Start Of Immune Checkpoint Inhibitors Research Articles

Abstract PS14-03: Delayed and post-treatment immune toxicities in patients with breast cancer receiving immune checkpoint inhibitors

Abstract Background: Immune checkpoint inhibitors (ICI) have improved outcomes in patients (pts) with breast cancer, however identification and management of immune-related adverse events (irAE) remains challenging. Delayed irAE have been observed, occurring even after ICI cessation. Prior analyses of delayed irAE have focused on patients with melanoma, lung, and head & neck cancer but data in patients with breast cancer are lacking. Methods: We identified pts with breast cancer who received ICI at our institution between 2012 and 2022 using pharmacy administration records. Charts were reviewed for delayed and post-treatment irAE. Delayed irAE were defined as occurring >90 days after ICI start; post-treatment irAE were defined as occurring >60 days after ICI discontinuation. Events were categorized as irAE if provider notes indicated that the toxicity was related to or possibly related to ICI. Results: 320 consecutive pts with breast cancer (219 metastatic, 96 localized disease) underwent treatment with ICI, of which 79 (25%) developed delayed irAE (40 with metastatic disease, 39 with localized disease). 54 pts had triple negative breast cancer (TNBC), 22 had hormone receptor positive (HR+) disease, and 4 had HER2+ disease. 44 pts received ICI on a clinical trial. The median number of ICI doses was 8, and the median length of follow-up after the first ICI infusion with 29 months. For delayed iRAE, median time to onset was 183 days (range 91-1800 days) with a total of 103 delayed irAE events (see table). 24 pts (7.5%) developed a post-treatment irAE with a total of 27 events. For post-treatment irAE, median time to onset was 112 days after ICI cessation (range 69-1100 days) and median time on ICI was 63 days (range 22-1724 days). 11 of 24 patients who experienced a post-treatment irAE also experienced an irAE while on treatment. Hypothyroidism, colitis, adrenal insufficiency, and hepatitis were the most common irAE at all time points. Rash primarily occurred while still on ICI. All irAE at any time point either self-resolved, resolved with systemic steroids, or continued with indefinite hormone replacement. 45 irAE required systemic steroids, not including hydrocortisone replacement for adrenal insufficiency. There were no grade 4 or 5 irAEs. Conclusions: This is the first evaluation of delayed/post-treatment irAE in a large cohort of patients with breast cancer. 79 pts (25%) experienced delayed irAEs occurring ≥ 90 days after ICI start, with median time to onset of 183 days. 89% of patients with delayed irAE also experienced an irAE at an earlier time point, indicating that early irAE may be a risk for delayed irAE. 24 pts (7.5%) experienced post-treatment irAE with median onset of 121 days after ICI cessation. Diagnosis of delayed irAE requires heightened awareness and prompt treatment. Future work is needed to identify key clinical and molecular markers that predict risk for delayed irAE to better inform treatment & monitoring. Table. Parameter Number of pts (%) Total pts receiving an ICI 320 Delayed irAE 79 (25) >1 delayed irAE 21 (27% of pts with delayed irAE) Patients with delayed irAEs who also had irAE occurring < 90 days after ICI start 70 (89% of pts with delayed irAE) Post-treatment irAE 24 (7.5) Types of delayed irAE (>90 days after ICI start) Any Grade Grade 3 Hypothyroidism 24 (23) 1 (1) Colitis/Diarrhea 19 (18) 3 (3) Rash 14 (14) 0 Adrenal Insufficiency/Hypophysitis 11 (11) 4 (4) Hepatitis 10 (10) 3 (3) Pneumonitis 4 (4) 1 (1) Arthralgia 4 (4) 0 Diabetes mellitus 3 (3) 0 Mucositis 2 (2) 1 (1) Neuropathy 2 (2) 0 Neutropenia 2 (2) 1 (1) Bronchitis 1 (1) 0 Fever 1 (1) 0 Neuromuscular Weakness 1 (1) 0 Autoimmune Hemolytic Anemia 1 (1) 1 (1) Myocarditis 1 (1) 1 (1) Acid Reflux 1 (1) 0 Sarcoidosis 1 (1) 0 Vitiligo 1 (1) 0 Types of post-treatment irAE (>60 days post ICI cessation) Any Grade Grade 3 Hypothyroidism 7 (26) 2 (7) Colitis 7 (26) 3 11) Adrenal Insufficiency/Hypophysitis 6 (22) 1 (4) Hepatitis 4 (15) 3 (11) Arthralgia 1 (4) 0 Neuropathy 1 (4) 0 Neutropenia 1 (4) 1 (4) Rash 1 (4) 0 Citation Format: Saya Jacob, Samantha Fisch, Carolyn Face, Laura Huppert, Zoe Quandt, Laura Quintal, Michelle Melisko, Melanie Majure, Jo Chien, Anne Blaes, Hope Rugo. Delayed and post-treatment immune toxicities in patients with breast cancer receiving immune checkpoint inhibitors [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PS14-03.

