Dose Of Immune Checkpoint Inhibitors Research Articles

Increased myositis and possible myocarditis in melanoma patients treated with immune checkpoint inhibitors in the COVID-19 era.

Immune checkpoint inhibitor (ICI)-mediated myocarditis results in significant morbidity and mortality. At our institution, we noted an increased incidence of ICI-mediated myocarditis cases, leading to further investigation in our database of advanced melanoma patients treated with ICI therapy. A single-center, retrospective cohort analysis of patients with advanced melanoma identified cases of ICI-mediated myocarditis and myositis. 366 patients with advanced melanoma received a dose of ICI from September 2014 to October 2019. Of these patients, there were 0 cases of ICI-mediated myocarditis (0%, 95% CI 0%-1.0%) and 2 cases of ICI-mediated myositis (0.55%, 95% CI 0.07%-1.96%). From November 2019 to December 2021, an additional 246 patients with advanced melanoma were identified. Of these patients, 10 (4.1%, 95% CI 1.97%-7.35%) developed ICI-mediated myocarditis and 10 developed ICI-mediated myositis. Our study suggests an increase in prevalence of ICI-mediated muscle damage including myositis and myocarditis in the COVID-19 era. Differentiation of these patients and further risk stratification may allow for development of guidelines for nuanced management of this serious complication.

Efficacy and safety of low-dose versus standard-dose immune checkpoint inhibitor as monotherapy in patients with solid tumors: A meta-analysis and systematic review.

188 Background: Immunotherapy is a novel anti-cancer therapy with different mechanisms compared with chemotherapy. Several studies have reported that low dose of immune checkpoint inhibitors (ICIs) is effective. However, it is unknown whether the efficacy of low-dose immunotherapy is inferior to that of standard dose immunotherapy. We aimed to compare the existing randomized clinical trials on the efficacy of immunotherapy at low dose and standard dose as a single agent for patients with solid tumors. Methods: We searched PubMed, EMBASE, and the Cochrane Library for randomized clinical trials with the clinical outcomes of low dose and standard dose of programmed cell death-1 (PD-1)/programmed cell death ligand 1 (PD-L1) inhibitor as monotherapy until November 30, 2023. The low dose is defined as lower than the dose approved by FDA. The hazard ratio (HR) and 95% confidence interval (CI) of overall survival (OS) and disease control rate (DCR) were collected. The Stata 15.0 software was used to analyze the data. Results: Twenty-two studies with 3226 patients with five ICIs for 22 solid tumors were included. There is no difference in OS (HR 1.12, 95% CI = 0.97-1.31; p > 0.05), ORR (Odds ratio (OR) 0.92, 95% CI = 0.76-1.11; p > 0.05) and DCR (OR 0.83, 95% CI = 0.65-1.06; p > 0.05) for patients with low dose and standard dose of PD-1/PD-L1 inhibitors. Conclusions: Our results suggested that PD-1/PD-L1 inhibitor as monotherapy with a low dose may be as effective as standard dose for patients with solid tumors. The regular dose-response relationship may not be appropriate for ICIs. Further work is needed to explore the optimal dose of ICIs based on the comprehensive consideration of efficacy, safety, and economic assessment.

Real-World Outcomes of Immunotherapy for Melanoma Brain Metastases in New Zealand.

Melanoma brain metastases (BMs) are associated with poor survival. Combination immune checkpoint inhibitors (ICIs) with anti-PD1 and anti-CTLA-4 are the international standard-of-care treatment. Most landmark clinical trials excluded real-world patients with symptomatic disease, poor performance status (PS), and steroid use. Despite the high incidence of melanoma in New Zealand (NZ), the only publicly funded systemic treatment is anti-PD1 monotherapy. The real-world outcomes for BMs after ICIs in NZ are unknown. Medical records of patients with melanoma BMs in seven cancer centers across NZ between September 1, 2016, and September 1, 2020, were evaluated. Clinicopathologic characteristics, treatment, intracranial (IC) tumor response rates, IC progression-free survival, and overall survival (OS) are reported. One hundred and forty-four patients received at least one dose of ICI. One hundred and thirty-three (93%) patients received anti-PD1 monotherapy. Almost a quarter of patients had poor baseline PS, 56% were symptomatic, and 33% had corticosteroids. Patients also received local therapies: 61 (42%) patients underwent surgery, 42 (29%) received whole brain radiation, and 47 (33%) received stereotactic radiation. The median OS was 15 months, and a third of patients were alive at 2 years. The toxicity of ICIs was at 28% and 15% for Common Terminology Criteria for Adverse Events grade 1-2 and 3-4 events, respectively. Of the patients who are still alive, 76% of patients remained symptomatic neurologically at last follow-up. Most patients in this NZ real-world study were symptomatic and received anti-PD1 monotherapy. Approximately one-third of treated patients are alive at 2 years, but most patients remained symptomatic. This highlights the need for more effective treatment and prospective management of their neurologic rehabilitation needs.

