, and ALBI G did not impact the OS. IrAE were reported just 4 (10%) patients. Conclusions: In this small retrospective cohort, lower volume of hepatic HCC lesions, use of ICI with bev, lower TB, longer DoT were associated with better OS, while more advanced disease, CPC, BCLC D, more LRTs and higher bilirubin resulted in worse survival. Our results suggest that prescribing ICI in line with FDA approval indications results in better outcomes. They must be validated in larger studies. [Table: see text]

The role of immune checkpoint inhibitors (ICI) as adjuvant treatment in renal cell carcinoma (RCC): A systematic review and meta-analysis.

Pembrolizumab, a PD-1 ICI is approved for the adjuvant treatment of postnephrectomy patients with clear cell RCC in some countries worldwide. However, recent negative data from randomized clinical trials (RCT) with another ICIs makes the benefit of this treatment uncertain. A systematic review and study-level meta-analysis was performed to evaluate the benefit of disease-free survival (DFS) with adjuvant ICI treatment for patients with localized and/or metastatic resected RCC. Using the Preferred Reporting Items for Systematic Review and Meta-Analysis (PRISMA) statement, a systematic search was performed in PUBMED/MEDLINE, Scopus and EMBASE up to September 15, 2022. The statistical analysis was performed by ProMeta 3 software in intention-to-treat (ITT) population and in predetermined subgroups. Four RCT totalizing 3407 patients were included in this analysis. Systemic immunotherapy was pembrolizumab, atezolizumab, nivolumab, and ipilimumab plus nivolumab in 496, 390, 404, and 405 patients, respectively. In the ITT population there was a nonstatistically significant DFS benefit with adjuvant ICI (HR: 0.85, 95% CI: 0.69-1.04). Regarding the subgroups, there was a DFS benefit for PD-L1 positive (HR: 0.72; 95% CI: 0.55-0.94), intermediate-high risk patients (HR: 0.77; 95% CI: 0.63-0.94), and patients with sarcomatoid component (HR: 0.66; 95% CI: 0.43-0.99). This meta-analysis did not demonstrate a statistically significant DFS benefit in overall population, however considering the heterogeneity between the RCTs the use of adjuvant ICI should be individualized.

Incidence and risk factors of acute kidney injury in cancer patients treated with immune checkpoint inhibitors: a systematic review and meta-analysis.

The incidence and risk factors of acute kidney injury (AKI) in patients with malignancies receiving immune checkpoint inhibitors (ICIs) are being extensively reported with their widespread application. This study aimed to quantify the incidence and identify risk factors of AKI in cancer patients treated with ICIs. We searched the electronic databases of PubMed/Medline, Web of Science, Cochrane and Embase before 1 February 2023 on the incidence and risk factors of AKI in patients receiving ICIs and registered the protocol in PROSPERO (CRD42023391939). A random-effect meta-analysis was performed to quantify the pooled incidence estimate of AKI, identify risk factors with pooled odds ratios (ORs) and 95% confidence intervals (95% CIs) and investigate the median latency period of ICI-AKI in patients treated with ICIs. Assessment of study quality, meta-regression, and sensitivity and publication bias analyses were conducted. In total, 27 studies consisting of 24048 participants were included in this systematic review and meta-analysis. The overall pooled incidence of AKI secondary to ICIs was 5.7% (95% CI: 3.7%-8.2%). Significant risk factors were older age (OR: 1.01, 95% CI: 1.00-1.03), preexisting chronic kidney disease (CKD) (OR: 2.90, 95% CI: 1.65-5.11), ipilimumab (OR: 2.66, 95% CI: 1.42-4.98), combination of ICIs (OR: 2.45, 95% CI: 1.40-4.31), extrarenal immune-related adverse events (irAEs) (OR: 2.34, 95% CI: 1.53-3.59), and proton pump inhibitor (PPI) (OR: 2.23, 95% CI: 1.88-2.64), nonsteroidal anti-inflammatory drug (NSAID) (OR: 2.61, 95% CI: 1.90-3.57), fluindione (OR: 6.48, 95% CI: 2.72-15.46), diuretic (OR: 1.78, 95% CI: 1.32-2.40) and angiotensin-converting enzyme inhibitors (ACEIs) or angiotensin-receptor blockers (ARBs) (pooled OR: 1.76, 95% CI: 1.15-2.68) use. Median time from ICIs initiation to AKI was 108.07 days. Sensitivity and publication bias analyses indicated robust results for this study. The occurrence of AKI following ICIs was not uncommon, with an incidence of 5.7% and a median time interval of 108.07 days after ICIs initiation. Older age, preexisting chronic kidney disease (CKD), ipilimumab, combined use of ICIs, extrarenal irAEs, and PPI, NSAID, fluindione, diuretics and ACEI/ARB use are risk factors for AKI in patients receiving ICIs. https://www.crd.york.ac.uk/prospero/, identifier CRD42023391939.

Waldenström macroglobulinemia with secondary pure red cell aplasia in a patient with metastatic castrate resistant prostate cancer receiving an immune checkpoint inhibitor: a case report

BackgroundHypoproliferative anemia is a frequently encountered adverse event in cancer patients receiving immune checkpoint inhibitors (ICI). Secondary pure red cell aplasia (PRCA) is a rare but recognized immune related adverse event. With the burgeoning use of ICIs, the association of secondary PRCA with an underlying lymphoproliferative disorder is often overlooked.Case presentationWe report a case of a 67-year-old non-Hispanic Caucasian male with metastatic castrate resistant prostate cancer, who developed severe transfusion dependent anemia with reticulocytopenia while receiving treatment with olaparib and pembrolizumab. His bone marrow findings demonstrated erythroid hypoplasia, in addition to a CD5-negative, CD10-negative monotypic B-cell population and a somatic MYD88L265P mutation. With a presence of an IgM-paraprotein, he was diagnosed with Waldenström macroglobulinemia (WM) with secondary PRCA and treated with 6 cycles of bendamustine and rituximab. He achieved a complete response with this regimen and was transfusion independent.ConclusionIn this case, underlying WM was uncovered through systematic investigation of anemia caused by ICI therapy. This report highlights the possibility of a lymphoproliferative disorder in patients with concerns for PRCA with prior ICI exposure. If identified, treating the underlying lymphoproliferative disorder is highly efficacious in the management of the secondary PRCA.