Cerebral 18F-FDG PET/CT Metabolism as Diagnostic Signature for Central Nervous System Toxicity After Immune Checkpoint Blockade Cancer Treatment.

Our aim was to investigate probable biomarkers specific to immune-related central nervous system toxicity (CNST) in cancer patients treated with immune checkpoint inhibitors (ICI) by analysis of 18F-FDG PET/CT images. Methods: Cancer patients receiving ICI treatment were enrolled in a multicenter observational study that analyzed regional metabolic changes before and during CNST onset from January 2020 to February 2022. In 1:1 propensity score-matched pairs, the regional SUVmean of each bilateral brain lobe of CNST patients (CNST+) was compared with that of patients who had central nervous system infections (CNSIs) and patients without CNST or CNSI (CNST-). In a validation cohort, patients were recruited from February 2022 to July 2023 and followed up for 24 wk after the start of ICI. Early changes in regional SUVmean at 5-6 wk after therapy initiation were evaluated for ability to predict later CNST onset. Results: Of 6,395 ICI-treated patients, 2,387 underwent prognostic 18F-FDG PET/CT and 125 of the scanned patients had CNST (median time from ICI treatment to onset, 9 wk; quartile range, 2-23 wk). Regional 18F-FDG PET/CT SUVmean changes were higher in CNST+ than in CNST- patients (117 patient pairs) but were lower than in CNSI patients (50 pairs). Differentiating analysis reached an area under the curve (AUC) of 0.83 (95% CI, 0.78-0.88) for CNST+ versus CNST- and of 0.80 (95% CI, 0.72-0.89) for CNST+ versus CNSI. Changes in SUVmean were also higher before CNST onset than for CNST- (60 pairs; AUC, 0.74; 95% CI, 0.66-0.83). In a validation cohort of 2,878 patients, preonset changes in SUVmean reached an AUC of 0.86 (95% CI, 0.79-0.94) in predicting later CNST incidence. Conclusion: Brain regional hypermetabolism could be detected during and before CNST clinical onset. CNST may be a distinct pathologic entity versus brain infections defined by 18F-FDG PET/CT brain scans. Regional SUV differences may be translated into early diagnostic tools based on moderate differentiating accuracy in our study.

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

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

Total metabolic tumor volume on 18F-FDG PET/CT is a game-changer for patients with metastatic lung cancer treated with immunotherapy

PurposeBecause of atypical response imaging patterns in patients with metastatic non-small cell lung cancer (NSCLC) treated with immune checkpoint inhibitors (ICPIs), new biomarkers are needed for a better monitoring of...

Abstract 1186: Moving beyond conventional autoimmune thyroiditis autoantibodies to predict immune checkpoint inhibitor induced hypothyroidism

Abstract INTRODUCTION: Treatment emergent adverse events (TEAEs) thyroiditis/thyrotoxicosis and hypothyroidism occur in up to 40% of patients treated with immune checkpoint inhibitors (ICIs). Conventional autoimmune thyroiditis autoantibodies (AutoAbs) (thyroglobulin (TG); thyroid peroxidase (TPO)) do not predict these TEAEs. We previously reported that pretreatment serum AutoAb profiles were associated with all severe TEAEs for melanoma patients treated with ICIs. Herein, we test if pre-existing AutoAbs could predict ICI induced hypothyroidism (TEAE ThyDis). METHODS: NYU Melanoma Program patients with stage IV metastatic melanoma treated with ICIs (Ipilumumab, Pembrolizumab, Nivolumab, or Combination) who had TEAE ThyDis (N = 14) or No TEAE (N = 11) were included. The HuProtTM human proteome microarray was used to profile proteins on cell surfaces or preferentially in extracellular spaces (N = 1061) in pretreatment and posttreatment (within ~4 months of ICI start) serum. Wilcoxon Rank Sum test was used to determine statistical significance (p < 0.05). RESULTS: 17 pretreatment pre-existing AutoAbs were detected (Table). All were higher in patients with TEAE ThyDis versus those with No TEAE. The pre-existing AutoAbs impacted immune cells (41%), extracellular matrix (ECM) (65%), or both (24%). P3H4 (p = 0.01) and ABCA2 (p = 0.01) were the only pre-existing AutoAbs that were statistically different posttreatment and were >10x higher in patients with TEAE ThyDis. They are both associated with intracellular vesicles but can be found in plasma membranes and extracellular spaces. No pre-existing AutoAbs were higher in patients with No TEAE ThyDis compared to those with TEAE ThyDis. However, posttreatment there was an increase in CSF1 AutoAbs that were not pre-existing (p = 0.05). CONCLUSIONS: Our data suggest that serum AutoAbs beyond TG and TPO can predict ICI TEAE ThyDis. Larger studies in other cancers (e.g., Breast) are required to validate these results. Pretreatment VS Posttreatment Pretreatment Pre-Existing Autoantibody Gene Name Impact TEAE ThyDis Present_median (N=14) TEAE ThyDis Absent_median (N=11) p-value COL14A1 ECM 17.35 7.99 0.01 DKK3 Cancer cells/ECM 14.74 3.75 0.01 LRFN1 Neurons 9.87 3.54 0.01 ABI3BP ECM 2.80 1.69 0.02 SELPLG Immune Cells 6.26 3.39 0.02 SMPDL3B Immune Cells/ECM 3.52 1.82 0.02 P3H4 Fibroplasts/ECM 13.41 6.29 0.02 C1QTNF2 Adipocytes/ECM 10.81 5.01 0.03 EMP1 Apoptosis 6.61 3.58 0.03 TMEF1 Neurons 6.44 3.03 0.03 CAPNS1 Cytoskeleton/ECM 3.27 2.13 0.04 FGFR2 Cancer Cells/ECM 2.96 1.62 0.04 GZMH Immune Cells 2.46 1.45 0.04 FSTL1 Immune Cells (autoantigen)/ECM 5.76 3.17 0.04 ABCA2 Immune Cells 11.81 7.00 0.05 ENPP1 Immune Cells/ECM 2.00 1.33 0.05 FGL2 Immune Cells/ECM 4.17 2.21 0.05 Posttreatment P3H4 Fibroplasts/ECM 61.82 6.09 0.01 ABCA2 Immune Cells 106.97 6.69 0.01 CSF1 Immune Cells 4.89 10.31 0.05 Citation Format: Kim Blenman, Ondrej Blaha, Courtney Gibson, Sherry Qiu, Holly Rushmeier, Milad Ibrahim, Shi Qiu, Michelle Krosgsgaard, Iman Osman. Moving beyond conventional autoimmune thyroiditis autoantibodies to predict immune checkpoint inhibitor induced hypothyroidism [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 1186.

