Vogt-Koyanagi-Harada disease-like immune-related adverse event with concurrent exacerbation of uveitis and vitiligo.

Immune-Related Adverse Events and Outcomes in Patients with Advanced Non–Small Cell Lung Cancer: A Predictive Marker of Efficacy?

Immune checkpoint inhibitors (ICIs) have improved survival in patients with advanced melanoma but can be associated with a spectrum of immune-related adverse events (AEs), including both autoimmune-related AEs and other immune-related inflammatory AEs. These associations have primarily been evaluated in clinical trials that include highly selected patients, with older adults often underrepresented. To evaluate the association between use of ICIs and immune-related AEs (autoimmune and other immune related) among older patients with cutaneous melanoma. A population-based cohort study was conducted from January 1, 2011, to December 31, 2015. Data were analyzed from January 31 to May 31, 2021. With use of a linked database of Medicare claims and Surveillance, Epidemiology, and End Results (SEER) Program population-based cancer registries, patients of White race diagnosed with stages II-IV or unknown (American Joint Committee on Cancer, AJCC Cancer Staging Manual 6th edition) first primary cutaneous melanoma during 2011-2015, as reported to SEER, and followed up through December 31, 2015, were identified. Immune checkpoint inhibitors for treatment of melanoma. The association between ICIs and immune-related AEs ascertained from Medicare claims data was estimated using multivariable Cox regression with hazard ratios (HRs) and 95% CIs and with cumulative incidence accounting for competing risk of death. The study included 4489 patients of White race with first primary melanoma (3002 men [66.9%]; median age, 74.9 [range, 66.0-84.9] years). During follow-up (median, 1.4 [range, 0-5.0] years), 1576 patients (35.1%) had an immune-related AE on a Medicare claim. Use of ICIs (reported for 418 patients) was associated with autoimmune-related AEs (HR, 2.5; 95% CI, 1.6-4.0), including primary adrenal insufficiency (HR, 9.9; 95% CI, 4.5-21.5) and ulcerative colitis (HR, 8.6; 95% CI, 2.8-26.3). Immune checkpoint inhibitors also were associated with other immune-related AEs (HR, 2.2; 95% CI, 1.7-2.8), including Cushing syndrome (HR, 11.8; 95% CI, 1.4-97.2), hyperthyroidism (HR, 6.3; 95% CI, 2.0-19.5), hypothyroidism (HR, 3.8; 95% CI, 2.4-6.1), hypopituitarism (HR, 19.8; 95% CI, 5.4-72.9), other pituitary gland disorders (HR, 6.0; 95% CI, 1.2-30.2), diarrhea (HR, 3.5; 95% CI, 2.5-4.9), and sepsis or septicemia (HR, 2.2; 95% CI, 1.4-3.3). Most associations were pronounced within 6 months following the first ICI claim and comparable with or without a baseline history of autoimmune disease. The cumulative incidence at 6 months following the first ICI claim was 13.7% (95% CI, 9.7%-18.3%) for autoimmune-related AEs and 46.8% (95% CI, 40.7%-52.7%) for other immune-related AEs. In this cohort study of older adults with melanoma, ICIs were associated with autoimmune-related AEs and other immune-related AEs. Although some findings were consistent with clinical trials of ICIs, others warrant further investigation. As ICI use continues to expand rapidly, ongoing investigation of the spectrum of immune-related AEs may optimize management of disease in patients.

Minimal Toxicity Seen When Pembrolizumab Is Added to Tyrosine Kinase Inhibitors in Patients with Chronic Myeloid Leukemia and Persistently Detectable Minimal Residual Disease: Early Results from an Ongoing Phase II Trial (ECOG-ACRIN EA9171)

BackgroundImmune checkpoint inhibitors (ICIs) have revolutionized cancer therapy over the last decade. Despite the efficacy of ICIs, immune-related adverse events (irAEs) occur in over a third of treated patients and...