Pathogenic Insights into DNA Mismatch Repair (MMR) Genes-Proteins and Microsatellite Instability: Focus on Adrenocortical Carcinoma and Beyond.

DNA damage repair pathways, including mismatch repair (MMR) genes, are prone to carcinoma development in certain patients. The assessment of the MMR system is widely recognized as part of strategies concerning solid tumors (defective MMR cancers), especially MMR proteins (through immunohistochemistry), and molecular assays for microsatellite instability (MSI). We aim to highlight the status of MMR genes-proteins (including MSI) in the relationship with ACC (adrenocortical carcinoma) according to current knowledge. This is a narrative review. We included PubMed-accessed, full-length English papers published between January 2012 and March 2023. We searched studies on ACC patients for whom MMR status was assessed, respectively subjects harboring MMR germline mutations, namely Lynch syndrome (LS), who were diagnosed with ACC. MMR system assessments in ACCs involve a low level of statistical evidence. Generally, there are two main types of endocrine insights: 1. the role of MMR status as a prognostic marker in different endocrine malignancies (including ACC)-which is the topic of the present work, and 2. establishing the indication of immune checkpoint inhibitors (ICPIs) in selective, mostly highly aggressive, non-responsive to standard care forms upon MMR evaluation (which belongs to the larger chapter of immunotherapy in ACCs). Our one-decade, sample-case study (which, to our knowledge, it is the most comprehensive of its kind) identified 11 original articles (from 1 patient to 634 subjects per study diagnosed with either ACC or LS). We identified four studies published in 2013 and 2020 and two in 2021, three cohorts and two retrospective studies (the publication from 2013 includes a retrospective and a cohort distinct section). Among these four studies, patients already confirmed to have LS (N = 643, respective 135) were found to be associated with ACC (N = 3, respective 2), resulting in a prevalence of 0.0046%, with a respective of 1.4% being confirmed (despite not having a large amount of similar data outside these two studies). Studies on ACC patients (N = 364, respective 36 pediatric individuals, and 94 subjects with ACC) showed that 13.7% had different MMR gene anomalies, with a respective of 8.57% (non-germline mutations), while 3.2% had MMR germline mutations (N = 3/94 cases). Two case series included one family, with a respective four persons with LS, and each article introduced one case with LS-ACC. Another five case reports (between 2018 and 2021) revealed an additional five subjects (one case per paper) diagnosed with LS and ACC (female to male ratio of 4 to 1; aged between 44 and 68). Interesting genetic testing involved children with TP53-positive ACC and further MMR anomalies or an MSH2 gene-positive subject with LS with a concurrent germline RET mutation. The first report of LS-ACC referred for PD-1 blockade was published in 2018. Nevertheless, the use of ICPI in ACCs (as similarly seen in metastatic pheochromocytoma) is still limited. Pan-cancer and multi-omics analysis in adults with ACC, in order to classify the candidates for immunotherapy, had heterogeneous results, and integrating an MMR system in this larger and challenging picture is still an open issue. Whether individuals diagnosed with LS should undergo surveillance for ACC has not yet been proven. An assessment of tumor-related MMR/MSI status in ACC might be helpful. Further algorithms for diagnostics and therapy, also taking into consideration innovative biomarkers as MMR-MSI, are necessary.

Challenges and Limitations of Endocrine Toxicity Evaluation in Non-Small Cell Lung Cancer Patients Treated with Immunotherapy-Retrospective Study from a Tertiary-Level Hospital in Romania.

(1) Background: The endocrine system has become a prominent target to autoimmune damage during treatment with immune checkpoint inhibitors (ICIs) in cancer patients. Real-world data regarding endocrine immune-related adverse events (irAEs) are needed to explore their impact in cancer patients. An analysis was conducted to evaluate endocrine irAEs caused by ICIs, besides the challenges and limitations of daily medical practice in oncology in Romania. (2) Methods: This was a retrospective cohort study of lung cancer patients treated with ICIs at Coltea Clinical Hospital, Bucharest, Romania, from 1 November 2017 to 30 November 2022. Endocrine irAEs were identified through endocrinological assessment and were distinguished as any occurring endocrinopathy during treatment with ICIs and related to immunotherapy. Descriptive analyses were performed. (3) Results: Of 310 cancer patients treated with ICIs, we identified 151 with lung cancer. From this cohort, 109 NSCLC patients qualified for baseline endocrine estimation and 13 patients (11.9%) developed endocrine irAEs, such as hypophysitis (4.5%), thyroid disorder (5.5%) and primary adrenal insufficiency (1.8%), with one or more endocrine glands being affected. There might be a correlation between endocrine irAEs and duration of ICI treatment. (4) Conclusions: Early diagnosis and adequate management of endocrine irAEs may be challenging in lung cancer patients. A high incidence of endocrine irAEs is expected with the growing use of ICIs, and because not all endocrine events are immune-related, cooperation between oncologists and endocrinologists is crucial in the management of these patients. More data are needed to confirm the correlation between endocrine irAEs and the efficacy of ICIs.

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