Immune-related adverse events in the treatment of Hodgkin lymphoma with immune checkpoint inhibitors.

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

2661 Background: Immune-related adverse effects (irAE) are autoimmune-like toxicities caused by immune checkpoint inhibitor (ICI) treatment and often necessitate interventions such as corticosteroids, treatment interruptions/discontinuation, or hospital admission. Although ICI related irAEs are well described in literature, data on the toxicity profile associated with long-term ICI use remains limited. Since the optimal duration of therapy with ICI agents is currently unknown, it is crucial to assess the risks of long-term ICI use. Methods: This was a retrospective, observational, single-center study of adult oncology patients who received at least 1 year of programed death 1 (PD-1) inhibitor or programmed death ligand-1 (PD-L1) inhibitor treatment. The objective of this study was to characterize late-onset irAEs defined as greater than 1 year with long-term ICI treatment. Clinically significant irAEs were defined as those requiring corticosteroid treatment, hospital admission, treatment interruption or treatment discontinuation. This study included patients who received at least 1 year of nivolumab, pembrolizumab, atezolizumab or durvalumab between January 2016 and September 2021. Disease states included head and neck cancer, renal cell carcinoma, non-small cell lung cancer, and melanoma. Patients with concurrent exposure to other treatment such as chemotherapy, radiation, surgery, tyrosine kinase inhibitors and monoclonal antibodies while on ICI treatment were included in the study. Exclusion criteria included patients with treatment breaks of greater than 6 months, two malignancies undergoing active treatment, and treatment administration outside of the study center. Results: Of 282 patients assessed, 143 met study inclusion criteria. The median ICI treatment duration was 19 months (IQR 14-27). There was a 30% incidence of late-onset irAEs, of which 22% were clinically significant. Most late-onset irAEs were low in severity, as 45 (90%) were grade 1-2 and 5 (10%) were grade 3. The most common late-onset irAEs were pulmonary (8%) and gastrointestinal (7%). Univariate analysis suggests risk factors potentially associated with late-onset irAEs include concurrent exposure to additional therapies during ICI treatment and past medical history of rheumatologic disease. Conclusions: Although the optimal duration of ICI therapy is unknown, this study suggests that long-term ICI use was associated with a low but notable incidence of toxicities, of which most were low in severity. [Table: see text]

BackgroundCutaneous immune-related adverse events (cirAEs) are the most common form of immune-related adverse events after immune-checkpoint inhibitor (ICI) treatment, affecting up to 40% of ICI recipients and ranging in severity...

Dose Optimization of Check-Point Inhibitors: A Comparison of Standard Dose and Low Dose Nivolumab in Relapsed/Refractory Hodgkin Lymphoma

Safety and Efficacy of Immune Checkpoint Inhibitors in the Treatment of Hodgkin Lymphoma in People Living with Human Immunodeficiency Virus: A Case Series

Classic Hodgkin lymphoma (cHL) treatment paradigms are undergoing a shift with the integration of immune checkpoint inhibitors (ICIs) into both first-line and relapsed/refractory (R/R) regimens. In first-line therapy, the synergy between ICIs and chemotherapy may surpass the previous standards of ABVD and BV-AVD established by landmark trials including RATHL and ECHELON-1. In R/R disease, the combination of ICIs with chemotherapy has begun to challenge the paradigm of chemotherapy as a bridge to consolidative autologous stem cell transplantation. The clinical advances heralded by ICI offer unique challenges to management. ICI treatment and the associated inflammatory response can make the traditional timing and modalities of treatment response assessment difficult to interpret. In contrast to ABVD and BV-AVD, pembrolizumab-AVD results in PET2 positivity rates that are higher and less predictive of treatment response even when ultimate outcomes may be superior. This suggests that the predictive value of PET2 may be less reliable in the ICI era, prompting a reevaluation of response assessment strategies. Looking forward, circulating tumor DNA (ctDNA) may be a promising tool in response-adapted therapy. Its potential to complement or even supersede PET scans in predicting response to ICIs represents a critical advancement. The integration of ctDNA analysis holds the promise of refining response-adapted approaches and enhancing precision in therapeutic decision-making for patients with cHL. This review navigates the evolving landscape of cHL therapy, emphasizing the paradigmatic shift brought about by ICIs. This article explores the impact of combining ICIs with chemotherapy in both relapsed/refractory and first-line settings, scrutinizes the challenges posed to response-adapted therapy by ICIs, and highlights the potential role of ctDNA as an adjunct in refining response-adapted strategies for cHL.

