Start Of Immune Checkpoint Inhibitors Research Articles

Immune-related adverse events in cancer patients referred to the palliative care team of a tertiary care center: a retrospective observational study.

The application of immune checkpoint inhibitors (ICIs) can cause multi-organ adverse events, namely immune-related adverse events (irAEs) in patients with cancer. This study aimed to characterize the epidemiological information on irAEs in patients with cancer referred to the palliative care team (PCT). The medical records of cancer patients with a history of ICI therapy referred to the PCT at a tertiary care center between January 2017 and July 2022 were retrospectively reviewed in this single-center, observational study. The median age of the 140 patients was 68years, and lung (39.3%) being the most common primary site. We observed irAEs in 46 patients (32.9%), and hypothyroidism was the most common irAE. For irAEs graded ≥ 3 in 21 patients, pneumonitis was the most common adverse event. As for strategies for management with irAEs, seventeen patients were treated with systemic steroids. irAEs ( +) had a significantly lower Performance Status at the start of ICI, a higher total number of ICI doses, and longer duration from start of ICI to date of death than irAEs (-). Among 140 cancer patients with a history of ICIs therapy consulted to the PCT, the prevalence of irAEs was 32.9%, and 21 patients (15.0%) developed irAEs with grade ≥ 3. As the use of ICI is expected to increase in the future, it is important for palliative care physicians to increase their awareness of the management of irAEs and collaborate with oncologists from an early stage.

Longitudinal liquid biopsy predicts clinical benefit from immunotherapy in advanced non-small cell lung cancer

High heterogeneity in clinical benefit characterizes the use of immune checkpoint inhibitors (ICIs) in non-small cell lung cancer (NSCLC). We prospectively enrolled 113 advanced NSCLC patients treated with ICIs and performed liquid biopsy at the time of ICI start (T1), after 3 weeks (T2) and at the time of radiological evaluation (T3). Molecular variables were associated with outcome endpoints: cfDNA quantification, its dynamic change (∆T2–T1), variant allele frequency (VAF) of the gene with the highest frequency detected at baseline with NGS (maxVAF) and its dynamic change (∆T2–T1). At multivariate analysis, PD-L1 negativity, T1 cfDNA, cfDNA increase (∆T2–T1), and T2 VAF were significantly associated with shorter progression-free survival (PFS); PD-L1 negativity, squamous histology, T1 cfDNA, cfDNA (∆T2–T1) increase, and T2 maxVAF affected overall survival (OS). Among high PD-L1 expressing patients treated in first-line, elevated T2 maxVAF and cfDNA increase (∆T2–T1) correlated with worse PFS; higher T2 maxVAF and cfDNA increase (∆T2–T1) with worse OS. Derived integrated models were used to build nomograms and categorize different risk groups.

The association of azole antifungals with overall survival in patients with non-small cell lung cancer receiving immune checkpoint inhibitors.

Preclinical data suggest antifungal azole derivatives have antitumor efficacy that may modulate response to immune checkpoint inhibitors (ICIs). We aimed to evaluate the association of azole drugs with overall survival (OS) in a population of patients with non-small cell lung cancer (NSCLC) treated with ICI within the Veterans Health Administration (VHA). In this retrospective study, the VA Corporate Data Warehouse was queried for patients diagnosed with NSCLC and treated with ICI from 2010 to 2018. Concomitant oral azole use was defined as dispensation by a VA pharmacy within 90 days of the first ICI infusion. Patients who received azole after 30 days were excluded from the analysis to mitigate immortal time bias. OS was measured from the start of ICI. Cox regression and propensity score matching were used to adjust for confounders. We identified 3413 patients with NSCLC receiving ICI; 324 (9.5%) were exposed to concomitant azoles. As a group, azole use was not associated with OS (hazard ratio [HR] = 0.96; 95% CI, 0.84-1.09; P = .51). After stratification by azole type, clotrimazole had an association with better OS on univariable (HR = 0.75; 95% CI, 0.59-0.96; P = .024) and multivariable analysis (HR = 0.71; 95% CI, 0.56-0.91; P = .007). Propensity score matching of patients who received clotrimazole vs no azole yielded 101 patients per matched cohort. Clotrimazole was associated with improved OS, although this did not meet the threshold for statistical significance (HR = 0.74; 0.54-1.01; P = .058). This observational study demonstrated an association between clotrimazole and OS among patients with advanced NSCLC receiving ICI. These findings build upon preclinical evidence and support further investigation into the potential for clotrimazole as a repurposed FDA drug to improve cancer outcomes.