<h3>Background</h3> The benefit from immune checkpoint inhibitors (IO) is tempered by immune-related adverse events (IrAEs), which involve diverse organs, have varying biology, onset time, and severity. Several reports have found correlation between IrAE and better outcome, suggesting they may even serve as a surrogate of response, but studies are conflicting on the magnitude and significance of this correlation. Estimating the true incidence of IrAEs is particularly important in the early phase 1/2 trial setting, in order to avoid the risk of both over- and under-estimation. A key issue is the lack of IrAE diagnostic criteria, necessary to discriminate pure IrAEs from other treatment-related adverse events not sustained by an autoimmune process. <h3>Methods</h3> Of 421 patients enrolled in phase 1-2 trials, we identified patients treated with immune-oncology (IO) drugs and analysed clinical characteristics, temporal dynamics and correlation with survival of treatment-related events, identifying "High Confidence IrAEs" (HC IrAE) by careful reconsideration of available clinical parameters. We developed an IrAE Scoring System (ISS) based on 5 parameters, each ranging 0-2: available biopsy or specific test, response to immunosuppression, temporal correlation, evidence ruling out alternative cause, known IO relationship. Correlation with Overall Survival was explored by multivariate Cox proportional hazard analysis including multiple covariates (BMI, Age, tumor type, NLR, prior IO, prior Autoimmune disease, PS, baseline disease burden). To mitigate immortal time-bias, analyses were conducted i) at 2-month landmark and ii) modeling IrAEs as time-dependent covariate. <h3>Results</h3> 204 patients were treated with IO agents (41 with anti-PD(L)1 alone, 33 with non-PD(L)1 agents, 130 with combinations). 53 (25.9%) patients developed ≥ 1 treatment-related adverse event (85 total events). ISS score ranged from 0 to 8; by ROC analysis, a cutoff ≥ 5 achieved 100% specificity and 90% sensitivity to identify bona fide IrAEs. Based on this, we identified 3 groups of patients: 151 never experiencing an IrAE ("no-IrAE"), 33 low-confidence IrAE with ISS score 0-4 ("LC-IrAE") and 20 high-confidence IrAE with ISS 5-8 ("HC-IrAE"). Compared to no-IrAE, patients experiencing HC-IrAEs had significantly lower Hazard ratio (HR) both in landmark analysis (HR=?0.242, 95% CI 0.117-0.500, p=0.0001) and IrAE as time-dependent covariate analysis ?(HR=0.244, 95% CI 0.116-0.511, p=0.0001); HR for patients experiencing LC IrAE, instead, was not statistically significant (figure 1). <h3>Conclusions</h3> ISS criteria provide a simple system to identify high confidence IrAEs, leading to more reliable estimates of IrAE incidence with significant impact on survival. <h3>Ethics Approval</h3> The study was approved by the local ethics committee with number UID 3560

74 Background: Widespread use of immunotherapeutic agents has transformed the profile of adverse events associated with systemic cancer therapy. Management of immune-related adverse events (IRAEs) is contingent upon grading severity using the National Cancer Institute’s Common Terminology Criteria for Adverse Events (CTCAE). Nivolumab and Pembrolizumab were recently approved for metastatic non-small cell lung cancer (NSCLC). United States Food and Drug Administration (US FDA)-approved package label inserts provide guidance on IRAE management and are predicated on CTCAE grade, including when to discontinue drug. Currently, clinicians in the thoracic oncology group are documenting CTCAE grade of IRAEs infrequently, and management is varied. Methods: A retrospective chart review of baseline data revealed 45 patients (8 on Pembrolizumab, 37 on Nivolumab) who initiated immunotherapy for metastatic NSCLC between March 2015 and August 2016. A team of clinicians developed a process map from diagnosis of IRAE to initiation of toxicity management. Physicians were surveyed. The team’s aim is by February 1, 2017, at least 50% of patients who develop an IRAE on immunotherapy for metastatic NSCLC have documentation of toxicity grade using the CTCAE criteria. Results: The physician survey response rate was 12 of 16 (75%). Physicians reported not using grade to guide management of IRAEs over two thirds (67%) of the time. Time to look up CTCAE criteria and knowing that grade is needed ranked as the top barriers. At baseline, 18 of 45 (40%) patients had 22 IRAEs, of which 6 IRAEs (27%) had grading documented; all graded IRAEs (100%) were managed according to guidelines in the drug-specific package insert. IRAEs included hypothyroidism, pneumonitis, hepatitis, dermatitis, adrenal insufficiency, colitis, and encephalitis. Conclusions: Education on toxicity grading and ease of accessibility to information regarding management of IRAEs are needed. Because clinicians were engaged, a survey to evaluate the current process succeeded with a high response rate. At baseline, there are significant gaps and variability in current practice. Interventions are underway to standardize documentation of grade and management of patients experiencing IRAEs.