Objectives Combining radiotherapy with immune checkpoint inhibitor (ICI) treatment has emerged as an important therapeutic regimen. However, this combined treatment may increase the risk of pneumonitis. The aim of this study is to analyze the incidence and risk factors for pneumonitis in non-small cell lung cancer (NSCLC) patients receiving combined thoracic radiotherapy and ICI (RT + ICI) treatment in the real-world clinical setting, offering a reference and guidance for clinical physicians. Methods This study identified 447 patients with pathologically confirmed NSCLC at West China Hospital of Sichuan University from 2016 to 2021. Clinical characteristics, treatment regimens, immune-related adverse events (irAEs), and hematological data were collected and analyzed. Results Patients receiving combined RT + ICI treatment had a higher risk of developing pneumonitis than those receiving ICI treatment alone (26.9 vs. 6.7 %, p<0.001). The multivariate logistic analysis identified the following independent risk factors for pneumonitis in patients undergoing combined RT + ICI treatment: history of lung disease (p=0.032), first-line ICI treatment (p=0.001), anti-PD-L1 instead of anti-PD-1 treatment (p=0.035), and the development of immunotherapy-related thyroid dysfunction (p=0.019). The independent risk factors were incorporated into a nomogram to predict the incidence of pneumonitis. The area under the receiver operating characteristic curve is 0.727, suggesting an acceptable predictive efficacy. Conclusions Compared to ICI monotherapy, NSCLC patients receiving the combination of thoracic radiotherapy and ICI treatment are at higher risk of developing pneumonitis. The nomogram holds promise for facilitating the risk assessment and early identification of pneumonitis in NSCLC patients receiving combined RT + ICI treatment.

Metachronous malignancies after response to checkpoint inhibition

e14599 Background: Immune checkpoint inhibitors (ICIs) are monoclonal antibodies that activate the immune system to treat malignancy. As a consequence of this activation, ICIs may cause autoimmunity in healthy tissues, termed “immune-related Adverse Events” (irAEs). The literature reports a wide range in irAE incidence (10-80%), with a higher incidence in patients exposed to combination therapy. ICI treatment of patients with pre-existing autoimmune disease presents a dilemma for oncologists because of concern that immune activation will lead to more frequent or severe irAEs. As a result, these patients have been excluded from ICI clinical trials. Prior studies suggested that approximately 40% of patients with pre-existing autoimmune disease experience an autoimmune exacerbation during ICI treatment, but more data are needed on the incidence and severity of irAEs in other tissues. Methods: This retrospective case-control study included adult patients who received an FDA-approved ICI for treatment of a solid malignancy (excluding non-melanoma skin cancer) from 2015-2021 at an academic medical center. Cases were patients with pre-existing autoimmune disease. Controls without pre-existing autoimmunity were matched 2:1 based on age, sex, ICI class, and cancer type. Severe IrAEs were defined as grade three or higher by CTCAE definitions and occurring after ICI exposure. ICD-9 and 10 codes were used to identify patients with subsequent data extraction by manual chart review. Results: Of 3,130 adult cancer patients treated with ICIs, 28 cases were identified with pre-existing autoimmune disease: antiphospholipid syndrome (n=1), inflammatory polyarthritis (n=3), juvenile arthritis (n=1), multiple sclerosis (n=3), psoriatic arthritis (n=3), rheumatoid arthritis (n=14), and type I diabetes (n=3). Six out of 28 cases (21.4%) developed severe irAEs, including three (50%) who received anti-PD1/PDL1 monotherapy and three (50%) who received ICI combination therapy. One case experienced a grade five irAE (death) attributed to ICI-colitis; the remaining five patients (83.3%) successfully recovered with suspension of ICI therapy and treatment with immunosuppressive medications. By comparison, 9/56 (16.1%) controls developed severe irAEs. The odds of developing a severe irAE were not significantly different in patients with pre-existing autoimmunity compared to controls (OR 1.42, 95% CI 0.42-4.68, p=ns). Subgroup analysis of 23 cases and 46 controls treated with anti-PD1/PDL1 monotherapy also found no difference in the odds of severe irAE development (OR 0.84, 0.22-3.70, p=ns). Conclusions: Our data suggest that the majority of solid tumor patients with pre-existing autoimmune disease can safely receive ICI monotherapy and combination therapy. Severe (grade 3 or higher) irAEs were infrequent, often treatable, and did not occur more frequently than in patients without pre-existing autoimmunity.

<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...

Acute Interstitial Nephritis Triggered by a Novel Anti-CD25 Antibody-Drug Conjugate, Camidanlumab Tesirine