Long-term survivals of immune checkpoint inhibitors as neoadjuvant and adjuvant therapy in dMMR/MSI-H colorectal and gastric cancers

BackgroundThe long-term survival benefit of immune checkpoint inhibitors (ICIs) in neoadjuvant and adjuvant settings is unclear for colorectal cancers (CRC) and gastric cancers (GC) with deficiency of mismatch repair (dMMR) or microsatellite instability-high (MSI-H).MethodsThis retrospective study enrolled patients with dMMR/MSI-H CRC and GC who received at least one dose of neoadjuvant ICIs (neoadjuvant cohort, NAC) or adjuvant ICIs (adjuvant cohort, AC) at 17 centers in China. Patients with stage IV disease were also eligible if all tumor lesions were radically resectable.ResultsIn NAC (n = 124), objective response rates were 75.7% and 55.4%, respectively, in CRC and GC, and pathological complete response rates were 73.4% and 47.7%, respectively. The 3-year disease-free survival (DFS) and overall survival (OS) rates were 96% (95%CI 90–100%) and 100% for CRC (median follow-up [mFU] 29.4 months), respectively, and were 84% (72–96%) and 93% (85–100%) for GC (mFU 33.0 months), respectively. In AC (n = 48), the 3-year DFS and OS rates were 94% (84–100%) and 100% for CRC (mFU 35.5 months), respectively, and were 92% (82–100%) and 96% (88–100%) for GC (mFU 40.4 months), respectively. Among the seven patients with distant relapse, four received dual blockade of PD1 and CTLA4 combined with or without chemo- and targeted drugs, with three partial response and one progressive disease.ConclusionWith a relatively long follow-up, this study demonstrated that neoadjuvant and adjuvant ICIs might be both associated with promising DFS and OS in dMMR/MSI-H CRC and GC, which should be confirmed in further randomized clinical trials.

Immune Checkpoint Inhibitors-Induced Endocrinopathies: Assessment, Management and Monitoring in a Comprehensive Cancer Centre.

To determine the incidence, presentation, frequency and management of immune checkpoint inhibitors (ICI)-related endocrinopathies in a comprehensive cancer centre in Oman, particularly with programme death 1/programme death-ligand 1 (PD-1/PD-L1) inhibitors. A high number of patients treated with PD-1/PD-L1 inhibitors for the management of solid tumours developed endocrinopathies. This is a retrospective study of patients admitted to Sultan Qaboos Comprehensive Cancer Care and Research Centre (SQCCCRC) from August 2021 to December 2022. All adults diagnosed with solid cancers and have received at least one dose of ICIs were included. Patients with incomplete data were excluded from the analysis. Data regarding the ICI-induced endocrinopathy were collected. A total of 139 patients were included in the study of which 58% were females. The median age of the cohort was 56 years. The incidence of endocrine-related adverse events was 28%. The mean time for the development of endocrine adverse events after treatment initiation was 4.1 ± 2.8 months. Of the patients who developed toxicity, 90% had hypothyroidism. Ten patients developed hyperthyroidism, two patients were diagnosed with secondary adrenal insufficiency/hypophysitis and one patient developed Type 1 diabetes mellitus (DM). Using univariable logistic regression weight and body mass index (BMI) significantly impacted the development of endocrine immune-related adverse events (irAEs). This is the first study from the Sultanate of Oman to assess PD-1/PDL-1 ICI-induced endocrinopathies. The most common endocrine adverse event is thyroid dysfunction, mainly hypothyroidism followed by hyperthyroidism. Hypophysitis, primary adrenal insufficiency and CIADM occur less frequently, but have a more significant effect on the patient's health. The treating physician should be aware of ICI-induced endocrinopathies, screening and treatment. Furthermore, our study showed that patients with a higher BMI have a greater risk of developing irAES. Further studies are needed to establish the predictors of endocrine irAEs.

Prospective cardiovascular events in patients with advanced thoracic cancer treated with immune checkpoint inhibitor

IntroductionMyocarditis is the most lethal cardiovascular immune related adverse events with a low incidence, depending on the studies. We prospectively studied the potential interest of a systematic screening to early detect immune related myocarditis and confirm the incidence of immune-induced myocarditis in advanced lung cancer and the impact of troponin systematic screening in early detection of other major cardiovascular events (MACE). Material and methodsThis prospective bicentric study includes adults who received at least one dose of immune checkpoint inhibitor (ICI) for advanced lung cancer. Cardiac biomarkers dosage, ECG and transthoracic echography (TTE) were done at baseline. Diagnosis of myocarditis was based on European Society of Cardiology recommendations. MACEs were reported during the observation period. ResultsAmong 298 patients, 5 (1.68 %) immune-induced myocarditis occurred, all being asymptomatic with at first troponin elevation, treated by corticosteroids and ICI’s discontinuation. No attributable death occurred, and no specific clinical characteristics were identified with myocarditis onset. Three patients were rechallenged with ICI after troponin normalization in the absence of other therapeutic options. Recurrence occurred in 2 patients, with a re-increase of troponin and a de novo modification of the ECG. Systematic cardiovascular screening also led to 14 cardiovascular diseases detection and 11 MACEs during ICI. ConclusionSystematic cardiovascular screening has uncovered slightly more immuno-induced myocarditis cases than reported previously, but without altering treatment strategies due to their subclinical nature. Additionally, it helps detecting other cardiovascular diseases in this comorbid population.