Immune Checkpoint Inhibitor-Associated Remitting Seronegative Symmetrical Synovitis With Pitting Edema: Description of a New Entity by CanRIO.

Remitting seronegative symmetrical synovitis with pitting edema (RS3PE) is characterized by symmetrical synovitis with pitting edema and negative rheumatoid factor (RF). It has been described in a setting of malignancy, suggesting a paraneoplastic association. With the increasing use of immune checkpoint inhibitors (ICIs) for the treatment of cancers and emergence of immune-related adverse events (irAEs), our objective was to identify and describe cases of ICI-associated RS3PE (ICI-RS3PE) and compare them to non-ICI-RS3PE. The Canadian Research Group of Rheumatology in Immuno-Oncology (CanRIO) network is a collaboration of Canadian rheumatologists with experience in the management of patients with rheumatic irAEs (Rh-irAEs). Standardized data on adult patients with Rh-irAE have been collected as part of retrospective and prospective cohorts. In this study, detailed information on all cases of ICI-RS3PE from both cohorts were extracted and analyzed. We identified 11 cases of ICI-RS3PE. The most frequently observed malignancy was nonsmall cell lung cancer (4 of 11), followed by malignant melanoma (2 of 11) and cutaneous squamous cell carcinoma (2 of 11). The median time to onset of ICI-RS3PE was 26 weeks from ICI start and 52 weeks from diagnosis of malignancy. Seven patients had stable cancer prior to onset of ICI-RS3PE, 3 had partial response, and 1 had complete response. All patients received glucocorticoids. Conventional synthetic disease-modifying antirheumatic drugs (csDMARD) were needed in 10 patients. ICI-RS3PE may be an independent Rh-irAE, separate from paraneoplastic RS3PE. The symptoms of ICI-RS3PE responded well to glucocorticoids, but concomitant treatment with csDMARDs may be necessary.

Factors predictive of primary resistance (PrimRes) to immune checkpoint inhibitors (ICIs) in patients (pts) with metastatic urothelial cancer (mUC).

703 Background: Response rates to ICIs in pts with mUC remain modest at around 20% and there are no reliable biomarkers to select pts most likely to respond to ICI. It is an unmet need to define factors associated with PrimRes (progressive disease (PD) clinically and/or radiologically after at least 2 cycles of ICI) to spare pts from unnecessary treatment and the associated physical and financial toxicity. PrimRes to ICI has not been well defined in mUC pts and we sought to study predictive factors in our real-world cohort. Methods: We retrospectively reviewed 335 pts at the Cleveland Clinic who received ≥ 2 cycles or at least 6 weeks of ICI with pembrolizumab (P) or atezolizumab (A) between 2015 and 2023. Pt characteristics such as age, sex, race, BMI, primary site (bladder vs upper tract UC (UTUC)), and antibiotic (Abx) use before or after start of ICI and pre-treatment platelet to lymphocyte (PLR) ratios (divided into quartiles) were collected. PrimRes was defined as pts who had clinical and/or radiologic PD or death from disease within 14 weeks (time period of 1st assessment with imaging) of ICI initiation. Pts with PrimRes were compared to rest (responders, stable disease and subsequent PD). Multivariate cox regression models were used to identify factors associated with PrimRes. Results: Of the 335 pts, 129 (38.5%) pts had PrimRes based on our criteria. Median age was 73 yrs (35-95). PLR quartiles were clarified as (<149, 149-207, 207-308, ≥308). In our multivariate regression model, we found that pts with PLR ≥308 had a significantly higher chance of PrimRes compared to those with PLR <149 (Hazard Ratio (HR): 2.49; 95% CI: 1.22-5.15; p = 0.0133). Being underweight (BMI < 18.5) was associated with significantly higher rates of PrimRes than normal weight pts (HR: 6.91; 95% CI: 1.55-48.81; p = 0.0211). Abx use within 60 days post ICI start (HR: 2.29; 95% CI: 1.38-3.83; p = 0.0015) and UTUC (HR: 0.46; 95% CI: 0.25-0.83; p = 0.0099) were associated with PrimRes to ICI. Conclusions: In our large cohort of pts with mUC receiving ICI, we report that PLR ≥308, BMI < 18.5, use of Abx within 60 days post- ICI, and UTUC were associated with development of PrimRes to ICI. Ongoing genomic and immune correlates from tissues collected from our cohort will help us better understand the mechanisms of PrimRes to ICI. Validation and harmonization with more datasets and prospective studies can inform future steps towards patient-directed approaches. [Table: see text]