Toxicity profiles of immune checkpoint inhibitors in nervous system cancer: a comprehensive disproportionality analysis using FDA adverse event reporting system

Background: Immune-related adverse events (irAEs) always occur during treatment with immune checkpoint inhibitors (ICIs). Patients with nervous system cancer (NSC) may gain clinical benefit from ICIs, but irAEs in NSC patients are rarely examined. Therefore, our study systematically summarized reports of irAEs in NSC. Methods: We obtained information from the FDA adverse event reporting system from the first quarter (Q1) of 2013 to the fourth quarter (Q4) of 2022. We examined use of a combination of ICIs and chemotherapy (ICI_Chemo) or chemotherapy only (ICI_Chemo) for patients with NSC. Multiple disproportionality analyses were applied to assess irAEs. Multiomics data from the gene expression omnibus (GEO) database were analyzed to explore potential molecular mechanisms associated with irAEs in NSC patients. Results: Fourteen irAEs were identified in 8,357 NSC patients after removing duplicates; the top five events were seizure, confused state, encephalopathy, muscular weakness and gait disturbance. Older patients were more likely to develop irAEs than were younger patients. From the start of ICIs_Chemo to irAE occurrence, there was a significant difference in the time to onset of irAEs between age groups. irAEs may occur via mechanisms involving the inflammatory response, secretion of inflammatory mediators, and aberrant activation of pathologic pathways. Conclusions: This study helps to characterize irAEs in NSC patients treated with ICIs. We combined GEO database analysis to explore the potential molecular mechanisms of irAEs. The results of this study provide a basis for improving the toxic effects of ICIs in NSC patients.

The impact of body mass index (BMI) on overall survival (OS) among patients receiving immune checkpoint inhibitors (ICIs): A population-based study.

12041 Background: While obesity is a risk factor for cancer, BMI has been previously identified as a potential prognostic marker in different solid tumors. Prior studies have identified that among cancer survivors receiving ICIs, higher BMI may be associated with better OS, but there have been heterogeneous results among studies. Here we use population-level administrative data to evaluate the association between BMI and OS among patients receiving ICIs. Methods: We used administrative data deterministically linked across databases to identify a cohort of solid tumors patients initiating ICI therapy in Ontario, Canada from June 2012 to October 2018 and obtained information on socio-demographics including BMI at start of ICI, clinical covariates, and OS. We applied multivariable Cox proportional hazards models to evaluate the impact of BMI on OS, adjusting for sex, age, cancer center, autoimmune history, recent hospitalization and comorbidity score. Subgroup analyses were performed based on disease site and sex. Results: Among 4863 patients, median age was 67, 57% male; 46% had lung cancer, 35% melanoma, 9% renal cancers; 40% received nivolumab, 36% pembrolizumab, 17% ipilimumab. Median BMI was 26.1, with 3% low, 29% normal, 27% overweight, 19% obese. Median OS 317 days. Overall, greater BMI was associated with better OS (aHR=0.98 per unit, 95% CI [0.97-0.99] p<0.001). When compared to normal BMI, obese (aHR=0.77 [0.70-0.85] P<0.001) and overweight patients (aHR=0.85 [0.78-0.93] p<0.001) had better OS while those with low BMI had poorer OS (aHR=1.39 [1.16-1.66] P<0.001). Among melanoma patients, those who were obese had better OS (aHR=0.84 [0.71-0.98] p=0.03) and low BMI patients had poorer OS (aHR=1.80 [1.20-2.69] p=0.004) when compared to normal BMI. For lung and renal patients, increased BMI was associated with better OS when BMI was evaluated continuously (aHRlung=0.99 per unit [0.98-1.00] p=0.05; aHRrenal=0.98 per unit [0.95-0.99] p=0.04), but no significant associations were observed when BMI was evaluated categorically (p>0.05). Among males, patients who were obese (aHR=0.70 [0.62-0.80] p<0.001) and overweight (aHR=0.80 [0.72-0.90] p<0.001) had better OS compared to those with normal BMI, while those with low BMI had poorer OS (aHR=1.58 [1.22-2.06] p<0.001). However, among females, low BMI were associated with poorer OS (aHR=1.29 [1.01-1.65] p=0.04) compared to normal BMI, while no significant associations with OS were observed for overweight (aHR=0.93,p=0.30) or obese (aHR=0.89, p=0.12) patients. Conclusions: BMI was identified as a potential prognostic factor among cancer survivors receiving ICIs where greater BMI was associated with better OS. This association varied by cancer type and sex and is particularly notable in melanoma and among males. Further studies understanding these prognostic associations are warranted.