A single institution review of immunotherapy use, adverse events, and outcomes in early-onset cancer.

e23320 Background: A significant portion of cancer patients are treated with immune checkpoint inhibitors (ICI) and many experience immune related adverse events (irAE) which impact treatment and outcomes. A paucity of data exists related to use of ICIs in Early Onset Cancers (EOC), their irAE, and its correlation to outcomes. Methods: A single institution database of immunotherapy use from an NCI-designated cancer center (NCI-CC) was reviewed with patients treated from 2010-2019. Two cohorts were examined: EOC (age ≤50 at diagnosis), and age > 50. Clinically significant irAEs were defined as those requiring hospitalization (≥grade 3). Pearson's Chi-squared test and Fisher's exact test were used for analysis. Significance was defined as p < 0.05. Results: A total of 1067 patients were identified, 173 were EOC. Race and ethnicity were similar between groups, the EOC group had significantly higher proportion of females, private insurance, working, single, treated at main campus, and ECOG 0. Main cancer types in EOCs were skin cancers (38.2%), lung (16.2%), and heme malignancies (11.6%); those > 50 were lung (46.6%), skin cancer (21.6%), and GU malignancies (11.2%). Stages of cancer were not statistically different nor was type or doses of ICI. EOCs were more likely to get a greater number of ICIs. IrAE requiring hospitalization were similar between groups; 20 (11.6%) in EOC vs 95 (10.6%) in > 50. There was no difference in the incidence of specific irAEs. Further stratification of EOC cohort by age group 13-30, 31-40, and 41-50 demonstrated no difference in experience of an irAE. Ipilimumab had the highest incidence of irAE in EOC; 12 (75.0%) vs 52 (33.1%), as did receiving 2+ ICIs: 11 (68.8%). The number of doses of a specific ICI was not correlated to irAE in EOC. EOC patients without an irAE were more likely to have a disease response; either stable disease, partial response, or a complete response: 21 (70.0%) vs 1 (12.5%); there was no difference in mortality. Conclusions: In a single NCI-CC review of ICI use, EOC had no difference in ≥grade 3 irAEs or in specific irAEs relative to older adults. Within EOCs, those who experienced a significant irAE were more likely to have received Ipilimumab or 2+ ICIs and were less likely to obtain a response to treatment, although mortality was not different. [Table: see text]

Impact of immune-related adverse events (irAE) onset on disease response and survival in patients (pts) with head-neck cancer treated with immune check point inhibitors (ICI).

6028 Background: ICI or combination chemo-immunotherapy are the mainstay of therapy for metastatic head-neck squamous cell carcinoma (mHNSCC) due to durable responses in certain pts. irAEs have emerged as a new challenge in the management of these pts. Some studies suggest a positive correlation between irAE onset and ICI efficacy in other cancers, however, whether such an association exists in HNSCC remains incompletely explored. Methods: We performed a retrospective, single-center cohort study of pts ≥ 18 years of age, with histologically confirmed mHNSCC who received ≥ 1 dose of ICIs at the University of Virginia Comprehensive Cancer Center, VA, USA between 2013-2022. Demographics, disease and treatment characteristics, and clinical outcomes related to irAEs and ICI re-challenge were analyzed. IrAEs were graded using CTCAE v4.0 criteria by chart review. Independent sample t-tests and chi-square analyses were used for univariate comparisons. Median PFS and OS from ICI therapy initiation were estimated using Kaplan-Meier methodology and censored at date of last follow up. P-values <0.05 were considered statistically significant. Results: Of 1979 pts who received ICI, 110 had mHNSCC (72.7% male; 84.5% White) with a median age of 62.4 years. ICI type included pembrolizumab or nivolumab in 109 pts, and nivolumab/ipilimumab in one pt. 53 (48%) pts experienced any grade irAE and 12 pts (11%) experienced >1 irAE. The most common irAEs were hypothyroidism (30.4%), dermatitis (14.3%), and hepatitis (10.7%). CTCAE ≥G3 irAEs were seen in 22.6% pts (n=12). These included hepatitis (n=3), colitis (n=3), hypothyroidism (n=1), arthritis (n=1), pneumonitis (n=1), adrenal insufficiency (n=1), vasculitis (n=1), and cardiomyopathy (n=1). Men (62% vs 37%, p= 0.015) and pts with prior radiation therapy (83% vs 17%, p=0.047) were more likely to experience irAEs. Treatment interruption/discontinuation occurred in 43% pts with irAEs. Topical/supportive therapy was required in 52.8%, and 35.8% required systemic corticosteroids, with more than half experiencing complete irAE resolution. A statistically significant association was observed between irAE onset and objective response rate (68% vs 39%, p= 0.009). 12 pts underwent ICI re-challenge, resulting in partial response in 3 (25%), stable disease in 4 (33.3%) and progressive disease in 3 (25%) pts. There was no statistically significant difference in PFS (4.9 vs 9.7 months, p = 0.731) or OS (30.5 vs 21 months, p = 0.159) in irAE vs non-irAE groups, respectively. Conclusions: irAEs onset was associated with improved best response to ICI therapy in mHNSCC. Although OS was numerically superior in the irAE group, it did not meet statistical significance. ICI re-challenge is feasible in select pts, however further studies are needed to evaluate long term benefit of ICI re-challenge.