Immune-related adverse events (IRAE) pose a significant diagnostic and therapeutic challenge in patients treated with immune-oncology (IO) drugs. IRAEs have been suggested to correlate with better outcome, but studies are conflicting. Estimating the true incidence of IRAEs is particularly difficult in the early phase I/II trial setting. A key issue is the lack of IRAE diagnostic criteria, necessary to discriminate "pure" IRAEs from other treatment-related adverse events not sustained by an autoimmune process. In patients treated with immune-oncology (IO) drugs in phases I-II trials at our institute, we identified high confidence (HC) or low confidence (LC) IRAEs by clinical consensus. We empirically developed an IRAE likelihood score (ILS) based on commonly available clinical data. Correlation with outcome was explored by multivariate Cox analysis. To mitigate immortal time-bias, analyses were conducted (1) at 2-month landmark and (2) modeling IRAEs as time-dependent covariate. Among 202 IO-treated patients, 29.2% developed >1 treatment-related adverse events (TRAE). Based on ILS >5, we classified patients in no IRAE (n = 143), HC IRAE (n = 24), or LC IRAE (n = 35). hazard ratios (HR) for HC were significantly lower than LC patients (HR for PFS ranging 0.24-0.44, for OS 0.18-0.23, all P < .01). ILS provides a simple system to identify bona fide IRAEs, pruning for other treatment-related events likely due to different pathophysiology. Applying stringent criteria leads to lower and more reliable estimates of IRAE incidence and identifies events with significant impact on survival.

Immunotherapy-Related Adverse Effects When Treating Cancer #375.

480 Background: Immune related adverse events (IRAEs) with immune checkpoint inhibitor (ICI) therapy are well recognized, but predictors for IRAEs are not well defined. We aim to characterize the type, timing, and clinical risk factors associated with (w/) IRAEs in ICI-treated, advanced urothelial carcinoma (UC) and renal cell carcinoma (RCC) patients (pts). Methods: We retrospectively reviewed charts of pts w/ advanced UC and RCC who received at least 2 ICI doses at our institution from 1/1/10 to 10/31/18. Patient baseline characteristics, treatment course, and clinical outcomes were collected. IRAEs were identified and graded (GR) based on CTCAE (v.4.0). Fisher’s exact test was used to study the differences between pts w/ versus without IRAE. Results: Of the 71 pts identified (UC n = 53; RCC n = 18), 27 pts (38%) developed IRAEs with 42 total events (38% GR1, 60% GR2, and 2% GR≥3) [table]. The majority of pts with dermatitis (70%) also developed a secondary, systemic IRAE(s). Systemic steroid (SS) was required in 17 events. The median time to any IRAE was 17.5 weeks (w, range 1-93). ECOG ≤ 1 predicted IRAE development (p &lt; 0.05). No other characteristics (demographics, co-morbidities, metastatic sites, ICI type, line of therapy, and duration of ICI &gt; 12w) were associated with IRAE. Conclusions: In our study, good function status is associated with the development of IRAE. Time to IRAE ranged from immediately to 93w after initiating ICI. Clinical validation with additional datasets will be needed to confirm these findings. [Table: see text]

BackgroundImmune checkpoint inhibitors (ICIs) are limited by the high incidence of immune-related adverse events (irAEs) occurring in up to 40% of solid tumor patients on anti-PD-1 monotherapy 1 2 and...