Effect of type of antibiotics (Abx) on outcomes with immune checkpoint inhibitors (ICIs) in patients (pts) with metastatic urothelial carcinoma (mUC) in a real-world setting.

640 Background: Use of Abx was associated with worse overall survival (OS) and progression-free survival (PFS) in our real-world cohort of mUC pts treated with ICI. (ASCO 2023). We now report the effect of type of Abx on ICI outcomes. Methods: In our cohort of 335 pts with mUC treated with ≥2 cycles of ICI with atezolizumab (A) or pembrolizumab (P) at CCF between 2015 and 2023, Abx class used in at least 20 pts was included. PFS and OS were calculated using Kaplan-Meier method, outcomes compared using log-rank testing and multivariate (MVA) Cox regression method. Results: Of 335 pts, 26.27% received A and 73.73% received P. Median follow-up was 26.8 mos. Details of type of Abx (cephalosporins (CPH), fluoroquinolones (FQ), penicillins (PCN) and trimethoprim-sulfamethoxazole (TMP-SMX), timing (30 or 60 (d) pre or post ICI start) and OS/PFS are shown in the Table. On MVA Cox regression analysis, Abx use within 60 (d) before ICI start was associated with worse OS (10.97 vs 16.03 mos.; (HR) 1.6 [1.2 -2.1], p=0.0004). Abx use within 30 (d) post ICI was associated with worse OS (6.9 vs 14.39 mos, p=0.008). Individual Abx and effect on OS and PFS are shown in Table. On MVA Cox regression analysis, Abx use within 60 (d) post ICI start was associated with worse PFS (3.12 vs 5.67 mos., HR 1.4; p=0.015). Conclusions: In our large cohort of pts with mUC treated with ICI, Abx PCN, CPH and FQ, within 30 and 60 (d) prior to starting ICIs demonstrated worse OS, Abx used after 30 and 60 (d) of ICI demonstrated worse OS and PFS, especially with CPH and PCN but not FQ. These findings have the potential to influence clinical practice, including using a higher threshold for prescribing antibiotics to pts with mUC when planned for or on ICI and the choice of Abx used. [Table: see text]

Evaluating intermediate endpoints (IE) for overall survival (OS) in metastatic renal cell carcinoma (mRCC) treated with immune checkpoint inhibitors (ICI): An IMDC study.

400 Background: In Ph3 trials, assessment for primary endpoint of OS necessitates extended follow-up (f/u) periods, larger pool of events, and higher associated costs. We sought to determine if shorter IEs like Time to Treatment Failure (TTF) and Time to Next Therapy (TTNT) are associated with OS in patients (pts) receiving ICI-based trt. Methods: We included all International mRCC Database Consortium (IMDC) pts who received contemporary approved first line(1L) ICI from 2013 to 2023. IEs were defined from ICI start until drug cessation or death for TTF, and initiation of next line or death for TTNT, or censored at date of last f/u. Associations of OS with TTF and TTNT status at 6-mo landmark were assessed using Cox regression adjusting for IMDC risk groups, metastatic sites, histology, age, and prior nephrectomy, stratified by treatment (trt) and yrs of ICI start. Endpoint associations across all f/u time were evaluated using Kendall’s Tau (KT) correlation by Clayton copula. A KT >0.49 indicates a strong correlation ( Wicklin R., 2023). Results: The cohort consisted of 1667 pts with a median f/u of 15.4 mo (IQR: 7.1-28.6). Median age at 1L start was 63 yrs (IQR: 56-70), with 73% being male and 65% undergoing nephrectomy before starting 1L. 1132 patients received dual ICI, while 535 received an ICI+TKI combination. Pts who discontinued their 1L regimen within the 6-mo landmark demonstrated poor OS, with a hazard ratio (HR) of 2.74 (95% CI: 2.15-3.49). Additionally, those who transitioned to a 2L therapy within the first 6 mo showed worse OS, reflected by an HR of 2.82 (2.22-3.59). KT correlation with OS across all follow up was 0.49 (0.45, 0.52) for TTF and 0.67 (0.64, 0.69) for TTNT. Consistent results were seen across all subgroups with the strongest association in the ICI+TKI group (Table). Conclusions: TTNT demonstrated the strongest association with OS, particularly in the ICI+TKI subgroup, making it a potentially clinically meaningful intermediate endpoint for evaluating efficacy in ICI-based regimens.[Table: see text]

Effect of neutrophil to lymphocyte ratio (NLR) on outcomes with immune checkpoint inhibitors (ICIs) in patients (pts) with metastatic urothelial carcinoma (mUC) in real-world setting.