Outcomes following long-term response to immune checkpoint inhibitors in patients with advanced melanoma.

9520 Background: Immune checkpoint inhibitors (ICI) targeting PD-1 and CTLA-4 can achieve durable responses. Historically, therapies in advanced malignancies were considered palliative, however long-term results from ICI melanoma studies suggest cure may be possible for some patients (pts). Despite clinical trial data, little is known about the risk, character, and clinical outcome of late recurrences after ICI. Methods: ICI treated pts with advanced melanoma who had a long-term disease control, defined as not requiring a subsequent line of systemic therapy within 3 years, were retrospectively identified at 11 centres. Those who had progressive disease managed with local therapies were included if no new systemic therapy was commenced within the 3 years. Demographics, disease characteristics, treatment, toxicity, recurrence patterns, management and outcomes were collected. Results: 567 pts were identified, with a median follow up of 7 years since start of therapy. At ICI commencement, 41% and 17% had M1c or M1d disease respectively, 26% had an elevated LDH, 33% were BRAF mutant and 24% had received prior therapy. The ICIs received were anti-PD-1 +/- an investigational agent (59.3%), anti-PD-1 plus anti-CTLA-4 (35.8%), or an anti-CTLA-4 (5%). The median duration of therapy was 18 months, with 31% of pts stopping due to toxicity. 63 pts (11.1%) had oligo-progression within 3 years from ICI start. 53 pts (9.3%) had progression after 3 years, with median time to progression of 16.3 months. Subsequent late progression was more common in those who had oligo-progression within 3 years of treatment compared to those who had not (14/63, 22% vs 39/504, 7.7%, P<0.001). The risk of late progression was lower in those who achieved a complete response (CR) compared to those without a CR (23/369, 6.2% vs 30/198, 15.2%, P<0.001). The landmark 5 year PFS was 95% compared to 89% in those with or without a CR respectively. Duration of therapy, treatment cessation due to toxicity, or corticosteroid use were not associated with the risk of late progression. Most late progression occurred within year 3 to 5 (38/53, 72%). 15 pts who progressed after 3 years were managed with local therapy alone. In progressors retreated with PD-1 alone as the next subsequent therapy, 14 of 26 (54%) responded (7 CR, 7 PR). In the total cohort, there were 31 (5.5%) deaths, 7 (1.2%) from melanoma. Of the pts with a CR, 14 (3.7%) died, only 1 (0.3%) from melanoma. Of the 53 pts who progressed after 3 years, 10 (19%) died, 7 (13%) from melanoma. Conclusions: In this population of pts with advanced melanoma with long term disease control from ICI, the risk of subsequent disease progression and death was low (1.2%). Predictors for late progression after 3 years were a non-CR best response and prior progression within 3 years. This and other data suggest a significant proportion of long-term ICI responders are likely cured, and may inform frequency and duration of follow up.

Safety and efficacy of immune checkpoint inhibitors (ICI) in patients (pts) with pre-existing neurologic autoimmune diseases (NAID) and Parkinson's disease.