Predictors of poor response to immune-checkpoint inhibitor (ICI) treatment among patient with hepatocellular carcinoma (HCC).

e16212 Background: No established risk factors or toxicity biomarkers exist for HCCs treated with ICI, even though they are commonly used in clinical practice. The outcomes in real-world practice are worse than those reported in clinical trials. This retrospective review aims to identify HCC patients at high risk of failing ICI therapy. Methods: HCC patients who received at least one ICI dose between 1/1/2017 and 5/30/2023 (before tremelimumab/durvalumab approval) at the Ohio State University were included in this study. The patient's baseline (BL) characteristics (at the first dose of ICI) were extracted with immune-related adverse event (irAE) details and survival outcomes. We examined BL characteristics significantly different in poor (progression-free survival (PFS) ≤ median (m)) and worst (PFS ≤ 25% percentile) responders, and poor (overall survival (OS) ≤ m) and worst (OS ≤ 25% percentile) survivors. Chi-square test and logistic regression were performed using JMP Pro 17 (SAS Institute Inc., Cary, NC). Results: Our cohort included 53 HCC patients. The median age was 66 years (range 40-86), with 81% male and 85% White (13% African American and 2% other). The median OS and PFS were 19 months (m) (95% confidence interval [CI], 8-26) and 5m (95% CI, 2-9), respectively. The poor responders (PFS ≤5m, N = 30) had patients with significantly higher alcohol history (AHx, 90% vs. 70%) and mean alpha-fetoprotein (AFP, 44, 155 vs. 811 ng/mL) levels, a higher proportion of Child-Pugh (CP) C (A/B/C %, 53/27/20 vs. 53/47/0), and negligible bevacizumab (bev, 77 vs. 24) use, all (p < 0.05). The worst response group (PFS ≤2m, N = 16), furthermore, had significantly (p < 0.05) higher Albumin-bilirubin (ALBI) grade (G) 3 patients (50% vs. 16%), higher mean total bilirubin (2 vs. 1,2 ng/mL), lower tyrosine-kinase inhibitor (TKI, 7% vs. 46%), and lower mean albumin (Ab, 3 vs. 3.4) levels. A significantly (p < 0.05) higher fraction (fx) of poor survivors (OS ≤19m, N = 33) got ICI In the first or second line (85% vs. 45%) and did not receive any locoregional therapy (LRT, 66% vs. 35%). The worst survivors (OS ≤8m, N = 14) got ICI in the first line (100% vs. 59%, p = 0.04, and significantly (p < 0.05) lower Alb (3 vs. 3,4) and higher AFP (90620 vs. 3104) levels. The irAE group (N = 10, 19%) had higher AFP (115289 vs. 3482, p = 0.01) and a lower distant metastasis rate (20% vs. 58%, p = 0.02), and none of them received bev (0% vs. 30, p = 0.04). Conclusions: Response to ICI depends on BL liver function (AHx, ALBI, CP, Alb) and combination therapy (bev). Survival depends on HCC management up to the administration of ICI (LRT and TKI).

Incidence and time to onset of immunotherapy-related adrenal insufficiency in the I-SPY2 trial.

584 Background: I-SPY2 was the first randomized trial to demonstrate an improvement in pCR and EFS when Immune Checkpoint Inhibitors (ICI) were added to standard neoadjuvant chemotherapy. This finding was validated in the phase 3 KEYNOTE 522 trial for triple-negative breast cancer, leading to approval of pembrolizumab (pembro) in this setting. ICIs add the risk of immune-related adverse events (irAEs); while most irAEs are reversible, endocrinopathies appear to persist. Higher rates of adrenal insufficiency (AI), either from primary adrenalitis or hypophysitis, have been reported with ICI-based therapy (tx) in early breast cancer (EBC) compared to advanced disease. Here we describe the incidence and time of onset of AI with ICI-based tx in I-SPY2. Methods: I-SPY2 is a multicenter, phase 2 trial using response-adaptive randomization within biomarker subtypes defined by hormone receptor, HER2, and MammaPrint status to evaluate novel agents in the neoadjuvant setting in patients (pts) with high-risk EBC. Treatment included weekly paclitaxel (T) plus ICI-based tx x 4 cycles, followed by doxorubicin/cyclophosphamide (AC) every 2-3 weeks x 4. 6 completed investigational arms included ICIs: T+pembro x 4, T+pembro x 8 (+/- AC), T+pembro+SD101 (TLR9 agonist), T+durvalumab+olaparib, T+cemiplimab (cemi), and T+cemi+REGN3767 (anti-LAG-3). AI diagnoses were made by treating providers with review from two board certified endocrinologists. AI was defined as AM serum cortisol level < 3 mcg/dl in absence of recent glucocorticoid treatment. If ACTH was low or normal, pt was dx with hypophysitis; if ACTH was elevated, pt was dx with primary AI. Results: 442 pts in I-SPY2 received ICI-based tx; 11.8% (n=52) developed AI (primary+hypophysitis). Mean age of pts who developed AI was 47.3 vs 48.6 yrs in those who did not (p=0.44). Incidence of AI was highest in arms with dual immune modulation (18.1%) as compared to single ICI tx (8.5%). Median time to onset varied by arm, ranging from 92-204 days from first ICI dose. While some cases occurred during ICI tx (13.5%), the majority occurred between 12-24 wks after tx initiation, with 21.2% diagnosed after completion of all tx. The majority (94.2%) of pts with AI were symptomatic; the most common presenting symptoms included fatigue (59.6%), nausea (48.1%), and vomiting (34.6%). All pts with AI remain on glucocorticoid replacement tx. Conclusions: The incidence of AI in EBC is higher than has previously been reported in advanced disease, with higher rates observed in those tx with dual immune modulation. No correlation was observed with age; correlation of AI with response predictive subtype and other clinicopathologic features is ongoing and will be presented. Given the high incidence of AI in EBC, close monitoring in the peri/postoperative setting and education of pts and providers is critical, as risk persists even after completion of tx. Work to identify risk factors for AI is ongoing. Clinical trial information: NCT01042379 .