678 Background: Elevated inflammatory biomarkers like the neutrophil to lymphocyte ratio (NLR) has been associated with poor prognosis in several cancers, including UC but there is limited evidence on its role as a prognostic biomarker in patients (pts) with mUC treated with ICIs. We studied the effect of baseline (pre-treatment) NLR on outcomes with ICI in mUC pts in our large cohort of patients with mUC treated with ICIs. Methods: We identified 335 adult pts with mUC at the Cleveland Clinic treated who received >/= 2 cycles of ICI with pembrolizumab (P) or atezolizumab (A) between 2015 and 2023. Patient characteristics including age, sex, race, primary site (bladder vs upper tract UC (UTUC)), tumor histology and pre-ICI treatment NLR values were collected and divided into four quartiles: (NLR <2.7, 2.7-4.0, 4.0-7.1, and >7.1). Impact of NLR on overall survival (OS) and progression free survival (PFS) post ICI start date was studied. OS and PFS were estimated using the Kaplan Meier method and compared by log rank test. Results: Of the 335 pts, NLR values were available for 320 pts. Median age was 73 yrs (35-95) and 76% pts were males. 247 pts (74%) received P and 88 (26%) received A. We found that in the 320 patients with available NLR values, the highest quartile values of NLR >/= 7.1 was significantly associated with worse OS (p=0.01). We did not find a statistically significant impact of NLR on PFS (p=0.06). (Table). Conclusions: In our large real-world cohort of pts with mUC receiving ICI, we report the effect of baseline NLR on outcomes with ICI and that NLR >/=7.1 was associated with significantly worse OS. Further validation studies are warranted to risk-stratify pts with mUC planned for ICI treatment. [Table: see text]

Radiotherapy with or without immunotherapy in metastatic melanoma: efficacy and tolerability

Introduction Radiotherapy (RT) is primarily considered as a palliative treatment in patients with metastatic melanoma. However, observations suggest that when RT is combined with immune checkpoint inhibitors (ICI), it can induce an immune response leading to an anti-tumoral effect also distant from the irradiated area – a phenomenon called ‘abscopal effect’. The frequency and circumstances of abscopal effect among metastatic melanoma patients remains uncertain and further research is necessary. Material and method This retrospective study included all metastatic melanoma patients who received non-stereotactic RT in Stockholm, Sweden in 2015–2020. Patients were grouped depending on if RT was given at start of ICI (RT + ICI(start)), at ICI progression (RT + ICI(salvage)) or without ICI (RT(only)). Response rates in irradiated (RR(irradiated)) and overall response rates in non-irradiated (ORR(non-irradiated)) metastases were evaluated together with survival and toxicity in each cohort. Results In the RT + ICI(start) (n = 47), RT + ICI(salvage) (n = 41) and RT(only) (n = 55) cohorts, RR(irradiated) was 70.7%, 67.5% and 43.1% (p = 0.018) while the ORR(non-irradiated) was 36.1%, 14.8% and 0.0% (p = 0.003), and the median overall survival was 18.2, 15.0 and 7.2 months, respectively (p = 0.014). Local response to RT was in all cohorts associated with longer survival (p < 0.001). The frequency of grade ≥3 immune-related adverse events was 17.0% and 19.5% in the RT + ICI(start) and RT + ICI(salvage) cohorts. No increased frequency of RT-related adverse events was seen in the RT + ICI cohorts, compared to the RT(only) cohort. Conclusion This retrospective study showed that melanoma patients receiving RT in combination with ICI had a superior antitumoral response in both irradiated and non-irradiated lesions as compared to patients receiving only RT. Additionally, a subgroup of patients receiving RT when progressing on ICI experienced tumor regression also in non-irradiated areas.