8633 Background: Immune checkpoint inhibition (ICI) has significantly improved survival in patients (pts) with metastatic non-small cell lung cancer (NSCLC). While ICI duration is commonly limited to two years, the optimal duration of ICI and post-progression treatment outcomes in pts who received at least two years of ICI are unknown. Methods: We conducted an international, multi-center study of pts with metastatic NSCLC treated with ICI for at least two years to characterize clinical outcomes and post-progression treatment patterns. Log-rank tests were used to test for differences in event-time distributions, and Cox proportional hazards models were used to estimate HRs. Results: We identified 255 pts with metastatic NSCLC treated with ICI alone (N=210, 82.3%) or ICI + chemotherapy (N=45, 17.7%) for least two years. Median age was 63.0, 42.4% were women, 93.0% had history of tobacco use, 79.2% had adenocarcinoma histology, 61.4% had a PD-L1 TPS ≥50%. From the start of ICI, the median time to progression (mTTP) was 6.9 years (95%CI 4.9-NR) and the median overall survival (mOS) was 9.5 years (95%CI 8.0-NR). Pts wo achieved a complete/partial response to ICI had a significantly longer mTTP (HR 0.41, P&lt;0.01) and mOS (HR 0.30, P&lt;0.01) compared to those with a best objective response of stable disease. Patients with high PD-L1 ≥50% (HR 0.6, P=0.02 vs PD-L1 &lt;50%), very high tumor mutational burden (TMB) ≥20 mut/Mb (HR 0.7, P=0.03, vs &lt;20 mut/Mb) and ever smoking status (HR 0.52, P=0.04, vs never smokers) had also significantly longer mTTP. There was no difference in mTTP (HR: 0.98, P=0.94) and mOS (HR: 0.61, P=0.06) between pts who stopped ICI at two years of treatment (N=112) and those who continued ICI beyond two years (N=143). Among 96 pts who progressed after ICI, 33.3% (N=32) received local ablative therapies (surgery or radiation), 9.3% (N=9) pts received systemic chemotherapy and 31.2% (N=30) pts received ICI retreatment. Among those retreated with ICI, the response rate was 63%, mTTP and mOS from the date of start of ICI retreatment were 22.7 (95%CI 11.2-NR), and 41.7 months (19.3-NR), respectively. Clinico-genomic predictors of response to ICI retreatment included higher TMB at baseline (15 vs 7.6 mut/Mb, P&lt;0.001), adenocarcinoma histology (94.4% vs 50.0%, P=0.01), and longer ICI treatment duration prior to retreatment (31.2 vs 24.5 months, P=0.02). Conclusions: Pts who received a minimum of two years of treatment with ICI experienced unprecedented long-term survival. There was no difference in outcomes between pts who stopped at two years compared to those who continue therapy. After completing two years of initial ICI therapy, a large fraction of pts who subsequently experience disease progression and are retreated with ICI experience an objective response, particularly those with longer duration of prior ICI treatment, higher TMB, and adenocarcinoma histology.

Simple SummaryImmune checkpoint inhibitor (ICPi)-induced thyroid dysfunction is a frequent immune-related adverse event (irAE). ICPi-induced thyrotoxicosis is usually the first stage of a biphasic thyroiditis with secondary hypothyroidism, whereas ICPi-induced Graves’ disease (GD), due to the stimulating activity of TSH-receptor autoantibodies, is extremely rare. The aim of this study was to describe the characteristics and evolution of GD during ICPi therapy. We showed that in five patients with induced GD, two patients evolved into classical GD and the three other patients evolved as thyroiditis with short-term thyrotoxicosis and secondary long-term hypothyroidism, with the initial scintigraphic appearance seeming to predict their evolution. Three other patients had a diagnosis of GD before ICPi treatment: all evolved towards definitive hypothyroidism during treatment, without the appearance of irAE. None of the eight patients developed severe hyperthyroidism with life-threatening symptoms, nor significant Graves’ orbitopathy. Use of ICPis in this population with induced or pre-existing autoimmune GD disease therefore appears to be safe.Thyrotoxicosis is an adverse event associated with immune checkpoint inhibitors (ICPis) that occurs in 0.6 to 3.2% of treated patients, depending on ICPi class. Presentation usually consists of a biphasic thyroiditis with transient thyrotoxicosis and secondary hypothyroidism. ICPi-induced Graves’ disease (GD), due to the stimulating activity of TSH-receptor autoantibodies (TRAb), is extremely rare. The aim of this retrospective study was to describe the characteristics and evolution of GD during ICPi therapy. Five among 243 patients followed for ICPi-induced thyrotoxicosis showed TRAb positivity (2% of the cohort). GD occurred quickly after initiation of ICPis; its course was typical for two patients, with prolonged requirement for antithyroid drug treatment (ATD). The three other patients experienced biphasic thyroiditis with secondary hypothyroidism requiring long-term substitution. Three other patients had a diagnosis of GD before starting ICPis; they evolved toward hypothyroidism with early cessation of ATD and long-term substitution treatment during ICPi treatment. None developed significant Graves’ orbitopathy. ICPi treatment was not interrupted for thyroid dysfunction. In conclusion, GD is a rare, immune-related adverse event of ICPis with an unusual course and frequent evolution to biphasic thyroiditis. In the case of ICPi-induced thyrotoxicosis in the presence of TRAb, observing the spontaneous evolution and performing a scintigraphy are useful before starting ATD treatment. Pre-existing GD is not exacerbated by ICPis and tends to evolve towards hypothyroidism. ICPi treatment can be maintained with adequate biochemical surveillance.

Liver toxicity as a limiting factor to the increasing use of immune checkpoint inhibitors.

Cardiac immune-related adverse events: animmune-cardio-oncology puzzle.