2653 Background: Patients with pre-existing NAID often flare with ICIs; neurological (neuro) immune related adverse events (irAEs) are often morbid or fatal, and little is known about safety of ICI in pts with NAID and other neuro conditions (e.g. Parkinson’s). Thus, we aimed to determine their safety and efficacy in these contexts. Methods: We retrospectively analyzed 71 pts from 5 institutions receiving ICIs with NAIDs and Parkinson’s disease. NAIDs included multiple sclerosis (MS), myasthenia gravis (MG), inflammatory neuropathy, transverse myelitis, Lambert-Eaton, myotonic dystrophy, and multifocal motor neuropathy. We collected demographics, cancer outcomes, NAID characteristics, and safety outcomes. We used descriptive statistics to analyze treatment outcomes, NAID flares, and irAEs. Results: We collected 71 pts, 40 with NAID and 31 with Parkinson’s. 24 had melanoma, 12 non-small cell lung cancer (NSCLC), 3 small cell lung cancer (SCLC), 6 urothelial/bladder, 4 renal cell carcinoma, and 22 other; 60 had metastatic and 11 had localized disease. Median age at ICI start was 72 years (61% male, 39% female); 8 received combination ICI and 63 received monotherapy. Of 40 pts with NAID, 30% had either NAID flares or neurologic irAEs and 33% experienced other (non-neuro) irAEs (Table). Toxicities were particularly severe in MG; 70% (n=7) had MG flare/neuro irAE, 3 of which were fatal. In addition, 31 had Parkinson’s; of these, 12.9% (n=4) had Parkinson’s flares, 3% (n=1) had neuro-irAEs, and 42% (n=13) had other irAEs. One pt died of grade 5 myocarditis/myositis following combination ICI (Table). 5 MS patients responded to therapy (23%), but none were those with NAID flare/neuro irAE. Both MG patients who had non-neuro irAEs responded to treatment. Conclusions: In this cohort of ICI treated pts with prior neuro disorders, we demonstrated that MG pts have high rates of MG flare/neuro irAEs, hospitalizations, and fatalities, but low response rates. In contrast, other NAID (particularly MS) as well as Parkinson’s appeared to have modest risks of flares/neuro irAEs. Notably, Parkinson’s pts had high rates of non-neuro irAEs and response rates. [Table: see text]

Delayed immune-related adverse events in patients with advanced melanoma treated with immune checkpoint inhibitors.

12047 Background: Immune checkpoint inhibitors (ICIs) have changed the treatment landscape of melanoma but can have serious or life-altering immune-related adverse events (irAEs). Most toxicities associated with ICIs occur within the first few months (mo) of treatment initiation, but delayed irAEs occurring 12 mo after ICI start are not well characterized. Further, clinical trials often have limited follow-up of AEs and thus, real world data is valuable. Methods: Patients (pts) ≥18 years with advanced melanoma who received ≥1 cycle of an ICI at BC Cancer from 2012-2019 with ≥12 mo of follow-up from time of ICI initiation were identified using the BC Cancer Registry and Pharmacy databases. Data on baseline clinicopathologic factors prior to the first cycle of ICI, and delayed irAE history and management were extracted. Delayed irAEs were graded using CTCAEv5. Results: In total, 530 pts treated with ≥1 cycle of an ICI were identified of which 309 pts had ≥12 mo of follow-up. Median follow-up for alive pts was 65.3 mo (13.0-143.5 mo). 96 (31%), 147 (48%), 19 (6%), and 47 (15%) pts received combination ICI (nivolumab/ipilimumab ± nivolumab maintenance), PD-1 inhibitor monotherapy (nivolumab or pembrolizumab), CTLA-4 inhibitor monotherapy (ipilimumab), and sequential CTLA-4 and PD-1 inhibitors, respectively. A total of 142 delayed irAEs were recorded in 94 (30%) pts. Median time to onset of delayed irAEs was 20.0 mo (12.2-80.6 mo). The most common delayed irAEs were dermatologic (27%), gastrointestinal (23%), and rheumatologic (20%). Most delayed irAEs were grade ≤2 (84%), but some were grade ≥3 (16%). Of individual delayed irAEs, 75 (51%) occurred on ICI treatment at time of onset, 39 (26%) after ≤3 mo of the last ICI cycle, and 34 (23%) after >3 mo of the last ICI cycle. 79 (56%) and 20 (14%) delayed irAEs were treated with systemic steroids and immunomodulators, respectively. Further, 12 (8%) delayed irAEs led to hospitalization, and 64 (45%) required subspecialty consultation. Pts with a history of autoimmune disease were more likely to have a delayed irAE (p=0.02), as were pts who achieved a partial or complete response (p=0.02). There was a trend towards a greater frequency of delayed irAEs in pts treated with PD-1 (37%) compared with combination (28%), CTLA-4 (11%), or sequential CTLA-4 and PD-1 (28%) (p=0.068). Conclusions: Delayed irAEs occurred in almost a third of pts with advanced melanoma treated with ICIs and followed for at least 1 year. Extended follow-up to monitor for delayed irAEs should be considered as many events required immunosuppressive therapy and rarely, may be life threatening. [Table: see text]

Relationship between dynamic changes in circulating tumor fraction and real-world imaging with real-world survival in patients with solid tumors treated with immunotherapy.