High bone tumor burden to identify advanced non-small cell lung cancer patients with survival benefit upon bone targeted agents and immune checkpoint inhibitors

BackgroundBone-targeted agents (BTA), such as denosumab (DN) and zoledronic acid (ZA), have historically reduced the risk of skeletal related events in cancer patients with bone metastases (BM), with no improvement in survival outcomes. In the immunotherapy era, BM have been associated with poor prognosis upon immune-checkpoint inhibitors (ICI). Currently, the impact of bone tumor burden on survival upon BTAs in advanced non-small cell lung cancer (aNSCLC) patients treated with ICI remains unknown. MethodsData from ICI-treated aNSCLC patients with BM (4/2013-5/2022) in one institution were retrospectively collected. BTA-ICI concurrent treatment was defined as BTA administration at any time before or within 90 days from ICI start. High bone tumor burden (HBTB) was defined as ≥ 3 sites of BM. Median OS (mOS) was estimated with Kaplan-Meier. Aikaike’s information criterion (AIC) was used to select the best model for data analysis adjusted for clinical variables. ResultsOf 134 patients included, 51 (38 %) received BTA. At a mFU of 39.6 months (m), BTA-ICIs concurrent treatment did not significantly impact on mOS [8.3 m (95% CI 3.9–12.8) versus (vs) 6.8 m (95% CI 4.0–9.6) p = 0.36]; these results were confirmed after adjustment for clinical variables selected by AIC. A multivariate model showed a significant interaction between BTA use and HBTB or radiation therapy to BM. In subgroup analyses, only HBTB confirmed to be associated with significantly longer mOS [8.3 m (95% CI 2.4–14.2) vs 3.5 m (95% CI 2.9–4.1), p = 0.003] and mPFS [3.0 m (95% CI 1.6–4.4) vs 1.8 m (95% CI 1.6–2.0) p = 0.001] upon BTA-ICI concurrent treatment, with the most pronounced OS benefit observed for DN-ICI concurrent regimen [15.2 m (95% CI 0.1–30.7) vs 3.5 m (95% CI 2.9–4.1) p = 0.002]. ConclusionsIn the immunotherapy era, HBTB can identify patients experiencing survival benefit with BTA, especially with DN-ICI combination. HBTB should be included as a stratification factor in the upcoming trials assessing BTA and ICI combinations in patients with aNSCLC and BM.

Immune Checkpoint Inhibitors in Patients with Pre-existing Neurologic Autoimmune Disorders.

The use of immune checkpoint inhibitors (ICIs) for oncologic indications is associated with immune-related adverse events (irAEs). Patients with pre-existing autoimmune diseases are at increased risk of irAEs and have largely been excluded from clinical trials of ICIs. Therefore, there is limited data on the safety of safety of ICIs in patients with pre-existing neurologic autoimmune diseases (nAIDs) such as myasthenia gravis and multiple sclerosis. This review aims to synthesize the literature on the post-marketing experience with ICI in patients with pre-existing nAID and to discuss possible strategies for mitigating the risk of post-ICI nAID relapses. Patients with pre-existing myasthenia gravis (MG), myositis, and paraneoplastic encephalitis appear highly susceptible to neurologic relapses of their underlying neurologic disorder following ICI initiation; these relapses can cause considerable morbidity and mortality. In patients with multiple sclerosis (MS), the risk and severity of MS relapses following ICI appears to be relatively lower compared to MG. Preliminary evidence suggests that older MS patients with no recent focal neuroinflammatory activity may be safely treated with ICI. Among the several case reports of ICI in patients with a history of Guillain-Barre syndrome (GBS), neurologic worsening was only recorded in one patient who was in the acute phase of GBS at the time of ICI start. Initiating an ICI in a patient with pre-existing nAID involves a complex risk-benefit discussion between the patient, their oncologist, and neurologist. Relevant issues to consider before ICI include the choice of disease-modifying therapy for nAID (if any) and strategies for promptly identifying and managing nAID relapses should they occur. Currently, the literature consists mainly of case reports and case series, subject to publication bias. Prospective studies of ICI in patients with nAID are needed to improve the level of evidence.

THU092 Characterizing Immune Checkpoint Inhibitor Induced Hypophysitis In A Large Urban Health Care System

Abstract Disclosure: M. Gogerly-Moragoda: None. U. Sharif Khawaja: None. K.C. Cheesman: None. A. Leiter: None. E.J. Gallagher: Consulting Fee; Self; Novartis Pharmaceuticals, Flare Therapeutics, Seagen, SynDevRx. INTRODUCTION Over the past decade, immune checkpoint inhibitors (ICIs) have transformed cancer therapy in multiple tumor types and improved outcomes. Endocrine immune related adverse events are well recognized side effects of ICIs. ICI induced hypophysitis is potentially life-threatening if not identified and treated. The present study examines the incidence and presentation characteristics of hypophysitis in a real-world cohort including a multitude of ICIs and tumor types. METHODS We conducted a retrospective analysis of all patients treated with ICIs at a large health system from 2011-2020. Patient demographics, type of cancer, type of ICI, endocrine symptoms and laboratory values were collected to characterize hypophysitis within the cohort. RESULTS A total of 1703 patients were treated with ICIs from 2011-2020 of whom 32 (1.9%) developed clinically apparent hypophysitis. Of the 32 patients, 26 patients were confirmed to have secondary adrenal insufficiency (AI), with 6 possible secondary AI. A majority were diagnosed in the outpatient setting (n=21, 66%). For those with hypophysitis, the most common tumor type was melanoma (n=12, 38%), followed by lung cancer (n=9, 28%) and genitourinary cancers (n=8, 25%). Combination cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) inhibitor, ipilimumab and programmed cell death protein 1 (PD-1) inhibitor, nivolumab (n=9, 28%) was the most common regimen, followed by monotherapies ipilimumab (n=6, 19%), nivolumab (n=6, 19%), pembrolizumab (n=6, 19%), the programmed cell death ligand 1 (PD-L1) inhibitor atezolizumab (n=3, 9%), with the remainder on durvalumab or combination durvalumab and tremelimumab. The most common presenting symptom was fatigue (n=21, 66%) with headache (n=8, 25%) and vision changes (n=2, 6%) being less common. The median time to presentation was 5 months with most presenting within 12 months of starting ICI (n=24, 75%). However, a subset of patients presented after 18 months on treatment (n=6, 19%), none of whom received ipilimumab. Seven patients underwent cosyntropin stimulation tests and six had muted responses, despite having low or inappropriately normal ACTH levels. DISCUSSION In this real-world dataset, we found a low percentage of hypophysitis across multiple tumor and ICI types. Secondary AI was most commonly seen with ipilimumab treatment. Notably, the subset of patients who presented after 18 months were all on PD-1 / PD-L1 inhibitors, which potentially indicates a distinct mechanism of hypophysitis with these agents compared with CTLA-4 inhibitors, and the new need to monitor these patients with labs and symptom review beyond the initial few months from ICI start. The muted cortisol response to cosyntropin was surprising in the setting of acute hypophysitis and warrants further investigation in these patients. Presentation: Thursday, June 15, 2023