<h3>Background</h3> Immune-related adverse events (irAEs) induced by immune checkpoint inhibitor (ICI) therapy can involve multiple organ systems, of which cutaneous irAEs (c-irAEs) are the most common.^1–5 Understanding co-occurrence patterns and...

6571 Background: Immune checkpoint inhibitors (ICIs) have been one of the most significant developments in Oncology over the last decade. Despite being very effective for certain patient subsets, they have a unique side effect profile different from conventional chemotherapy that can manifest as immune-related adverse events (IRAEs). With increasing ICI use, clinicians will increasingly encounter these adverse events and thus, adequate knowledge on recognition and management of IRAEs is very important. Methods: To assess physician knowledge on IRAEs of ICIs, an online survey was administered to resident physicians in internal medicine (IM), emergency medicine (EM) and family medicine (FM) as well as to faculty physicians in IM, and FM at 3 tertiary care hospitals in Indiana. Results: We sent the survey to 413 physicians out of which 155 responded with a response rate of 38%. Out of 155 physicians, 110 were residents and 45 were faculty (27 hospitalists and 17 primary care physicians). Pembrolizumab was identified as a checkpoint inhibitor correctly by 79% of physicians, nivolumab by 64% and ipilimumab by 55%. Twenty-five percent of physicians incorrectly believed infliximab and adalimumab were ICIs. Most physicians (93%) were able to identify the gastrointestinal tract as an IRAE site whereas only 57% and 67% were able to identify cardiovascular and renal systems as an IRAE site, respectively. Fifty-nine percent of physicians believed steroids negatively affect efficacy of ICIs and should be used with caution to treat IRAEs. Sixty-five percent of physicians incorrectly thought endocrinopathies due to IRAEs are usually reversible. Most physicians (79%) believed IRAEs most commonly manifest in the first 6 months of treatment. Forty-five percent of FM residents considered antibiotics as the mainstay of treatment in ICI associated immune mediated colitis; this was significantly different from EM (15%) and IM (8%) residents(p = 0.0004). When comparing between residency programs, on a scale of 0-100, IM residents felt significantly more comfortable identifying IRAEs secondary to ICIs (27.1±24.2) when compared to EM (12.2±12.7) and FM residents (9.4±13.8; p = 0.0009). There was no significant difference among IM (19.8±20.1), EM (11.9±13.6), and FM residents (11.6±18.9; p = 0.11) when comparing how comfortable they were in treating IRAEs. When asked what the best way would be to learn about IRAEs, 36% chose printed material and algorithms, 30% picked online teaching module and 30% chose one time in-person lecture from an Oncologist. Conclusions: Resident and faculty physicians in multiple specialties are not comfortable in the management and treatment of IRAEs due to ICIs. Given that most of these physicians are usually the first point of contact with patients, physician education on identification and treatment of IRAEs is needed. Early detection of these toxicities is critical for their resolution.

BackgroundImmune checkpoint inhibitors (ICI) associated neurotoxicity is a rare but serious immune-related adverse event (IrAE), and literature on immunotherapy (IO) re-challenge in these patients remains sparse.MethodsWe performed a single center...