Immune checkpoint inhibitor-associated gastrointestinal adverse events in patients with colorectal cancer.

e14708 Background: Immune checkpoint inhibitors (ICI) are successfully used to treat microsatellite instability-high (MSI-H) tumors. While immune checkpoint inhibitor related colitis is a frequent and devastating immune related adverse event (irAE) of these agents, the incidence and characteristics of this inflammatory toxicity in patients with MSI-H colorectal cancers has not been examined. We aimed to describe the characteristics and clinical profile of patients diagnosed with luminal gastrointestinal irAE in patients treated with ICI for colorectal cancer in a tertiary cancer care center. Methods: This is a retrospective analysis that included adult cancer patients diagnosed with colorectal cancer that received ICI between 6/1/2014 and 12/31/2022. We report data on those that developed colitis as an irAE up to 3 months after the last dose of ICI confirmed by laboratory and/or imaging report. We included patients’ demographic characteristics, oncologic profile and outcomes as well as clinical course, endoscopic features as well as treatment and outcomes in terms of luminal gastrointestinal irAEs. Results: Out of 474 patients with colorectal cancer on ICI in our study period, only 18 developed a gastrointestinal irAE with an incidence of 3.8%. Patients were primarily Caucasian (88.8%) males (61.1%) with a median age of 69.5 years. The majority of these patients received combination therapy with anti-PD1/L1 and CTLA-4 (50%). 66.6 % received ICI for MSI-H colorectal cancer. 11.1% of our sample were noted to have a second cancer-melanoma. The major-ity of patients had grade 1-2 colitis (61.2%) and grade 1-2 diarrhea (88.8%). Only 5 patients underwent endoscopic evaluation of whom, 2 had ulcerative inflammation necessitating use of selective immunosuppressive therapy with biologics. 61.1% had to withhold cancer treatment due toxicity. With regards to other gastrointestinal irAEs among this population, 41.4% and 5.8% were noted to have liver and pancreas toxicity respectively, with a median CTCAE grade of severity 2. The most common treatment for these toxicities were steroids. Conclusions: Luminal gastrointestinal irAEs seem to occur less frequently and at a lower severity among patients with MSI-H colorectal cancer after checkpoint inhibitors exposure compared to the overall incidence of the same among other cancers reported in literature. Larger prospective studies are necessary to determine the role of tumor biology and the gut microbiome in the disease profile and severity of immune related adverse events of the GI organ system. [Table: see text]

Increasing serum complement component 1q is associated with worse prognosis in advanced non-small cell lung cancer treated with immune checkpoint inhibitors: a single-center, retrospective study.

There is a lack of readily available clinical markers of non-small cell lung cancer (NSCLC) immunotherapy efficacy. Previous studies have found that overexpressed complement component 1q (C1q) promotes macrophage M2 polarization and an immunosuppressive tumor microenvironment. This study aimed to evaluate the association between serum C1q and the efficacy of immune checkpoint inhibitors (ICIs) in patients with advanced NSCLC. A total of 168 patients with advanced NSCLC who received ICIs in the Renmin Hospital of Wuhan University were included in this study. Serum C1q levels were collected before and 3 weeks after immunotherapy treatment, together with other data on clinical and demographic characteristics. The primary outcome was overall survival (OS) (months from first dose of ICIs to death, censored at date of last follow-up). Secondary outcome was progression-free survival (PFS) [defined as months from first dose of ICIs to clinical or radiographic progression by Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST 1.1) or death, censored at date of last follow-up] and objective response rate (ORR) which was defined as rate of complete response (CR) or partial response (PR) at best response by RECIST 1.1. A total of 168 patients were included in this study, including 127 males (75.60%) and 41 females (24.40%). Thirty-nine patients achieved objective response (2 CR, 37 PR), and 111 patients (66.07%) had stable disease (SD) as best response. The ORR was 23.21% and the disease control rate was 89.28%. The upward trends of serum C1q levels between baseline and post-treatment were strongly associated with the shorter PFS [hazard ratio (HR) =1.554, 95% confidence interval (CI): 1.07-2.10, P=0.01] and OS (HR =1.444, 95% CI: 1.01-1.98, P=0.03). Moreover, taking the median OS 18.9 months as the cut-off of prognosis, receiver operating characteristic (ROC) analysis showed that serum baseline C1q yielded an area under the ROC curve of 0.785 (95% CI: 0.711-0.869). The optimal serum baseline C1q cut-off point to predict immunotherapy prognosis was 216.2 mg/L. These findings suggested that elevated serum C1q after ICIs treatment was related to a worse prognosis in NSCLC. Monitoring the baseline and dynamic data of C1q during hospitalization showed the potential to predict the prognosis of NSCLC patients.