Sex and anti-inflammatory treatment affect outcome of melanoma and non-small cell lung cancer patients with rheumatic immune-related adverse events

BackgroundRheumatic immune-related adverse events (R-irAEs) occur in 5–15% of patients receiving immune checkpoint inhibitors (ICI) and, unlike other irAEs, tend to be chronic. Herein, we investigate the factors influencing cancer...

Melanoma patients with immune-related adverse events after immune checkpoint inhibitors are characterized by a distinct immunological phenotype of circulating T cells and M-MDSCs

ABSTRACT Treatment with immune checkpoint inhibitors (ICIs) has improved the prognosis of melanoma patients. However, ICIs can cause an overactivation of the immune system followed by diverse immunological side effects known as immune-related adverse events (irAE). Currently, the toxicity of irAE is limiting the usage of ICIs. Here, we studied circulating monocytic myeloid-derived suppressor cells (M-MDSCs) and T cells in course of irAE after the ICI therapy. Our longitudinal study involved 31 melanoma patients with and without adverse events during anti-PD-1 monotherapy or anti-CTLA-4/PD-1 combination therapy. Peripheral blood samples were analyzed before ICI start, during ICI treatment, at the time point of irAE and during immunosuppressive treatment to cure irAE. We observed an enhanced progression-free survival among patients with irAE. In patients with irAE, we found an upregulation of CD69 on CD8+ T cells and a decreased frequency of regulatory T cells (Tregs). Moreover, lower frequencies of Tregs correlated with more severe side effects. Patients treated with immunomodulatory drugs after irAE manifestation tend to show an elevated number of M-MDSCs during an immunosuppressive therapy. We suggest that an activation of CD8+ T cells and the reduction of Treg frequencies could be responsible for the development of irAE.

Outcomes with atezolizumab in metastatic urothelial cancer: real-world data from a single institution.

Immune checkpoint inhibitors (ICIs) have been incorporated in the treatment of metastatic urothelial carcinoma (mUC) upon platinum-based chemotherapy according to the positive results of large clinical trials. Nevertheless, results from unselected populations reflecting real-world data (RWD) are highly informative to the clinician. We reviewed daily clinical practice outcomes in patients with mUC who received atezolizumab in our institution. Here we evaluated the clinical activity and safety of atezolizumab in an unselected population of mUC patients who received atezolizumab between 2018 and 2022 reflecting RWD. Efficacy and safety information were retrospectively collected. A total of 63 patients were included. The mean age was 68years and the objective response rate was 14.3%. The median progression-free survival was 3months and the median overall survival 6months. At 1year, 42% of the patients were alive. ECOG (0 vs 1) and neutrophil-lymphocytes ratio < 2 at the start of ICI were positive prognostic factors that discriminated between long vs short survivors. Overall tolerance was good with no new safety signals. Fivepatients (17%) had treatment-related adverse events grade ≥ 2 that required corticosteroids. In this retrospective study, atezolizumab was an effective and tolerable treatment option for patients with mUC after progression to platinum-based chemotherapy. Yet, patient selection remains critical to improve outcomes.

Can physiologic colonic [18F]FDG uptake in PET/CT imaging predict response to immunotherapy in metastatic melanoma?