While some literature has provided limited information about the potential cardiovascular risk and immune-related adverse events (irAEs) risk associated with PD-1/PD-L1 inhibitors in the treatment of Head and Neck Squamous Cell Carcinoma (HNSCC), the exact relevance is still uncertain. To assess the pharmacovigilance (PV), constituent ratio, severity, and reaction outcomes of major adverse cardiovascular events (MACE) and immune-related adverse events (irAEs) related to PD-1/PD-L1 inhibitors for HNSCC reported to the United States Food and Drug Administration Adverse Event Reporting System (FAERS). We analyzed reports of cardiovascular adverse events and irAEs associated with drug therapy for HNSCC submitted to FAERS from the 1st quarter 2015 to the 3rd quarter of 2023. Three PD-1/PD-L1 inhibitors were identified: nivolumab, pembrolizumab and durvalumab. Our primary composite endpoint was the PV of MACE and irAEs related to PD-1/PD-L1 inhibitors in the treatment of HNSCC, and the secondary endpoint was PV of other cardiovascular events. The software implemented was STATA 17.0 MP. 19,372 suspected drug-adverse event reports related to drug treatment in patients with HNSCC were identified, of which 916 reports were cardiovascular events, including 555 reports of MACE and 361 reports of other cardiovascular events. The PV signal regarding MACE was detected in durvalumab (PRR = 2.12, 95% CI: 1.24–3.61; χ2 = 7.71; ROR = 2.19, 95% CI: 1.24–3.86; IC = 1.01; IC025 = 0.07) but not in nivolumab and pembrolizumab. The constituent ratio of MACE in all adverse events caused by nivolumab (OR = 0.38, 95% CI: 0.19–0.73) and pembrolizumab (OR = 0.48, 95% CI: 0.23–0.99) was significantly decreased, compared with durvalumab. A PV signal about other cardiovascular events was detected in durvalumab (PRR = 3.04, 95% CI: 1.73–5.31; χ2 = 16.13; ROR = 3.15, 95% CI: 1.74–5.70; IC = 1.46; IC025 = 0.48), but it was not detected in nivolumab or pembrolizumab. The constituent ratio of other cardiovascular events in all adverse events caused by nivolumab (OR = 0.25, 95% CI: 0.13–0.48) and pembrolizumab (OR = 0.40, 95% CI: 0.20–0.80) was significantly decreased, compared with durvalumab. The constituent ratio of other cardiovascular events in all adverse events caused by nivolumab (OR = 0.61, 95% CI: 0.38–0.99) was significantly decreased, compared with pembrolizumab. There were 40 cases of hypertension. A PV signal about hypertension was detected in pembrolizumab (PRR = 3.72, 95% CI: 1.87–7.43; χ2 = 15.99; ROR = 3.75, 95% CI: 1.87–7.51; IC = 1.53, IC025 = 0.45), but it was not detected in nivolumab. The constituent ratio of hypertension in all adverse events caused by nivolumab (OR = 0.09, 95% CI: 0.09–0.39) was significantly decreased, compared with pembrolizumab. There were 737 cases of irAEs. A PV signal about irAEs was detected in nivolumab (PPR = 1.27, 95% CI: 1.05–1.53; χ2 = 6.38; ROR = 1.28, 95% CI: 1.06–1.56; IC = 0.29, IC025 = −0.00) and pembrolizumab (PPR = 2.20, 95% CI: 1.79–2.71; χ2 = 56.55; ROR = 2.31, 95% CI: 1.84–2.88; IC = 1.03; IC025 = 0.68), but it was not detected in durvalumab. The constituent ratio of irAEs in all adverse events caused by nivolumab (OR = 0.58, 95% CI: 0.44–0.76) significantly decreased, compared with pembrolizumab. By comparing the PV signals, constituent ratio, severity, and reaction outcome of the three drugs, we suppose that nivolumab can be used as the safest PD-1/PD-L1 inhibitor for HNSCC.

BackgroundWith indications for immune checkpoint inhibitor (ICI) therapy steadily growing, immune related adverse events (irAEs) are increasingly common in the oncologists’ practice. In the absence of prospective irAE management trials,...