Outcomes of Budesonide as a Treatment Option for Immune Checkpoint Inhibitor-Related Colitis in Patients with Cancer.

Current treatment guidelines for moderate to severe colitis (IMC) secondary to immune checkpoint inhibitors (ICI) recommend systemic corticosteroids as the primary therapy in conjunction with biologics, namely infliximab and/or vedolizumab. We aimed to explore the efficacy and safety of oral budesonide in the treatment of IMC. We performed a retrospective analysis at MD Anderson Cancer Center of adult cancer patients with a confirmed (based on clinical, radiographic and laboratory assessment) diagnosis of IMC between 1 January 2015 and 31 November 2022, treated with budesonide. Data collection included demographics, oncologic history, IMC-related information and outcomes up to 6 months after the last dose of ICI. Our sample (n = 69) comprised primarily of Caucasian (76.8%) females (55.1%). The majority of patients received combination therapy with anti-PD-1/L1 and anti-CTLA-4 (49.3%), and the most common malignancy treated was melanoma (37.6%). The median grade of diarrhea was 3 and of colitis was 2. Of the 50 patients who underwent endoscopic evaluation, a majority had non-ulcerative inflammation (64%) and active colitis on histology (78%). Budesonide was used as primary treatment at onset of IMC in 56.5% patients, as well as a bridging therapy from systemic corticosteroids in 33.3%. Less than half of the patients (44.9%) required additional therapies such as biologics or fecal microbiota transplant. Additionally, 75.3% of patients achieved full remission of IMC and 24.6% had a recurrence of IMC. ICI was resumed in 31.9% of patients and 17.4% received other forms of cancer therapies. Budesonide may be an effective strategy to treat and prevent the recurrence of IMC. The remission rates observed in our analysis with budesonide alone are comparable to systemic corticosteroids. Patients that require an extended duration of steroid exposure and those with moderate to severe colitis may benefit from budesonide given its lower risk of infection and complications. Furthermore, we observe that budesonide may serve as a successful bridge from systemic corticosteroids with subsequent biologic treatment. Larger prospective studies are necessary to determine the role of budesonide as well as its safety profile.

Sarcoid-like reactions to immune checkpoint inhibitors: Incidence, treatment course, and impact on cancer progression and survival

IntroductionSarcoid-like reactions (SLRs) to immune checkpoint inhibitors (ICIs) are a rare but increasingly recognized immune-related adverse event of which the clinical significance is unclear. MethodsWe conducted a retrospective cohort study at a tertiary academic center of consecutive patients who received at least one dose of ICI from 2013 to 2020. Patient characteristics, risk factors, and outcomes were compared between patients with and without SLR following ICI treatment. ResultsA total of 2963 cancer patients received at least 1 dose of ICI between 2013 and 2020, and 7 patients (0.24 %) developed SLR. There were no significant demographic differences between patients with and without SLR following ICI. SLRs occurred in 5 of 451 (1.07 %) melanoma patients and 2 of 840 (0.24 %) non-small cell lung cancer patients. Two of the 7 patients had multi-organ SLR, and both were symptomatic requiring systemic corticosteroids and permanent ICI discontinuation, while single organ SLR patients did not require immune suppression. Development of SLR did not appear to have negative impact on cancer progression or overall survival; in fact, a trend towards improved progression-free and overall survival was observed (median time: 1363 days vs 127 days, p = 0.091; 1387 days vs 428.5 days, p = 0.19, respectively). ConclusionsSLRs are a known but understudied complication associated with ICI therapy. Multisystem SLR patients were more symptomatic and required ICI discontinuation and immune suppression. Larger studies are needed to fully evaluate the impact of SLR on cancer outcomes.

Ocular Findings on Patients after Anti-PD-1/PD-L1 Antibodies Treatment: A Prospective Observation Report, A Pilot Study

Purpose: Immune checkpoint inhibitors (ICIs) cause ICI-related adverse events (irAEs) such as dry eye and uveitis, which can be severe, sometimes necessitating the suspension of ICI treatment. Retrospective studies have targeted ocular irAEs which can detect only moderate to severe symptomatic uveitis. To the best of our knowledge, this is the first prospective study on ocular irAEs. We aimed to investigate symptomatic and subclinical ocular changes in ICI-treated eyes, to identify early changes in ocular irAE and control conditions without suspending ICI treatment. Methods: 22 participants who began ICI treatment between July 2020 and July 2021 in Keiyu Hospital, Japan (3 women and 19 men; age, 69.1 ± 7.9 years, range, 53–83 years) were prospectively evaluated. The patients underwent ocular examinations before and 1, 3, and every 2 months after the initial dose of ICI. Examinations included measurement of best-corrected visual acuity, fundus biomicroscopy, spectral domain optical coherence tomography (OCT) and aqueous flare. Central choroidal thickness (CCT) was measured using OCT. Results: Among the 22 participants, 6 developed systemic irAEs. Of these 6 patients, one experienced ocular pain after ICI treatment, likely due to dry eye disease. We did not observe any change in CCT or aqueous flare, even in patients with systemic AEs. We were unable to ascertain whether CCT or aqueous flare are valuable clues for the early identification of ocular irAEs. We continue this prospective study with a larger sample size. Conclusions: Systemic irAEs are not necessarily accompanied by ophthalmological changes.