3046 Background: There is an unmet need for a sensitive biomarker that can determine which patients will confer long term benefit from immune checkpoint inhibitors (ICI). While radiologic imaging is the current standard of care for assessing ICI response, imaging can be difficult to interpret and is typically only assessed at 3 month intervals. Dynamic changes in circulating tumor fraction (TF) is a potential biomarker for monitoring ICI response. Here we evaluate the clinical benefit of a molecular biomarker, xM for treatment response monitoring (TRM), in addition to imaging, in a real-world (rw), pan-cancer cohort treated with ICIs. Methods: Using the Tempus liquid biopsy assay, ctDNA TF was computed by applying an ensemble algorithm incorporating copy number variant data and pathogenic variant allele frequencies. Deidentified patient records from the Tempus multimodal database were analyzed if patients had a baseline xF test ≤ 40 days prior to the start of ICI (alone or in combination with chemotherapy [CT], median = 13 days) and an on-treatment xF test 15-180 days post-ICI (median=93 days) and clinical response evaluated via imaging 15-126 days post ICI (median=77 days). Molecular responders (MR) were defined as patients with a ≥ 50% decrease in TF between tests. Rw-imaging, as documented by a provider in their clinical notes, was categorized as complete response (CR), partial response (PR), stable disease (SD), or progressive disease (PD), Rw overall survival (rwOS) was defined as time from the imaging date closest to on-treatment xF test to death. A likelihood ratio test at a two-sided 5% significance level was performed to assess if a Cox proportional hazards model incorporating both xM Monitor and rw-imaging as covariates (full model) had predictive power over a reduced model with only rw-imaging as a covariate. Results: The evaluable cohort (N=51) – 53% female, median age 64 yrs – had >10 advanced solid tumors (NSCLC 29% and breast cancer 18%). The majority of patients (69%) received ICI + CT, while 31% received ICI alone. 24 patients achieved MR (79% on ICI monotherapy, 21% on ICI + CT). Concordance of response markers is shown in the table. In the full model, xM was a significant predictor of rwOS (HR=0.33 [0.13, 0.84], p=0.02). The added information provided from xM was significant and superior compared to the reduced model of only rw-imaging (p=0.02). For patients with nMR and CR/PR/SD predicted median survival was 10 months whereas for patients with MR and CR/PR/SD predicted median survival was 16 months. Conclusions: MRs achieved significantly longer rwOS than nMRs and provides significant power in predicting rwOS beyond rw-imaging response. xM used for TRM can help identify nMRS who can discontinue therapy and be spared ICI toxicity. [Table: see text]

Safe Stop IPI-NIVO trial: early discontinuation of nivolumab upon achieving a complete or partial response in patients with irresectable stage III or metastatic melanoma treated with first-line ipilimumab-nivolumab – study protocol

BackgroundPatients with irresectable stage III or metastatic melanoma presenting with poor prognostic factors are usually treated with a combination of immune checkpoint inhibitors (ICIs), consisting of ipilimumab and nivolumab. This combination therapy is associated with severe immune related adverse events (irAEs) in about 60% of patients. In current clinical practice, patients are usually treated with ICIs for up to two years or until disease progression or the occurrence of unacceptable AEs. The incidence of irAEs gradually increases with duration of treatment. While durable tumour responses have been observed after early discontinuation of treatment, no consensus has been reached on optimal treatment duration. The objective of the Safe Stop IPI-NIVO trial is to evaluate whether early discontinuation of ICIs is safe in patients with irresectable stage III or metastatic melanoma who are treated with combination therapy.MethodsThe Safe Stop IPI-NIVO trial is a nationwide, multicentre, prospective, single-arm, interventional study in the Netherlands. A total of 80 patients with irresectable stage III or metastatic melanoma who are treated with combination therapy of ipilimumab-nivolumab and have a complete or partial response (CR/PR) according to RECIST v1.1 will be included to early discontinue maintenance therapy with anti-PD-1. The primary endpoint is the rate of ongoing response at 12 months after start of ICI. Secondary endpoints include ongoing response at 24 months, disease control at different time points, melanoma specific and overall survival, the incidence of irAEs and health-related quality of life.DiscussionFrom a medical, healthcare and economic perspective, overtreatment should be prevented and shorter treatment duration of ICIs is preferred. If early discontinuation of ICIs is safe for patients who are treated with the combination of ipilimumab-nivolumab, the treatment duration of nivolumab could be shortened in patients with a favourable tumour response.Trial registrationClinicalTrials.gov ID NCT05652673, registration date: 08–12-2022.

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.

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.