AimThe development of biomarkers that can reliably and early predict response to immune checkpoint inhibitors (ICIs) is crucial in melanoma. In recent years, the gut microbiome has emerged as an important regulator of immunotherapy response, which may, moreover, serve as a surrogate marker and prognosticator in oncological patients under immunotherapy. Aim of the present study is to investigate if physiologic colonic [18F]FDG uptake in PET/CT before start of ICIs correlates with clinical outcome of metastatic melanoma patients. The relation between [18F]FDG uptake in lymphoid cell-rich organs and long-term patient outcome is also assessed.MethodologyOne hundred nineteen stage IV melanoma patients scheduled for immunotherapy with ipilimumab, applied either as monotherapy or in combination with nivolumab, underwent baseline [18F]FDG PET/CT. PET/CT data analysis consisted of standardized uptake value (SUV), metabolic tumor volume (MTV), and total lesion glycolysis (TLG) calculations in the colon as well as measurements of the colon-to-liver SUV ratios (CLRmean, CLRmax). Visual grading of colon uptake based on a four-point scale was also performed. Moreover, the spleen-to-liver SUV ratios (SLRmean, SLRmax) and the bone marrow-to-liver SUV ratios (BLRmean, BLRmax) were calculated. We also measured serum lipopolysaccharide (LPS) levels as a marker for bacterial translocation and surrogate for mucosal defense homeostasis. The results were correlated with patients’ best clinical response, progression-free survival (PFS), and overall survival (OS) as well as clinical signs of colitis.ResultsMedian follow-up [95%CI] from the beginning of immunotherapy was 64.6 months [61.0–68.6 months]. Best response to treatment was progressive disease (PD) for 60 patients, stable disease (SD) for 37 patients, partial response (PR) for 18 patients, and complete response (CR) for 4 patients. Kaplan–Meier curves demonstrated a trend for longer PFS and OS in patients with lower colonic SUV and CLR values; however, no statistical significance for these parameters as prognostic factors was demonstrated. On the other hand, patients showing disease control as best response to treatment (SD, PR, CR) had significantly lower colonic MTV and TLG than those showing PD. With regard to lymphoid cell-rich organs, significantly lower baseline SLRmax and BLRmax were observed in patients responding with disease control than progression to treatment. Furthermore, patients with lower SLRmax and BLRmax values had a significantly longer OS when dichotomized at their median. In multivariate analysis, PET parameters that were found to significantly adversely correlate with patient survival were colonic MTV for PFS, colonic TLG for PFS, and BLRmax for PFS and OS.ConclusionsPhysiologic colonic [18F]FDG uptake in PET/CT, as assessed by means of SUV, before start of ipilimumab-based treatment does not seem to independently predict patient survival of metastatic melanoma. On the other hand, volumetric PET parameters, such as MTV and TLG, derived from the normal gut may identify patients showing disease control to immunotherapy and significantly correlate with PFS. Moreover, the investigation of glucose metabolism in the spleen and the bone marrow may offer prognostic information.

Real-world analysis of ICI efficacy in ES-SCLC patients with and without brain metastases: A call for inclusion in clinical trials.

e20621 Background: Immune checkpoint inhibitors (ICIs) have proven successful in treating extensive stage small-cell lung cancer (ES-SCLC). Atezolizumab, a PD-L1 inhibitor, is approved as first-line therapy for ES-SCLC in combination with chemotherapy. SCLC has a high incidence to spread to the brain with more than 50% of patients developing brain metastases (BM) during their clinical course. However, patients with BM have frequently been excluded from clinical trials due to their perceived poor prognosis. This study aimed to assess the efficacy of ICI in achieving disease response and managing intracranial disease in patients with ES-SCLC. Methods: We conducted a retrospective study on patients with biopsy-confirmed ES-SCLC treated with at least one cycle of atezolizumab/carboplatin/etoposide combination from 2015 to 2022. Overall survival (OS), progression-free survival (PFS) and radiographic response were noted in patients with and without BM. Intracranial (IC) response was documented in patients with radiographic evidence of BM who had at least one follow-up brain imaging after the start of ICI. Results: A total of 83 patients were included, 39.3% (n = 33) of which had BM. Median follow-up was 8 (95%CI: 4.5-11.6) months. Baseline characteristics were summarized in the table below. Disease progression occurred in 90.9% patients with BM and death in 51.5%. Among 21 patients who fulfilled IC response assessment criteria, one (4.8%) had complete response, four (19.0%) had partial response, two (9.5%) had stable disease and fourteen (66.7%) had disease progression. Median duration of IC response was 5.3 (95%CI: 0.00-20.35) months; IC objective response rate was 23.8%. No difference was found in OS (10 vs. 30 months, P = 0.3) or PFS (6 vs. 7 months, P = 0.18) in patients with and without BM respectively. Patients with &gt; 3 BM (n = 16) had inferior OS (7 vs. 21 months, P = 0.01) and PFS (5 vs. 6 months, P = 0.002) compared to those with ≤3 BM. Conclusions: This study demonstrated that ICI achieved similar outcomes in patients with and without BM and produced meaningful intracranial response in patients with BM. Therefore, further clinical trials on ES-SCLC should encompass patients with BM, especially those with ≤3 BM. Future research on a larger, more diverse patient population is warranted. [Table: see text]

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 &lt; 6 months, 6-12 months, 1-2 years, 2-5 years, and &gt;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 &gt;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 &gt;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]