Effectiveness of Immune Checkpoint Inhibitors in Various Tumor Types Treated by Low, Per-Weight, and Conventional Doses at a Tertiary Care Center in Mumbai.

The cost of immune checkpoint inhibitors (ICIs) limits their accessibility to a small number of patients with cancer in low- and middle-income countries. Early-phase clinical trials have shown target inhibition and high activity at doses lower than those registered and evaluated in clinical trials. Here, we report everyday experience of using ICIs in 100 Indian patients, many of whom received lower doses of ICIs. Consecutive patients who received at least one dose of an ICI irrespective of tumor type at a tertiary care hospital in Mumbai, India, that was able to access ICIs for its patients were enrolled. The objectives were to study the doses used over a 3-year time period, and the effectiveness of therapy, assessed primarily by the overall response rate (ORR), overall survival (OS), and progression-free survival were secondary end points. Twenty-five patients were treated with conventional doses of ICIs, 29 patients received lower doses per body weight, and 46 patients received low-dose treatment. The median number of cycles received was 5 (range, 1-28). Seventy-eight patients received ICIs in a palliative setting. The median follow-up time was 10.2, 9.8, and 3.9 months for those receiving fixed approved dosing, per body weight dosing, and low-dose treatment, respectively. There was a trend with time to prescribe lower doses. Response evaluation was available for 92 patients. Twenty-one (five-adjuvant and 16-palliative) patients received ICIs only. The ORR did not differ statistically among different dosing groups, but comparisons are confounded by inclusion of different ICIs, different tumor sites, and concurrent treatments. The median OS was 6.8 (range, 4.6-9.0) months. Adoption of per-body weight and lower dosing of ICIs appears to give acceptable outcomes. Lower dosing can improve access and timely delivery of ICIs in low- and middle-income countries.

Effect of pre-treatment with EGFR-TKIs on immune checkpoint inhibitor-associated interstitial lung disease in lung cancer patients: Analysis using a Japanese claims database.

Immune checkpoint inhibitors (ICI) and epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKI) are key drugs for the treatment of EGFR mutation-positive lung cancer. While previous studies reported that the concomitant use of these drugs increases the risk of interstitial lung disease (ILD), the impact of sequential treatment on ILD risk is unknown. This study aimed to analyze the impact of EGFR-TKI pre-treatment on the risk of developing ILD after subsequent ICI administration. We conducted a retrospective study using a Japanese health insurance claims database. ILD-naive lung cancer patients who had first ICI administration during the screening period from July 2014 to February 2019 were selected. Patients who had ILD within 1 year of receiving the first ICI dose were included in the ILD group. Multivariate logistic regression analysis was conducted to evaluate the effect of pre-treatment with EGFR-TKI on the development of ICI-associated ILD. A total of 353 patients were included, of which 61 were included in the ILD group. The median time to onset of ILD after ICI administration was 3 months. Multivariate logistic regression analysis revealed that pre-treatment with EGFR-TKI was not associated with ICI-associated ILD (odds ratio: 0.26, 95% confidence interval: 0.033-2.01). Although further analyses are required to confirm our findings, this study indicated that pre-treatment with EGFR-TKI might not increase the ILD risk after ICI treatment.

Pan-cancer assessment of antineoplastic therapy-induced interstitial lung disease in patients receiving subsequent therapy immediately following immune checkpoint blockade therapy

BackgroundDrug-induced interstitial lung disease (DIILD) is a serious adverse event potentially induced by any antineoplastic agent. Whether cancer patients are predisposed to a higher risk of DIILD after receiving immune checkpoint inhibitors (ICIs) is unknown.MethodsThis study retrospectively assessed the cumulative incidence of DIILD in consecutive cancer patients who received post-ICI antineoplastic treatment within 6 months from the final dose of ICIs. There was also a separate control cohort of 55 ICI-naïve patients with non-small cell lung cancer (NSCLC) who received docetaxel.ResultsOf 552 patients who received ICIs, 186 met the inclusion criteria. The cohort predominantly comprised patients with cancer of the lung, kidney/urinary tract, or gastrointestinal tract. The cumulative incidence of DIILD in the entire cohort at 3 and 6 months was 4.9% (95% confidence interval [CI] 2.4%–8.7%) and 7.2% (95% CI 4.0%–11.5%), respectively. There were significant differences according to cancer type (Gray’s test, P = .04), with the highest cumulative incidence of DIILD in patients with lung cancer being 9.8% (95% CI 4.3%–18.0%) at 3 months and 14.2% (95% CI 7.3%–23.3%) at 6 months. DIILD was caused by docetaxel in six of these 11 lung cancer patients (54.5%). After matching, the cumulative incidence of docetaxel-induced ILD in patients with NSCLC in the post-ICI setting was higher than that in the ICI-naïve setting: 13.0% (95% CI 3.3%–29.7%) vs 4.3% (95% CI 0.3%–18.2%) at 3 months; and 21.7% (95% CI 7.9%–39.9%) vs 4.3% (95% CI 0.3%–18.2%) at 6 months. However, these were not significant differences (hazard ratio, 5.37; 95% CI 0.64–45.33; Fine–Gray P = .12).ConclusionsPatients with lung cancer were at high risk of developing DIILD in subsequent regimens after ICI treatment. Whether NSCLC patients are predisposed to additional risk of docetaxel-induced ILD by prior ICIs warrants further study.

Abstract 16450: Increased Monocyte Count and Neutrophil-to-Lymphocyte Ratio With ICI Myocarditis

Introduction: Diagnosing immune checkpoint inhibitor (ICI) myocarditis remains complex in practice, often requiring advanced imaging or invasive endomyocardial biopsy. We constructed an institutional cohort of patients who received at least 1 dose of ICI and developed probable or definite ICI myocarditis. Hypothesis: We hypothesized that routine serum biomarkers, including troponin I, neutrophil-to-lymphocyte ratio (NLR), monocytes, and AST/ALT, would be elevated and peak at diagnosis. Methods: This retrospective cohort study used EHR data from patients on ICI at a single academic institution who developed probable or definite myocarditis from 7/2015 - 1/2023. Inclusion criteria and diagnosis date were defined using Bonaca criteria and/or documented clinical consensus, e.g. initiation of steroids for presumed myocarditis. Primary outcomes were levels of troponin I/high sensitivity troponin I, monocytes, NLR, and AST/ALT. LOESS regression with default smoothing parameter α = 0.75 was used to evaluate biomarker patterns 7 days pre- and post- diagnosis. Results: We included 16 cases of myocarditis. At diagnosis, most patients had at least 1 significant elevation in troponin I (100%), AST (81%), ALT (63%), or monocytes (69%) while on ICI (Figure 1). After diagnosis, absolute monocyte and lymphocyte count initially decreased before rebounding. Serum NLR rose prior to and briefly after diagnosis (Figure 2). Conclusions: Peripheral cardiac and non-cardiac biomarkers change with ICI myocarditis. Further research on routine non-cardiac biomarkers associated with myocarditis and other ICI toxicities may help prevent high-grade adverse events.

Incidence and treatment of checkpoint inhibitor induced immune related adverse events in the emergency department.

438 Background: Immune checkpoint inhibitors (ICPis) are currently indicated for the treatment of various types of cancers. Through inhibition of the cancer cell’s checkpoint mediated T-cell evasion, ICPis allow for sustained T-cell activation and proliferation, resulting in increased cancer cell death. However, due to increased activation and proliferation of cytotoxic T-cells, ICPis have been associated with a wide spectrum of adverse effects, known as immune related adverse effects (irAEs). Although recently updated, the 2018 NCCN and ASCO guidelines state that treatment is based on the location and severity of irAEs. In general, grade 3 toxicities warrant suspension of ICPis and initiation of high-dose corticosteroids. Corticosteroids should then be tapered over the course of at least 4-6 weeks. The diagnosis of an irAE is challenging, toxicities may be misdiagnosed as there is a diverse familiarity with ICPis and their associated irAEs. Subsequently, care may be delayed, and patients may not receive appropriate guideline directed care. Methods: This multi-center chart review included 7 hospitals within a large health system. Our electronic health record was utilized to compile a report of patients who had received ICPIs within 12 months of presentation to an ED within the health system between 9/1/2019 and 9/1/2022. Assessed outcomes included incidence and type of irAE, time between last ICPi dose and presentation to the ED, steroid used for treatment, time to steroid, treatment driver, and the action that deviated from the 2018 ASCO/NCCN guideline directed treatment if applicable. Results: Of the 241 patients receiving an ICPi, 26 (10.8%) experienced an irAE that prompted a visit to an ED within our health system. Guideline directed treatment of irAE(s) was followed 76.9% of the time, with the steroid dose being too low (15.4%) and the steroid taper occurring too quickly (7.7%) being the two reasons for discordant treatment. Treatment started a median of 1.1 after presentation to an ED, with colitis as the most prevalent irAE in 11 patients (42%) presenting. For all patients, there was an average of 20 days between the last ICPi dose and presentation to ED. The main steroid used was methylprednisolone (42%). Conclusions: The 10.8% of patients who experienced an irAE that prompted a visit to an ED within our health system is a lower rate than what has been described in the literature previously, where rates of presentation to an ED due to an irAE ranged from 25-37%. This could be due to previous data coming from before or shortly after the publication of ASCO and NCCN guidelines in 2018, or because our outpatient medical staff has become more aware of irAEs and their appropriate treatment. Limitations include this review was retrospective, no patients had an irAE that was refractory to steroids, and the study period being soon after national guidelines were published.